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Mitochondrial leukoencephalopathies: A border zone between acquired and inherited white matter disorders in children?

Published:January 06, 2018DOI:https://doi.org/10.1016/j.msard.2018.01.003

      Highlights

      • Clinical features of mitochondrial-leukoencephalopathy mimick acquired demyelinating disorders.
      • Early age at onset and primary optic atrophy in mitochondrial- leukoencephalopathy are helpful differentiating features.
      • MRI findings included contrast enhancement, restricted diffusion, white matter cysts & lactate peak.
      • Steroid responsiveness was noted during acute phase as well as during relapses.
      • On follow up, residual motor deficits were more common in mitochondrial- leukoencephalopathy.

      Abstract

      Background

      There is emerging evidence implicating mitochondrial dysfunction in the pathogenesis of acquired demyelinating disorders such as multiple sclerosis. On the other hand, some of the primary mitochondrial disorders such as mitochondrial leukoencephalopathies exhibit evidence of neuroinflammation on MRI. The inter-relationship between mitochondrial disorders and episodic CNS inflammation needs exploration because of the therapeutic implications.

      Objective

      We sought to analyze the clinical course and MRI characteristics in a cohort of patients with mitochondrial leukoencephalopathy to determine features, if any, that mimic primary demyelinating disorders. Therapeutic implications of these findings are discussed.

      Patients and methods

      Detailed analysis of the clinical course, magnetic resonance imaging findings and therapeutic response was performed in 14 patients with mitochondrial leukoencephalopathy. The diagnosis was ascertained by clinical features, histopathology, respiratory chain enzyme assays and exome sequencing.

      Results

      Fourteen patients [Age at evaluation: 2–7 yrs, M: F-1:1] were included in the study. The genetic findings included variations in NDUFA1 (1); NDUFV1 (4); NDUFS2 (2); LYRM (2);MPV17(1); BOLA3(2); IBA57(2). Clinical Features which mimicked acquired demyelinating disorder included acute onset focal deficits associated with encephalopathy [10/14, 71%], febrile illness preceding the onset [7/14, 50%] unequivocal partial or complete steroid responsiveness [11/11], episodic/ relapsing remitting neurological dysfunction [10/14, 71%] and a subsequent stable rather than a progressive course [12/14, 85%]. MRI characteristics included confluent white matter lesions [14/14, 100%], diffusion restriction [11/14,78.5%], contrast enhancement [13/13,100%], spinal cord involvement [8/13,61.5%], lactate peak on MRS [13/13] and white matter cysts [13/14, 92.8%].

      Conclusion

      Clinical presentations of mitochondrial leukoencephalopathy often mimic an acquired demyelinating disorder. The therapeutic implications of these observations require further exploration.

      Keywords

      1. Introduction

      White matter involvement is increasingly being recognized as a manifestation of mitochondrial disorders and the term mitochondrial leukoencephalopathy or leukodystrophy has been used to designate these disorders (
      • Kevelam S.H.
      • Steenweg M.E.
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      • Naidu S.
      • Schiffmann R.
      • Blaser S.
      • Vanderver A.
      • Wolf N.I.
      • van der Knaap M.S.
      Update on leukodystrophies: a historical perspective and adapted definition.
      ). They are mainly defined by the MRI characteristics such as cystic lesions in the abnormal white matter, additional gray matter lesions, restricted diffusion, contrast enhancement, and elevated lactate on magnetic resonance spectroscopy of the brain (
      • van der Knaap MS V.J.
      Magnetic Resonance of Myelin, Myelination and Myelin Disorders.
      ). Clinically, patients with mitochondrial leukoencephalopathy most often present with monophasic or recurrent episodes of neurological regression (
      • Dallabona C.
      • Abbink T.E.
      • Carrozzo R.
      • Torraco A.
      • Legati A.
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      • Niceta M.
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      • Verrigni D.
      • Rizza T.
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      • Piemonte F.
      • Lamantea E.
      • Fang M.
      • Zhang J.
      • Martinelli D.
      • Bevivino E.
      • Dionisi-Vici C.
      • Vanderver A.
      • Philip S.G.
      • Kurian M.A.
      • Verma I.C.
      • Bijarnia-Mahay S.
      • Jacinto S.
      • Furtado F.
      • Accorsi P.
      • Ardissone A.
      • Moroni I.
      • Ferrero I.
      • Tartaglia M.
      • Goffrini P.
      • Ghezzi D.
      • van der Knaap M.S.
      • Bertini E.
      LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance.
      ). Acute onset neurological deficits in combination with large confluent white matter lesions on MRI often lead to diagnosis of an acquired demyelinating disorder such as acute disseminated encephalomyelitis (ADEM). In some disorders, predominant visual impairment and white matter lesions may suggest diagnosis of neuromyelitis optica spectrum disorders, which are further emphasized by the presence of spinal cord signal changes on MRI.
      On the other hand, it is increasingly being evident that mitochondrial abnormalities are involved in the development and progression of multiple sclerosis (MS) (
      • Mao P.
      • Reddy P.H.
      Is multiple sclerosis a mitochondrial disease?.
      ). The most compelling evidence implicating the role of mtDNA comes from the observation of susceptibility of LHON [Leber's hereditary optic neuropathy] patients to develop white matter lesions resembling MS (
      • Matthews L.
      • Enzinger C.
      • Fazekas F.
      • Rovira A.
      • Ciccarelli O.
      • Dotti M.T.
      • Filippi M.
      • Frederiksen J.L.
      • Giorgio A.
      • Kuker W.
      • Lukas C.
      • Rocca M.A.
      • De Stefano N.
      • Toosy A.
      • Yousry T.
      • Palace J.
      • Network M.
      MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis.
      ). However studies interrogating the presence of LHON-associated mutations in patients with multiple sclerosis (
      • Hanefeld F.A.
      • Ernst B.P.
      • Wilichowski E.
      • Christen H.J.
      Leber's hereditary optic neuropathy mitochondrial DNA mutations in childhood multiple sclerosis.
      ,
      • Kalman B.
      • Lublin F.D.
      • Alder H.
      Mitochondrial DNA mutations in multiple sclerosis.
      ) as well as those probing an increased MS risk in particular mitochondrial haplogroups (
      • Ban M.
      • Elson J.
      • Walton A.
      • Turnbull D.
      • Compston A.
      • Chinnery P.
      • Sawcer S.
      Investigation of the role of mitochondrial DNA in multiple sclerosis susceptibility.
      ,
      • Kalman B.
      • Li S.
      • Chatterjee D.
      • O'Connor J.
      • Voehl M.R.
      • Brown M.D.
      • Alder H.
      Large scale screening of the mitochondrial DNA reveals no pathogenic mutations but a haplotype associated with multiple sclerosis in Caucasians.
      ,
      • Otaegui D.
      • Saenz A.
      • Martinez-Zabaleta M.
      • Villoslada P.
      • Fernandez-Manchola I.
      • Alvarez de Arcaya A.
      • Emparanza J.I.
      • Lopez de Munain A.
      Mitochondrial haplogroups in Basque multiple sclerosis patients.
      ,
      • Tranah GJ S.A.
      • Caillier S.J.
      • D'Alfonso S.
      • Martinelli Boneschi F.
      • Hauser SL O.J.N.J.
      Mitochondrial DNA sequence variation in multiple sclerosis.
      ), have revealed conflicting results. An exploratory study on the mitochondrial DNA variations and haplogroups in children with acquired demyelinating syndromes (ADS) have raised the possibility that mtDNA variants or haplogroups may influence the age at onset and subsequent MS risk (
      • Venkateswaran S., Z.K.
      • Sacchetti M.
      • Gagne D.
      • Arnold D.L.
      • Sadovnick A.D.
      • Scherer S.W., B.B.
      • Bar-Or A.
      • Simon D.K.
      • Canadian Pediatric Demyelinating, Network., D
      Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination.
      ). These observations suggest that the link between mitochondrial dysfunction and ADS is unclear and needs to be explored further.
      Importance of MRI in the interpretation and diagnosis of mitochondrial leukoencephalopathies has been already emphasized. Even though the characteristics of mitochondrial leukoencephalopathy have been highlighted in literature, the therapeutic implications of these findings still needs to be elucidated. This study analyzed the clinical and MRI characteristics in a cohort of children with mitochondrial leukoencephalopathy so as to define the features that mimic acquired demyelinating disorders.

