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Subacute Necrotizing Encephalomyelopathy
Introduction
Subacute necrotizing encephalomyelopathy (SNE), also known as Leigh syndrome, is a genetically heterogeneous disease that primarily affects the central nervous system. Originally characterized in 1951, the syndrome is characterized by focal and bilaterally symmetrical, necrotic lesions involving the thalamus, brainstem, and posterior columns of the spinal cord.[1]
Etiology
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Etiology
ATP is the primary energy currency in human cells. The production of this energy currency is mandated by the flux of hydrogen ions down a concentration gradient. This gradient is maintained by mitochondrial respiratory chain complexes during the process of oxidative phosphorylation.[2] In subacute necrotizing encephalomyelopathy, mutations in mitochondrial respiratory chain complexes lead to the disruption of ATP synthesis. It is this disruption of ATP synthesis that leads to the characteristic pathology of SNE. SNE is genetically heterogeneous since mutations can appear at any point in the mitochondrial respiratory chain. Pathologic mutations have been identified in over 85 different genes that have been shown to be inherited via autosomal, X-linked, or mtDNA patterns.[3][4][5]
Epidemiology
Subacute necrotizing encephalomyelopathy is primarily a disease of infancy, typically first becoming clinically evident between three and 12 months of age. SNE occurring later in life have been seen, but adult-onset cases are rare.[6] The incidence of the disease is affected by the type of inheritance pattern. Disease resulting from genes encoded in the cell nucleus has an incidence of approximately 1 in 40,000 live births.[7] However, the mitochondrial inheritance pattern in much rarer, affecting roughly 1 in 100,000 to 1 in 140,000 newborns. SNE has also been shown to have a predilection towards certain populations. In a region between Norway and Iceland, on the Faroe Islands, SNE incidence increases to 1 in 1,700 births, while 1 in 2,000 newborns are affected in Quebec, Canada, specifically the Lac-Saint-Jean region.[7][8] Current data suggests earlier disease onset in patients harboring mutations in nuclear DNA compared to mitochondrial DNA.[1]
History and Physical
The history and physical exam findings of patients with subacute necrotizing encephalomyelopathy manifest primarily in neuromuscular fashion. Developmental delay or regression is the most common finding in over 50% of patients. Affected individuals demonstrate motor delay, progressive cognitive decline, dystonia, ataxia, and brainstem dysfunction. Epileptic seizures and respiratory dysfunction are found in approximately 33% and 34% of cases, respectively.[1] Other clinical manifestations are weakness, fatigue, hypotonia, tremor, poor sucking and feeding, ptosis, nystagmus, abnormal ocular findings, and failure to thrive. The most common cardiac abnormalities are hypertrophic cardiomyopathy, followed by arrhythmia and dilated cardiomyopathy. Due to SNE's high mortality rate early in life, a family history of affected individuals is frequently not able to be ascertained. Occasionally, the mitochondrial DNA variant of the disease is present in only a small portion of maternal mitochondrial DNA. In these rare cases, the mother of a proband may have mild symptoms later in life or remains asymptomatic.
Evaluation
Subacute necrotizing encephalomyelopathy demonstrates a wide array of laboratory, molecular, and radiographic findings. While there are no established diagnostic criteria, affected individuals often share key features. A recent meta-analysis demonstrated that the lactate levels in the blood and CSF of affected patients are elevated in up to 72% of patients. On a molecular level, 80% of SNE cases lack a complete mitochondrial respiratory chain enzyme complex with DNA mutations of the mitochondria (32%) and cell nucleus (38%).[1] Symmetric CNS lesions are the hallmark of imaging studies for SNE. CT and MRI imaging commonly reveal lesions affecting the spinal cord, basal ganglia, cerebellum, diencephalon, and brainstem. Radiographic T1-weighted MRI and CT images show a hypointense signal, while T2-weighted MRI images are hyperintense.[1] