Involvement of the Spinal Cord in Primary Mitochondrial Disorders: A Neuroimaging Mimicker of Inflammation and Ischemia in Children

DISCUSSION

Although a few publications have reported spinal cord lesions may occur in very select mitochondrial disorders, limited evaluation has been performed to characterize correlations between spinal cord imaging findings and clinical phenotypes in a broad range of patients with primary mitochondrial disease with well-defined pathogenic causes.^{3,8⇓⇓⇓⇓-14} Here, we performed a comprehensive retrospective review of all spine imaging in patients with confirmed primary mitochondrial disease over the past 2 decades, which has clearly demonstrated that a high frequency of spinal cord lesions occurs in children with primary mitochondrial disorders. Indeed, spinal cord lesions were observed in more than half of our pediatric patients with primary mitochondrial disease who underwent spine imaging.

A detailed description of the histopathologic features of spinal cord lesions in mitochondrial disorders has shown damage of motor, sensory, and autonomic fibers.^{2,3,6,8⇓–10,15,16} Moreover, a variety of findings, including the presence of ischemia, necrosis, relative sparing of neurons, edema of the gray matter, vascular congestion, and demyelination around the central canal and dorsal columns of the cervical cord, have been reported in the neuropathologic literature.^5,17 These data support our study’s findings that imaging features resemble different forms of pediatric demyelination and that more frequent distribution of lesions occurs around the central canal and in the posterior columns of the spinal cord.

Studying the broad spectrum of imaging findings and patterns, we were able to classify the imaging appearance of the spinal cord lesions into 2 distinct patient subtypes, group A and group B. Group A patterns included individuals with overlapping imaging features of lesions observed in demyelinating disorders. These lesions tend to be distributed in the cervical and thoracic segments and were restricted to the white matter or affected both white and gray matter. Group A patterns were present in half of the patients with imaging findings typical of NMOSD,¹⁸ including tumefactive effect, longitudinal extensive lesions, and involvement of the area postrema. These patients were clinically evaluated for demyelinating diseases but with negative results for AQP4-Ab. Possible associations linking NMOSD and mitochondrial disorders have been considered for many years, mainly based on a few patients who demonstrated imaging similarities of NMOSD in the context of having a diagnosis of Leber hereditary optic neuropathy (LHON).^19,20 As one example, Hudson et al²¹ sequenced the mtDNA genes commonly known to cause LHON in patients with NMOSD, in addition to specific mtDNA haplogroups that are preferentially associated with pathogenic variants in complex I mtDNA gene that cause LHON, in both patients with NMOSD and control participants. The authors did not find any statistically significant association between these 2 disorders.²¹

However, in recent literature, mtDNA has been increasingly recognized as an agonist of the innate immune system. Its role in inflammasome activation as a damage-associated molecular pattern is shown by its ability to induce the secretion of interleukin-1β from microglia.^22,23 Interestingly, levels of CSF mtDNA have been noted to be higher in NMOSD AQP4-Ab–positive patients compared with those with other neurologic disorders. Moreover, transfected cells that express AQP4 when incubated with serum from NMOSD AQ4-Ab–positive patients were shown to release mtDNA.²⁴ NMOSD AQP4-Ab–negative patients may show similar imaging findings, including spinal cord features resembling positive AQP4-Ab.¹⁸ Furthermore, primary mitochondrial dysfunction may induce microglial activation. Microglial cells, in turn, can release reactive oxygen species and proinflammatory cytokines, which are able to damage essential components of the mitochondria such as mtDNA.²⁵

We postulate that the mtDNA insult and release may trigger neuroinflammation in predisposed individuals, as exemplified by specific case observations. Interestingly, 2 patients in group A who had lesions affecting the whole cross-section of the spinal cord that involved most pronounced signal abnormality in the central gray matter to give the “H sign” appearance were suspected in their differential diagnosis of having anti-MOG demyelination.²⁶ Indeed, 1 of these children harbored a heteroplasmic m.14484T>C known pathogenic variant and positive family history of LHON and had a confirmed anti-MOG Ab diagnosis. Although the spinal cord imaging features for the other patient were compatible for anti-MOG Ab phenotype, this child was not tested because there had been no other supporting clinical indication.

Two children had short-length spinal cord lesions that occurred in the periphery of the cord that involved only the white matter in the cervical and thoracic segments, mimicking MS. However, neither the brain imaging findings nor the laboratory results supported the imaging-based diagnosis of MS.²⁷ Reports from the scientific literature highlight the difficulty of a clinical approach to patients affected by mitochondrial disorders who also present with brain lesions resembling demyelination.^28,29 We believe that our study’s focus on spinal cord MR imaging findings further supports the hypothesis of the mitochondrial cause of these MS-like cases, which also present with overlapping imaging features of autoimmunity.