      1.1 Patients and methods

      The cohort was derived from a database of patients who underwent exome sequencing as part of a study on phenotype genotype correlations in mitochondrial disorders, over a period of two years (2015–2017). The institute ethics committee approved the study and all subjects gave written informed consent.

      1.2 Phenotypic characterization

      Patients were recruited into the study if they satisfied the clinical criteria of mitochondrial disorder as defined by Bernier et al. (
      • Bernier F.P.
      • Boneh A.
      • Dennett X.
      • Chow C.W.
      • Cleary M.A.
      • Thorburn D.R.
      Diagnostic criteria for respiratory chain disorders in adults and children.
      ) and a comprehensive evaluation, including estimation of serum lactate, muscle histopathology, assay of respiratory chain complex enzymes, brain magnetic resonance imaging, nerve conduction studies, electroencephalography (EEG) and evoked potential studies suggested a probable diagnosis of mitochondrial disorder. Exome sequencing was performed using illumina sequencing platform and the gene panel consisted of 6440 genes inclusive of all nuclear-encoded mitochondrial genes that are strongly associated with a disease on OMIM (Online Mendelian Inheritance in Man). The details are provided in the supplementary file.
      Among the 85 patients who underwent exome sequencing, 36 showed variations in mitochondrial disease related genes. Among these, 14 patients (Age range: 2–7yrs, M: F- 1:1) displayed significant white matter involvement and qualified for a diagnosis of mitochondrial leukoencephalopathy and were included in final analysis. Their clinical features, MRI findings and therapeutic responses were analyzed retrospectively. All patients had significant white matter hyperintensities involving one or more of the white matter zones viz. periventricular, deep white matter and subcortical white matter as well as involvement of multiple lobes [frontal, parietal, temporal and occipital white matter]. The sequences analyzed included T1 weighted (T1W), T2 weighted (T2W) and Fluid attenuated inversion recovery (FLAIR) sequences in all. Additional sequences included diffusion weighted images (DW1, n=13), Contrast images (n=13) & Magnetic resonance spectroscopy (n = 13). Majority of the children received evaluation and treatment during the acute phase in peripheral hospitals. The information on the CSF studies and the details of the immunomodulation were retrieved from the referral notes and treating physician's notes. All patients were evaluated and followed up by the same clinical team [PSB, ABT, MN &SS]. MRI findings were independently reviewed by two neurologists (PSB &ABT) and one neuroradiologist (HRA). Descriptive statistics were used to describe the key findings. The comparison of proportions in different groups were done by t- test.

