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Departments of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Clinical Neurosciences, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Clinical Neurosciences, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Departments of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Departments of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Departments of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, IndiaNeuromuscular Lab, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Clinical features of mitochondrial-leukoencephalopathy mimick acquired demyelinating disorders.
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Early age at onset and primary optic atrophy in mitochondrial- leukoencephalopathy are helpful differentiating features.
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MRI findings included contrast enhancement, restricted diffusion, white matter cysts & lactate peak.
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Steroid responsiveness was noted during acute phase as well as during relapses.
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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.
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 (
). 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 (
). 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) (
). 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 (
), 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 (
). 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. (
) 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/Gender
Episodes
Age at presentation
Clinical features
MRI characteristics
Immunomodulation &other treatment
Response
[T2/FLAIR signal changes/DWI/CE/MRS]
Patient 1/M
1st episode
2.5yrs
Febrile illness, vomiting, encephalopathy, ataxia
Multifocal discrete hyperintense lesions in bilateral supratentorial white matter, thalami and left cerebellar hemisphere with nodular CE
Inj. MP X 5days, oral steroids taper X 4weeks
Improved, no residual deficits
2nd episode
4.5yrs
Fever,vomiting, seizures, encephalopathy, left hemiparesis, ataxia
Bilateral temporo- parietal, occipital and frontal regions in deep white matter and subcortical zones, patchy CE, no restricted diffusion, moderately increased lipid lactate peak
Inj.MP X 5days, oral steroid taper
Improved, no residual deficits
Follow up
4yrs& 10mo
Asymptomatic period
Residual bright signals in bilateral peritrogonal white matter and scattered focal hyperintense lesions in bilateral corona radiate and subcortical regions of fronto-parietal lobes, no CE
New 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 weeks
Improved, no deficits
4th episode
5yrs 5mo
Sub acute onset, Lt focal seizures,visual agnosia,irritability
Bilateral 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 weeks
Improved
Follow up MRI after one month in the asymptomatic period
Interval MRI-Persisting signal changes in the bilateral fronto-parieto-temporal and occipital region and left half of pons. Reduction in the extent and mass effect
Started on Inj.Interferon x 4 months
Asymptomatic
Two new enhancing nodular lesions seen in left frontal region
5th episode
5yrs 8mo
Left sided focal seizures
Conflent hyperintensities in periventricular white matter in occipital, frontal and temporal regions, Lactate peak, no CE, no restricted diffusion
Inj. MPX 5days monthly X 6mo once in two months X 6months, once in three months X 1 dose
No episodes for 1.5 yrs
Follow up MRI in the asymptomatic period after six months
Confluent asymmetrical lesions in bifrontal and biparietal regions, no diffusion restriction, no CE, Lactate peak+
Nil, On multivitamins
No further episodes
6th episode
6.5yrs
Rt focal seizures, Rt hemiparesis
Confluent white matter lesions in frontal, parietal and temporal lobes, No CE or restriction,SC +
Inj.MPX5days
Improved
Follow up
10yrs
No neurological deficits
ND
High dose vitamins
Stable course
Patient 2/ F
1st episode
3yrs
Febrile illness, loss of mile stones, encephalopathy
Confluent white matter lesions in frontal parietal and temporal lobes with rarefaction, CE +
Inj.MPX 5days
Full improvement
Corpus callosal lesions- splenium and body
2nd episode
One month after
Encephalopathy
ND
Inj.MP monthly pulse dosesX6 months
Partial improvement
Follow up
6 years
GDD, optic atrophy, seizures, spastic parapresis
Bilateral symmetrical nonhomogeneous signal changes in cerebral white matter, rarefied appearance +, cysts+, SC+, restricted diffusion, lactate peak
Nil. Maintained on high dose vitamins
Progressive course
Patient3/M
1st episode
9 mo
Encephalopathy, regression
Multifocal confluent white matter signals in frontal parietal and temporal region, rarefied appearance of white matter, restricted diffusion along the edges
Inj.MP X 5days, steroids taper X 6 weeks
Partial response, toe walking
2nd episode
2yrs
Febrile illness, loss of mile stones, seizures, pyramidal signs
Confluent hyperintense lesions bilateral periventricular and subcortical white matter, putamen, substantia nigra, medial thalamus, SC, white matter cysts, lactate peak, restricted diffusion, CE+, SC signal changes
Inj.MP X5 days.
Improvement
Corpus callosum is affected in full extent.