Two other group A children from our cohort presented with the typical imaging findings of LBSL (following previously established features).⁸ These included 1 child with DARS2 pathogenic variants (a gene that encodes mitochondrial aspartyl-tRNA synthetase described in association with this imaging pattern)⁸ and the other with NDUFS1 pathogenic variants, a nuclear gene encoding a mitochondrial complex I subunit that has not previously been associated with this unique imaging phenotype. Further imaging characterization of larger prospective cohorts affected by these 2 pathogenic genes and related gene classes may be helpful to differentiate and optimize care for individuals with these genetic disorders.

The children in group B included patients who presented with features typical of spinal cord infarct, with all lesions localized within the gray matter. Even though other disorders, such as acute flaccid myelitis caused by viral infection, may present with similar findings,³⁰ there is indirect evidence that mitochondrial dysfunction that impairs cellular energy production may be a causal or contributing factor to ischemic tissue changes.³¹ Thus, we believe that ischemic lesions remain the primary pathogenic cause of isolated gray matter spinal cord lesions and accordingly should be excluded in this context. Indeed, some of the ischemic lesions that we identified in children with primary mitochondrial disease occurred within the lower thoracolumbar segment, extended to the conus medullaris, and had the classic ischemic “snake-eye” appearance.³²

Upon review of clinical phenotypes in our cohort with spinal cord lesions, Leigh syndrome was the most frequently observed; it was present in three-quarters of our cohort. Leigh syndrome cases with spinal cord lesions had diverse gene causes in both genomes, a range of pathogenic variants and lesions that could be grouped into both spinal cord imaging patterns (groups A and B).

Patients with primary mitochondrial disease and spinal cord lesions may present with several different neurologic symptoms, such as monoparesis, spasticity, autonomic dysfunction, or sensory or motor transverse syndrome. Less frequently, asymptomatic cases may occur. Spinal deformities are also commonly observed.² However, it has not previously been clear in the literature whether these neurologic symptoms are sufficiently common to support establishment of a standard MR imaging protocol or interval to routinely analyze the spinal segment for patients with primary mitochondrial disease. In our study, the most common clinical symptoms that led to performing spine MR imaging or brain MR imaging with subsequent spine evaluation (because of lesions depicted on brain imaging in the upper spine) were acute or progressive weakness and respiratory failure. Acute bowel or bladder incontinence or retention, change in gait, neuromuscular scoliosis, hyperreflexia, and myoclonus were also neurologic symptoms observed in our cohort. Moreover, individuals with acute weakness had a higher frequency of group A spinal cord lesions identified both at the cervical level and with longitudinally extensive lesions. These data provide strong support to consider updating imaging protocols for children with mitochondrial disease when they have concerning neurologic manifestations. Further study will be needed to determine the potential utility of obtaining spinal MR imaging in patients with definite primary mitochondrial disease before the onset of severe neurologic evidence of spinal cord involvement.

The only statistically significant association observed was between the location of the lesions and the cross-sectional imaging pattern, with lesions involving the cervical segment more frequently observed in group A (demyelination features, white ± gray matter involvement) and lower segment lesions (thoracic or thoracolumbar) more often observed in group B (ischemic features, selective gray matter involvement).

Ascertainment bias is a potential limitation of our study to estimate the frequency of spinal cord lesions in pediatric patients with primary mitochondrial disease because most individuals who had brain MR imaging performed during the 2 decades of the study period did not undergo full spine MR imaging. Indeed, all children evaluated in this study had MR imaging performed for at least part of the spinal cord because of pronounced neurologic signs or symptoms indicative of potential spinal cord involvement. Retrospective analysis of spinal cord images in this symptomatic cohort demonstrated the relatively high frequency of and value of clinical spine MR imaging to identify spinal cord lesions in patients with primary mitochondrial disorders who have concerning neurologic presentations. Despite the relatively low number of patients with definite mitochondrial disease who had spine MR imaging available for review, this study is the largest cohort reported to date and clearly demonstrates that spinal cord lesions are not an infrequent finding in children with a diverse array of primary mitochondrial diseases.

Furthermore, these analyses discovered that 2 main imaging patterns for spinal cord lesions occur in the context of primary mitochondrial disease, which may help to broaden the differential diagnosis of other common entities such as demyelination, ischemic, or viral disorders.