      1.3 Results

      The detailed clinical features, MRI characteristics, and immunomodulation and follow up are provided in Table 1. The genetic findings included variations in NDUFA1(1); NDUFV1(4); NDUFS2 (2) ; LYRM (2); MPV17(1); BOLA3(2); IBA57(2). The details of the genetic findings are provided in the Supplementary table.
      Table 1Clinical and MRI Features during the episodes in children with mitochondrial leukoencephalopathy.
      Pt No/GenderEpisodesAge at presentationClinical featuresMRI characteristicsImmunomodulation &other treatmentResponse
      [T2/FLAIR signal changes/DWI/CE/MRS]
      Patient 1/M1st episode2.5yrsFebrile illness, vomiting, encephalopathy, ataxiaMultifocal discrete hyperintense lesions in bilateral supratentorial white matter, thalami and left cerebellar hemisphere with nodular CEInj. MP X 5days, oral steroids taper X 4weeksImproved, no residual deficits
      2nd episode4.5yrsFever,vomiting, seizures, encephalopathy, left hemiparesis, ataxiaBilateral temporo- parietal, occipital and frontal regions in deep white matter and subcortical zones, patchy CE, no restricted diffusion, moderately increased lipid lactate peakInj.MP X 5days, oral steroid taperImproved, no residual deficits
      Follow up4yrs& 10moAsymptomatic periodResidual bright signals in bilateral peritrogonal white matter and scattered focal hyperintense lesions in bilateral corona radiate and subcortical regions of fronto-parietal lobes, no CENilNo deficits
      3rd episode5yrsFebrile illness, Rt hemiparesis, Rt focal seizure, aphasiaNew areas of bright signals in deep white matter in left parietal lobe & subcortical region in left occipital lobe resembling tumefactive demyelination. CE +Inj.MP X 5days, oral steroid taper for three weeksImproved, no deficits
      4th episode5yrs 5moSub acute onset, Lt focal seizures,visual agnosia,irritabilityBilateral fronto parieto temporal and occipital lesions on left>Rt. New areas of T2 bright signals involving left half of midbrain &pons. CE+Inj.MP X 5days followed by steroid taper for three weeksImproved
      Follow up MRI after one month in the asymptomatic periodInterval MRI-Persisting signal changes in the bilateral fronto-parieto-temporal and occipital region and left half of pons. Reduction in the extent and mass effectStarted on Inj.Interferon x 4 monthsAsymptomatic
      Two new enhancing nodular lesions seen in left frontal region
      5th episode5yrs 8moLeft sided focal seizuresConflent hyperintensities in periventricular white matter in occipital, frontal and temporal regions, Lactate peak, no CE, no restricted diffusionInj. MPX 5days monthly X 6mo once in two months X 6months, once in three months X 1 doseNo episodes for 1.5 yrs
      Follow up MRI in the asymptomatic period after six monthsConfluent asymmetrical lesions in bifrontal and biparietal regions, no diffusion restriction, no CE, Lactate peak+Nil, On multivitaminsNo further episodes
      6th episode6.5yrsRt focal seizures, Rt hemiparesisConfluent white matter lesions in frontal, parietal and temporal lobes, No CE or restriction,SC +Inj.MPX5daysImproved
      Follow up10yrsNo neurological deficitsNDHigh dose vitaminsStable course
      Patient 2/ F1st episode3yrsFebrile illness, loss of mile stones, encephalopathyConfluent white matter lesions in frontal parietal and temporal lobes with rarefaction, CE +Inj.MPX 5daysFull improvement
      Corpus callosal lesions- splenium and body
      2nd episodeOne month afterEncephalopathyNDInj.MP monthly pulse dosesX6 monthsPartial improvement
      Follow up6 yearsGDD, optic atrophy, seizures, spastic parapresisBilateral symmetrical nonhomogeneous signal changes in cerebral white matter, rarefied appearance +, cysts+, SC+, restricted diffusion, lactate peakNil. Maintained on high dose vitaminsProgressive course
      Patient3/M1st episode9 moEncephalopathy, regressionMultifocal confluent white matter signals in frontal parietal and temporal region, rarefied appearance of white matter, restricted diffusion along the edgesInj.MP X 5days, steroids taper X 6 weeksPartial response, toe walking
      2nd episode2yrsFebrile illness, loss of mile stones, seizures, pyramidal signsConfluent hyperintense lesions bilateral periventricular and subcortical white matter, putamen, substantia nigra, medial thalamus, SC, white matter cysts, lactate peak, restricted diffusion, CE+, SC signal changesInj.MP X5 days.Improvement
      Corpus callosum is affected in full extent.
      Follow up3yrsAmbulent, spastic paraparesis, optic atrophyNDNil. On high dose vitaminsNo further episodes
      Patient 4, FInsidious onset6moDiarrhoeal illness, loss of mile stones, seizures, family history positivelarge confluent bilateral hyperintense signal changes in white matter lesions restricted diffusion, CE+, spinal cord signal changes,white matter cysts-present, Lactate peakNot received, high dose vitaminsSpastic paraparesis, Optic atrophy
      Follow up3yrsNo further episodes, gaining mile stonesNDHigh dose vitamins
      Patient 5, MInsidious onset9moLoss of acquired mile stonesLarge multifocal confluent hyperintense lesions, restricted diffusion& CE, SC signal changesInj.MPX 5 days followed by oral steroids X one yearFully improved
      Follow up10yrsAchieved independent walking, running, language delayConfluent lesions in bifrontal, parietal and occipital lobes Lt temporal lobe, restricted diffusion and CE, multiple cystsNil, on high dose vitaminsPoor scholastic performance
      Patient 6,MIst episode9moFever, seizures, regression of mile stonesMultiple large confluent T2/FLAIR lesions, restricted diffusion, CE, SC signal changesInj.MP X 5daysComplete improvement
      2nd episode13moFever seizures, regression, pyramidal signs, optic atrophyNDInj.MPX5 daysPartial response, spastic paraparesis
      Patient 7,FInsidious onset6moOne episode of neuroregression, seizures, pyramidal signs, optic atrophyMultiple large confluent symmetrical signal changes in white matter, restricted diffusion, CE, white matter cysts, lactate peakInj.MPX5 daysPartial response, spastic paraparesis
      Patient 8, F1st episode8moFebrile illness, Visual loss, irritability, neuroregressionMultifocal discrete and confluent lesions, restricted diffusion, CE, SC lesions, lactate peakInj.IVIG X 5days, oral steroids.Complete improvement
      2nd episode2yrsSeizures, visual loss, irritability, neuroregressionMultiple focal and confluent lesions, restricted diffusion,Inj.MP X 5days.Partial improvement
      Patient 9, MIst episode5.5 yrsLt hemiparesis progressing to quadriparesis in few days. No encephalopathyMultifocal confluent lesions white matter, restricted diffusion, patchy CE, multiple cysts, Lactate peak presentInj.MP X 5 dayscomplete improvement
      2nd episode6yrsHemiparesis progressing to quadriparesis. No encephalopathyNDInjMPX5daysImproved
      3rd episode7yrsLt hemiparesisNDInj.MPX5daysImproved
      4th episode7.5 yrsSuddden bilateral vision lossSymmetrical confluwnt cystic white matter lesions in periventricular region, cervical spional cord lesionsInj.MPX5daysImproved
      5th episode8yrsFebrile illness, quadriparesisNANAExpired
      Patient 10, F1st episode2.5 yrsFebrile illness, Jaundice, Gait difficulty, falls followed by ataxia, quadriparesis, recurrent unexplained vomitingMultifocal confluent lesions in fronto parietal region with central hypointensity on FLAIR, restricted diffuson & enhancement. Spinal cord signal changes presentInj. MPX 5 days followed by oral steroids for 6 monthsDistinct steroid responsiveness
      2nd episode3.5yrsInsidious onset lower limb weaknessNDOral steroidsX1monthImproved
      3rd episode6yrsBulbar symptoms/ progressive slurring of speechMultifocal confluent white matter lesions in fronto parietal region. Restricted diffusion present, CE+Inj.MPX5days,oral steroids for one monthMinimal improvement, spasticity of LL
      Follow up11 yrsSpastic quadriparesis, seizures, bedridden statusSymmetrical confluent white matter signal changes with cysts and bilateral dentate nuclei and cerebellar white matter hyperintensities, SC signal changes +Not received.On High dose vitaminsspastic quadriparesis
      siblings
      Patient 11, F
      1st episode18moInsidious onset regression, gait difficulty falls Improved over nextSignal changes in periventricular and deep white matter, diffusion restriction, contrast enhancementNot ReceivedSpastic paraparesis
      2nd episode2.5yrsFebrile illness, transient regressionNDInj.MP X 5daysPartial improvement
      siblings
      Patient 12, F
      Onset1.5yrsMinor head injury followed by insidious onset gait difficulty, recurrent falls,speech regression, pyramidal signsFronto-parietal lesionsNot receivedMild spastic paraparesis, independent in all daily activities
      Follow up12yrsSpastic paraparesisPosterior periventricular and deep white matter signal changes, Lactate peakNil, on high dose vitaminsStable course, attends school, IDD
      Patient 13, M1st episode18 moFebrile illness, loss of acquired mile stones, difficulty in standing and walkingLarge confluent hyperintense lesions in frontal parietal and occipital regions with restricted diffusion& CE, Lactate peakInj.MP X 5daysPartial improvement
      2nd episode19moBulbar weakness, quadriparesisNDInj.MPX5 days followed by oral steroids for 2 weeksGradual improvement, spastic paraparesis
      Patient14, M1st episode20 moFebrile illness, Rt hemiparesis progressing to quadriparesisLarge confluent hyperintense lesions in frontoparietal white matter; genu, splenium and anterior part of the body of corpus callosum, multiple white matter cysts, restricted diffusion, lactate peakInj.MP X 5 days followed by oral steroidsPartial improvement
      2nd episode22moProgressive loss of walking and language mile stonesNDInj X MP pulse doses for three monthsImprovement in motor cognitive and social mile stones
      Follow up31moSpastic paraparesisBilateral symmetrical hyperintensities in periventricular corona radiata and centrum semi ovale, cysts increased in number. No diffusion restriction or CEHigh dose vitaminsNo further episodes
      Abbreviations: CE- contrast enhancement; DWI-Diffusion weighted; ; GDD- Global developmental delay; IDD- Intellectual disability; Inj.MP- Methyl Prednisolone injections; mo -months; Lt- left; MRS-Magnetic resonance spectroscopy; NA- Not available; ND-Not done; Rt- Right; SC-Spinal cord
      * siblings