Follow up
3yrs
Ambulent, spastic paraparesis, optic atrophy
ND
Nil. On high dose vitamins
No further episodes
Patient 4, F
Insidious onset
6mo
Diarrhoeal illness, loss of mile stones, seizures, family history positive
large confluent bilateral hyperintense signal changes in white matter lesions restricted diffusion, CE+, spinal cord signal changes,white matter cysts-present, Lactate peak
Not received, high dose vitamins
Spastic paraparesis, Optic atrophy
Follow up
3yrs
No further episodes, gaining mile stones
ND
High dose vitamins
Patient 5, M
Insidious onset
9mo
Loss of acquired mile stones
Large multifocal confluent hyperintense lesions, restricted diffusion& CE, SC signal changes
Inj.MPX 5 days followed by oral steroids X one year
Fully improved
Follow up
10yrs
Achieved independent walking, running, language delay
Confluent lesions in bifrontal, parietal and occipital lobes Lt temporal lobe, restricted diffusion and CE, multiple cysts
Nil, on high dose vitamins
Poor scholastic performance
Patient 6,M
Ist episode
9mo
Fever, seizures, regression of mile stones
Multiple large confluent T2/FLAIR lesions, restricted diffusion, CE, SC signal changes
Hemiparesis progressing to quadriparesis. No encephalopathy
ND
InjMPX5days
Improved
3rd episode
7yrs
Lt hemiparesis
ND
Inj.MPX5days
Improved
4th episode
7.5 yrs
Suddden bilateral vision loss
Symmetrical confluwnt cystic white matter lesions in periventricular region, cervical spional cord lesions
Inj.MPX5days
Improved
5th episode
8yrs
Febrile illness, quadriparesis
NA
NA
Expired
Patient 10, F
1st episode
2.5 yrs
Febrile illness, Jaundice, Gait difficulty, falls followed by ataxia, quadriparesis, recurrent unexplained vomiting
Multifocal confluent lesions in fronto parietal region with central hypointensity on FLAIR, restricted diffuson & enhancement. Spinal cord signal changes present
Inj. MPX 5 days followed by oral steroids for 6 months
Distinct steroid responsiveness
2nd episode
3.5yrs
Insidious onset lower limb weakness
ND
Oral steroidsX1month
Improved
3rd episode
6yrs
Bulbar symptoms/ progressive slurring of speech
Multifocal confluent white matter lesions in fronto parietal region. Restricted diffusion present, CE+
Inj.MPX5days,oral steroids for one month
Minimal improvement, spasticity of LL
Follow up
11 yrs
Spastic quadriparesis, seizures, bedridden status
Symmetrical confluent white matter signal changes with cysts and bilateral dentate nuclei and cerebellar white matter hyperintensities, SC signal changes +
Minor head injury followed by insidious onset gait difficulty, recurrent falls,speech regression, pyramidal signs
Fronto-parietal lesions
Not received
Mild spastic paraparesis, independent in all daily activities
Follow up
12yrs
Spastic paraparesis
Posterior periventricular and deep white matter signal changes, Lactate peak
Nil, on high dose vitamins
Stable course, attends school, IDD
Patient 13, M
1st episode
18 mo
Febrile illness, loss of acquired mile stones, difficulty in standing and walking
Large confluent hyperintense lesions in frontal parietal and occipital regions with restricted diffusion& CE, Lactate peak
Inj.MP X 5days
Partial improvement
2nd episode
19mo
Bulbar weakness, quadriparesis
ND
Inj.MPX5 days followed by oral steroids for 2 weeks
Gradual improvement, spastic paraparesis
Patient14, M
1st episode
20 mo
Febrile illness, Rt hemiparesis progressing to quadriparesis
Large 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 peak
Inj.MP X 5 days followed by oral steroids
Partial improvement
2nd episode
22mo
Progressive loss of walking and language mile stones
ND
Inj X MP pulse doses for three months
Improvement in motor cognitive and social mile stones
Follow up
31mo
Spastic paraparesis
Bilateral symmetrical hyperintensities in periventricular corona radiata and centrum semi ovale, cysts increased in number. No diffusion restriction or CE
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.
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. 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 (
). 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. 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 (
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 (
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 (
). 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 (
). 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 (
). In lesions with restricted diffusion, presence of gadolinium enhancement has been used as a differentiating feature between acute demyelinating lesions and ischemia (
). Another alternative explanation is that the myelin breakdown may reduce the water movement in the extracellular space because of the reduced fiber tract organization (
). 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 (
). 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 (
). 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. (
) 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 (
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]
International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
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