      1.4 Clinical features

      The age at onset of the symptoms in the patients ranged from 6 months to 5.5 years (Mean ± SD − 1.67 ± 1.3 yrs). In six children age of onset was in infancy. The period of follow up ranged from 1 to 7 years and the mean duration of illness at last follow up was 4.5±3.6 years. Majority had an acute presentation (n=10). History of an inciting event was present in 10 [febrile illness, n=8; jaundice, n=1; minor head trauma, n=1]. Infants in the cohort manifested with regression of acquired milestones. Neurological examination showed pyramidal signs in all and additional ataxia in four. Primary optic atrophy was present in eight (57%). Even though visual loss was the presenting manifestation in two patients optic disc swelling was not reported. Except for three patients who had insidious onset of symptoms all received immunomodulation presuming a diagnosis of an acquired demyelinating syndrome and most common diagnosis considered was acute disseminated encephalomyelitis. The response to immunomodulation was either partial or complete. In those with partial response the residual deficits were spasticity in the lower limbs and mild incoordination of the upper limbs. Even those patients, who did not have overt spasticity, had pyramidal signs in lower limbs.

      1.5 Relapses

      Details of relapses are provided in Table 1. Ten patients had multiple episodes (median number of episodes −2). For seven patients the second episode occurred within 2 months of the first episode. Three children had multiple episodes [patient 1,9 &10]. While the episodes were heralded by seizures in patient 1, there were no seizures in patient 9 and 10.

      1.6 Cerebrospinal fluid (CSF) examination

      Results of the cerebrospinal fluid examination during the acute presentation was available in 11 patients. Pleocytosis was noted in none while elevated CSF protein was noted in three.

      1.7 Magnetic resonance imaging findings

      Description of the MRI findings is provided in Table 1 and summary is provided in Table 2. MRI findings included large confluent white matter signal changes that showed diffusion restriction and patchy contrast enhancement in the acute phase and on follow up, in some patients. In those children with discrete lesions in the initial scans, the signal changes tended to become confluent and bilaterally symmetrical on follow up images (Fig. 1A-C). Cysts inside the white matter were evident in all except one, either at the time of acute presentation or on follow up (Fig. 2B). Corpus callosal involvement was prominent in all but involvement of internal capsule, brainstem and pyramidal tract were seen in only one patient each. Likewise the presence of signal changes in basal ganglia, thalamus and dentate was seen in only one patient each.
      Table 2Comparison of clinical and mri features in patients with mitochondrial leukoencephalopathy with cohorts of patients with ADEM.
      ParametersMito LEADEM-IndiaADEM- IndiaADEM-JapanADEM-UK
      (Present study)(Same institute)(Singhi et al.)(Yamaguchi et al.)(Absoud et al.)
      No of patientsN=14N=35N=52N=66N=40
      Mean Age at onset1.67 ± 1.3 yrs8.2 ± 4.1 yrs
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      6.14±3.17yrs
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      5.5 ± 3.8 yrs
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      Median age−5.3yrs
      Gender [M: F]1:11.2:12.7:12:11.5:1
      Febrile illness7 [50%]31 [88.8%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      13 [25%]45/66[68%]NA
      Neurological Features
       Encephalopathy9 [64.2%]35 [100%]Majority66/66[100%]40[100%]
       Pyramidal signs14 [100%]13 [37%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      42 [80.7%]NA24 [60%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Ataxia7 [50%]8 [25%]6 [11.5%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      NA18 [45%]
       Visual loss3 [21.4%]5 [14%]11 [21.2%]7/66[11%]3 [0.1%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Optic atrophy8 [57%]NANANANA
       Seizures8 [57.1%]8 [22%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      19 [36.5%]21 [32%]8 [20%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      CSF pleocytosisNil18 [32%]Majority56/66[85%]23[58%]
      MRI Findings
       Periventricular lesions14 [100%]11 [31%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      NA20/66[30%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      9 [22.5%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Lobar/DeepWM14 [100%]18 [51%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      NANA24 [60%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Subcortical/ Juxtacortical6 [15%]29 [68%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      NA41/61[67%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      20 [50%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Cerebral cortexNil7 [20%]NA28/61 [46%]14 [35%]
       Corpus callosum14 [100%]9 [25.7%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      7 [13.5%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      11/61 [18%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      3 [0.1%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Thalamus2 [14.3%]8 [23%]16 [30.8%]30/61[49%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      24 [60%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Basal Ganglia1 [7.0%]6 [17%]9 [17.3%]
       Cerebellum4 [28.6%]9 [25.7%]14 [26.9%]20/66[30%]17 [42%]
       Brainstem2 [14.3%]14 [40%]9 [17.3%]19/66[29%]22 [55%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
       Spinal cord8 [61.5%]4/6 [66%]5 [9.6%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      16/42[38%]8/12[67%]
       Contrast enhancement13/13[100%]13/27[48%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      5 [48%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      NANA
       Diffusion restriction11/14[78.5%]8/26 [30%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      NANANA
       Lactate peak on MRS13/13 [100%]NANANANA
       White matter cysts13/14 [92.8%]NANANANA
      Residual deficits12 [92.3%]2[5.7%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      20[38.7%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      11 [16.7%]
      P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      NA
      Death1/13[7.6%]1/35[2.9%]nonenone1 [2.5%]
      * P<0.05, Abbreviations: ADEM-Acute disseminated encephalomyelitis; CSF- cerebro spinal fluid; MRS- Magnetic resonance spectroscopy; NA-Not available;WM-white matter.
      Fig. 1
      Fig. 1MRI Brain in a 2-year-old child with Mitochondrial leukoencephalopathy and mutations in IBA57 (Patient 14). A) T2W axial image at the time of first presentation shows large asymmetrical confluent white matter signal changes B-D) Follow up study shows rarefied white matter on T2W axial view (B), cysts inside the affected white matter on FLAIR(C), contrast enhancement (D).
      Fig. 2
      Fig. 2MRI brain in patient 1 with NDUFA1 variation. A-C –MRI at 2.5yrs at the time of initial presentation shows multiple discrete white matter and gray matter T2/FLAIR hyper intensities with contrast enhancement. D-F- MRI during the third episode at the age of 4.5 yrs shows large asymmetrical white matter lesions with contrast enhancement and patchy restricted diffusion. G. The lesions shows tendency to become symmetrical and diffuse on follow up imaging at 7.5yrs H. MRS shows lactate peak.

      1.8 Clinical and MRI findings in mitochondrial LE vs. acquired demyelinating syndrome

      The clinical features and MRI findings in this cohort was compared with that of children with acute disseminated encephalomyelitis (ADEM). The cohorts included 35 children with ADEM presented to our institute as well as with another cohort from India (
      • Singhi P.D.
      • Singhi R.M.
      • Kumar Khandelwal S.
      Acute disseminated encephalomyelitis in North Indian children: clinical profile and follow-up.
      ) and two recent series on ADEM from Japan (
      • Yamaguchi Y., T.H.
      • Kira R.
      • Ishizaki Y.
      • Sakai Y.
      • Sanefuji M.
      • Ichiyama T.
      • Oka A., K.T.
      • Kimura S.
      • Kubota M.
      • Takanashi J.
      • Takahashi Y.
      • Tamai H.
      • Natsume J.
      • Hamano S H.S.
      • Maegaki Y.
      • Mizuguchi M.
      • Minagawa K.
      • Yoshikawa H.
      • Kira J.
      • Kusunoki S H.T.A.
      A nationwide survey of pediatric acquired demyelinating syndromes in Japan.
      ), and UK (
      • Absoud M.
      • Lim M.J.
      • Chong W.K.
      • De Goede C.G.
      • Foster K.
      • Gunny R.
      • Hemingway C.
      • Jardine P.E.
      • Kneen R.
      • Likeman M.
      • Nischal K.K.
      • Pike M.G.
      • Sibtain N.A.
      • Whitehouse W.P.
      • Cummins C.
      • Wassmer E.
      • Uk, Ireland Childhood, C.N.S.I.D.W.G
      Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features.
      ). The age at onset, clinical features and MRI findings were compared and provided in Table 2. The patients with mitochondrial LE presented at a significantly younger age and had more chance of having residual motor deficits compared to children with ADEM (p value <0.05). Comparison of MRI features showed that presence of periventricular and deep white matter lesions, corpus callosal lesions, contrast enhancement and restricted diffusion were significantly higher compared to children with ADEM (p value <0.05). In contrast presence of subcortical/juxta cortical lesions were less common compared to ADEM. Even though the details of MRS and white matter cysts were not available for comparison in the ADEM series, both the features were consistently seen in mitochondrial LE.

      1.9 Clinical and MRI findings in mitochondrial LE vs other mitochondrial disorders

      Clinical phenotypes in the rest of the children with mitochondrial disorders included Leigh and Leigh like syndrome (n=15), encephalomyopathy (n=2), chronic progressive external ophthalmoplegia with epilepsy (n=4), and mitochondrial neurogastrointestinal encephalopathy (MNGIE, n=1). The MRI findings included bilateral symmetrical signal changes in the basal ganglia, brain stem and cerebellum (n=15) predominantly noted in children with Leigh and Leigh like syndrome. Normal MRI findings were noted in children with encephalomyopathy and chronic progressive external ophthalmoplegia. The child with MNGIE had bilateral symmetrical T2/FLAIR signal changes involving the periventricular and deep white matter without any contrast enhancement or diffusion restriction. Subcortical fibers were spared. There was presence of lactate peak on MRS.
      The detailed case history and investigation results including brain biopsy findings of one of the patients is described below to demonstrate the diagnostic and therapeutic challenge posed by these patients.
      Patient 1: This 10 year old boy of Indian origin was the first child of non-consanguineous parents with normal birth history and developmental milestones. He was apparently normal till 2.5 years when he developed ataxia, seizures and encephalopathy following a febrile illness. CSF study was normal. MRI demonstrated T2/FLAIR hyper intense lesions involving both gray and white matter with contrast enhancement [Fig. 2A-C]. He received pulse methyl prednisolone for presumptive diagnosis of acute disseminated encephalomyelitis and made complete clinical recovery. Thereafter he presented with multiple relapsing remitting neurological episodes characterized by seizures, hemiparesis and ataxia associated with relapsing remitting white matter lesions on MRI [Table 1, Fig. 2D-H]. He was referred to our institute at the age of 6 years during the fifth episode.
      Review of the evaluations done elsewhere revealed high serum alanine, lactic acid metabolites on urinary organic acid estimation and an elevated serum lactate on multiple occasions. Muscle biopsy showed complex I deficiency on respiratory chain enzyme assays. Complete mitochondrial DNA sequencing revealed only polymorphisms. Targeted sequencing of complex 1 nuclear genes revealed a previously reported hemizygous variation in NDUFA1 (c.94G>C, p. G32R), which was confirmed by Sanger sequencing. His mother and sister carried the same variation.
      Biopsy from the right frontal cortex revealed a small fragment of cortex with white matter (Fig. 3A). Extensive loss of myelin was seen on Luxol Fast Blue stain (Fig. 3B). A few preserved strands of myelinated axons traversing the white matter was seen. In contrast, there was relative preservation of axonal tracts in the demyelinated segment (Fig. 3C). Tissue response in the form of scattered CD68 labelled ramified microglia and few clusters of histiocytes were detected within the zone of demyelination (Fig. 3D), in addition to fibrillary gliosis and several hypertrophic reactive astrocytes (Fig. 3F). There was no perivenular demyelination or foamy histiocytes.
      Fig. 3
      Fig. 3Brain biopsy findings in Patient 1 (A- F): Brain biopsy included a small fragment of right frontal cortex with white matter (A) which reveals extensive loss of myelin (B). Note few preserved strands of myelinated axons traversing the white matter (arrows, B). In contrast, there is relative preservation of axonal tracts in the demyelinated segment (C). Tissue response in the form of scattered CD68 labelled ramified microglia and few clusters of histiocytes are seen within this zone (D) and several hypertrophic reactive astrocytes with fibrillary gliosis (F). [A:H&E; B: Luxol Fast Blue (LFB); C: Neurofilament; D: CD68; F:GFAP. Magnification= scale bar (200 µm)].
      Prior to presentation to us, he had received methyl prednisolone injection during each episode followed by short and tapered steroid treatment. He also received Inj. Interferon for a brief period of time presuming a diagnosis of pediatric MS. In view of the relapsing remitting neurological episodes responsive to steroid therapy, the initial diagnosis considered was an acquired demyelinating disorder. In view of the multiple relapses, patient was initiated on monthly pulses of methyl prednisolone. He also received high dose vitamins. After the genetic report, the patient was maintained only on high dose vitamins. The patient remained relapse-free thereafter and is being maintained on high dose vitamins from the age of eight years.

      2. Discussion

      We have described a cohort of children with mitochondrial leukoencephalopathy with special reference to clinical course, therapeutic response and MRI findings. Even though there are descriptions on clinical and MRI features of mitochondrial leukoencephalopathies in the literature, the specific evidence of neuroinflammation with therapeutic implications are relatively unknown highlighting the novelty of the present study.
      The diagnoses most often considered by the referring physicians were acute disseminated encephalomyelitis (ADEM) or multiphasic ADEM. This was substantiated by the presence of acute onset focal deficit associated with encephalopathy as defined by international pediatric multiple sclerosis criteria (
      • Gordon-Lipkin E.
      • Banwell B.
      An update on multiple sclerosis in children: diagnosis, therapies, and prospects for the future.
      ,
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • Ghezzi A.
      • Hintzen R.
      • Kornberg A.
      • Pohl D.
      • Rostasy K.
      • Tenembaum S.
      • Wassmer E.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ). History of febrile illness preceding the onset, unequivocal steroid responsiveness, and a subsequent stable course albeit with deficits rather than a progressive degenerative course also corroborated the diagnosis of an acquired demyelinating disorder. However, comparison of the clinical features with other cohorts of children with ADEM brought out the differences from the primary demyelinating disorder. One of the important differentiating features was an early age of presentation as compared to children with primary demyelinating disorder. The usual age of onset of ADEM in children ranges from 5 to 8 years (
      • Gordon-Lipkin E.
      • Banwell B.
      An update on multiple sclerosis in children: diagnosis, therapies, and prospects for the future.
      ,
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • Ghezzi A.
      • Hintzen R.
      • Kornberg A.
      • Pohl D.
      • Rostasy K.
      • Tenembaum S.
      • Wassmer E.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ). On the other hand patients with mitochondrial LE presented either in the infantile or late infantile period and some of them had insidious rather than acute presentation. The second point pertains to the presence of primary optic atrophy in many patients at the time of initial presentation. Even though the information on optic atrophy was not available for comparison in the demyelination groups, primary optic atrophy was present in more than half of the patients in this series at the time of presentation. Thirdly, children with mitochondrial LE most often had residual motor deficits on follow up even though they showed complete or partial clinical response to steroids in the acute phase. On the other hand residual motor deficits are less commonly reported in ADEM (
      • Absoud M.
      • Lim M.J.
      • Chong W.K.
      • De Goede C.G.
      • Foster K.
      • Gunny R.
      • Hemingway C.
      • Jardine P.E.
      • Kneen R.
      • Likeman M.
      • Nischal K.K.
      • Pike M.G.
      • Sibtain N.A.
      • Whitehouse W.P.
      • Cummins C.
      • Wassmer E.
      • Uk, Ireland Childhood, C.N.S.I.D.W.G
      Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features.
      ;
      • Yamaguchi Y., T.H.
      • Kira R.
      • Ishizaki Y.
      • Sakai Y.
      • Sanefuji M.
      • Ichiyama T.
      • Oka A., K.T.
      • Kimura S.
      • Kubota M.
      • Takanashi J.
      • Takahashi Y.
      • Tamai H.
      • Natsume J.
      • Hamano S H.S.
      • Maegaki Y.
      • Mizuguchi M.
      • Minagawa K.
      • Yoshikawa H.
      • Kira J.
      • Kusunoki S H.T.A.
      A nationwide survey of pediatric acquired demyelinating syndromes in Japan.
      ). Seizures were a major part of the episodes and sometimes the heralding event in some patients as exemplified in the patient with NDUFA1 variation. The difference was significant compared to two out of three ADEM cohorts and may be another useful differentiating point.
      The clinical features in other mitochondrial phenotypes and that of mitochondrial leukoencephalopathy also showed distinct differences. Systemic features such as peripheral neuropathy, auditory involvement, and myopathic features were absent in children with leukoencephalopathy. The clinical features were related to long tract involvement in comparison to other phenotypes. This also may pose a major diagnostic dilemma for suspecting a mitochondrial etiology in patients primarily presenting with neuroregression and leukoencephalopathy. But familiarity with the MRI patterns compared to other leukodystrophies may help the physician to suspect a mitochondrial etiology.
      MRI in the acute phase demonstrated large asymmetrical confluent lesions simulating acute disseminated encephalomyelitis or tumefactive MS. The lesions most often involved the frontal and parietal region and the periventricular and deep white matter and corpus callosum compared to subcortical or juxta cortical regions and thalamus in children with acquired demyelinating disorders. Contrast enhancement, diffusion restriction, presence of lactate peak and white matter cysts were consistently seen in mitochondrial LE. The evidence of inflammation on MRI is one of the important defining feature of mitochondrial leukoencephalopathies (
      • Kevelam S.H.
      • Steenweg M.E.
      • Srivastava S.
      • Helman G.
      • Naidu S.
      • Schiffmann R.
      • Blaser S.
      • Vanderver A.
      • Wolf N.I.
      • van der Knaap M.S.
      Update on leukodystrophies: a historical perspective and adapted definition.
      ). Restricted diffusion without contrast enhancement is most often seen in ischemia and is attributed to cytotoxic edema. Delayed restricted diffusion with contrast enhancement has been described in tumefactive MS lesions (
      • Hyland M.
      • Bermel R.A.
      • Cohen J.A.
      Restricted diffusion preceding gadolinium enhancement in large or tumefactive demyelinating lesions.
      ). In lesions with restricted diffusion, presence of gadolinium enhancement has been used as a differentiating feature between acute demyelinating lesions and ischemia (
      • Balashov K.E.
      • Aung L.L.
      • Dhib-Jalbut S.
      • Keller I.A.
      Acute multiple sclerosis lesion: conversion of restricted diffusion due to vasogenic edema.
      ). This has been attributed to intramyelinic edema or myelin vacuolation as in toxic demyelination or inborn error of metabolism (
      • Sener R.N.
      Diffusion magnetic resonance imaging patterns in metabolic and toxic brain disorders.
      ). Another alternative explanation is that the myelin breakdown may reduce the water movement in the extracellular space because of the reduced fiber tract organization (
      • Abou Zeid N.
      • Pirko I.
      • Erickson B.
      • Weigand S.D.
      • Thomsen K.M.
      • Scheithauer B.
      • Parisi J.E.
      • Giannini C.
      • Linbo L.
      • Lucchinetti C.F.
      Diffusion-weighted imaging characteristics of biopsy-proven demyelinating brain lesions.
      ). The presence of concomitant contrast enhancement along with restricted diffusion in mitochondrial leukoencephalopathies may suggest that the pathology is similar to acute demyelinating lesions.
      The therapeutic implications of these findings in mitochondrial disorders have not been fully explored. The most important being the utility of glucocorticoid administration in acute stages, as in acute demyelinating disorders. Steroid responsiveness in patients with mitochondrial leukoencephalopathy has been described in patients with LYRM mutations and DARS associated leukoencephalopathy (
      • Dallabona C.
      • Abbink T.E.
      • Carrozzo R.
      • Torraco A.
      • Legati A.
      • van Berkel C.G.
      • Niceta M.
      • Langella T.
      • Verrigni D.
      • Rizza T.
      • Diodato D.
      • Piemonte F.
      • Lamantea E.
      • Fang M.
      • Zhang J.
      • Martinelli D.
      • Bevivino E.
      • Dionisi-Vici C.
      • Vanderver A.
      • Philip S.G.
      • Kurian M.A.
      • Verma I.C.
      • Bijarnia-Mahay S.
      • Jacinto S.
      • Furtado F.
      • Accorsi P.
      • Ardissone A.
      • Moroni I.
      • Ferrero I.
      • Tartaglia M.
      • Goffrini P.
      • Ghezzi D.
      • van der Knaap M.S.
      • Bertini E.
      LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance.
      ;
      • Wolf N.I.
      • Toro C.
      • Kister I.
      • Latif K.A.
      • Leventer R.
      • Pizzino A.
      • Simons C.
      • Abbink T.E.
      • Taft R.J.
      • van der Knaap M.S.
      • Vanderver A.
      DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder.
      ). Remarkable corticosteroid response and dependence have been described in patients with MELAS (
      • Gubbay S.S.
      • Hankey G.J.
      • Tan N.T.
      • Fry J.M.
      Mitochondrial encephalomyopathy with corticosteroid dependence.
      ). The similarity in clinical presentation and overlap with primary demyelinating disorder such as MS is already emphasized in literature (
      • Kovacs G.G.
      • Hoftberger R.
      • Majtenyi K.
      • Horvath R.
      • Barsi P.
      • Komoly S.
      • Lassmann H.
      • Budka H.
      • Jakab G.
      Neuropathology of white matter disease in Leber's hereditary optic neuropathy.
      ,
      • Matthews L.
      • Enzinger C.
      • Fazekas F.
      • Rovira A.
      • Ciccarelli O.
      • Dotti M.T.
      • Filippi M.
      • Frederiksen J.L.
      • Giorgio A.
      • Kuker W.
      • Lukas C.
      • Rocca M.A.
      • De Stefano N.
      • Toosy A.
      • Yousry T.
      • Palace J.
      • Network M.
      MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis.
      ,
      • Weisfeld-Adams J.D.
      • Katz Sand I.B.
      • Honce J.M.
      • Lublin F.D.
      Differential diagnosis of Mendelian and mitochondrial disorders in patients with suspected multiple sclerosis.
      ). In the sole autopsy study available in patients with LHON-MS, the inflammatory responses are highlighted in detail (
      • Kovacs G.G.
      • Hoftberger R.
      • Majtenyi K.
      • Horvath R.
      • Barsi P.
      • Komoly S.
      • Lassmann H.
      • Budka H.
      • Jakab G.
      Neuropathology of white matter disease in Leber's hereditary optic neuropathy.
      ). Introduction of corticosteroids in this patient intermittently did improve the visual and neurological dysfunction suggesting an early immunological mechanism. It was proposed that mitochondrial dysfunction might occasionally aggravate or initiate the autoimmune process (
      • Kovacs G.G.
      • Hoftberger R.
      • Majtenyi K.
      • Horvath R.
      • Barsi P.
      • Komoly S.
      • Lassmann H.
      • Budka H.
      • Jakab G.
      Neuropathology of white matter disease in Leber's hereditary optic neuropathy.
      ). It remains to be seen if maintenance of the steroid therapy as in other immune mediated disorders can keep a stable course in children with mitochondrial LE. The report of the relapsing remitting MS-like illness in a child with NDUFA1 variation may support this hypothesis. The patient received steroids for achieving as well as maintaining remission. After the remission is maintained, the patient remained clinically stable on mitochondrial cocktail medications. As suggested in the study by Kowacs et al. (
      • Kovacs G.G.
      • Hoftberger R.
      • Majtenyi K.
      • Horvath R.
      • Barsi P.
      • Komoly S.
      • Lassmann H.
      • Budka H.
      • Jakab G.
      Neuropathology of white matter disease in Leber's hereditary optic neuropathy.
      ) the mitochondrial dysfunction in this patient might have initiated the immune response, which got stabilized by the use of steroids. Various mechanisms have been postulated by which glucocorticoids exert its effect on mitochondria (
      • Lee S.R.
      • Kim H.K.
      • Song I.S.
      • Youm J.
      • Dizon L.A.
      • Jeong S.H.
      • Ko T.H.
      • Heo H.J.
      • Ko K.S.
      • Rhee B.D.
      • Kim N.
      • Han J.
      Glucocorticoids and their receptors: insights into specific roles in mitochondria.
      ,
      • Psarra A.M.
      • Sekeris C.E.
      Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor.
      ,
      • Tiao M.M.
      • Lin T.K.
      • Chen J.B.
      • Liou C.W.
      • Wang P.W.
      • Huang C.C.
      • Chou Y.M.
      • Huang Y.H.
      • Chuang J.H.
      Dexamethasone decreases cholestatic liver injury via inhibition of intrinsic pathway with simultaneous enhancement of mitochondrial biogenesis.
      ).
      In conclusion, this study highlights that episodic neuroinflammation is a feature of mitochondrial leukoencephalopathies as evidenced by the clinical presentation and MRI features. These features may overlap with acquired demyelinating disorders. The role of glucocorticoids in inducing and maintaining remission during the neurological episodes in patients with mitochondrial leukoencephalopathy needs to be explored further in prospective studies.

      Author contributions

      ABT- concept and design, acquisition, analysis and interpretation of data PSB- concept and design, acquisition, analysis and interpretation of data, performed the literature search and wrote the manuscript. ABT, PSB, MN, SS, SC, KS and CV represent the clinical team involved in the evaluation, management and follow up of the patients. HRA carried out the acquisition and interpretation of the radiological data. NG and AM were involved in the acquisition and interpretation of histopathological data. MMSB, JP and KS were involved in the acquisition and interpretation of respiratory chain assays. SC and PG contributed to the interpretation of genetic data. All authors reviewed and approved the final manuscript

      Declaration of conflicting interests

      The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

      Funding

      The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a grant from Indian Council of Medical Research to PSB (Grant no. 54/9/2012-HUM-BMS). The sponsor did not have any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication

      Ethical approval

      This study was approved by the Institutional Ethics Committee [No. NIMHANS/91st/2014]

      Appendix A. Supplementary material

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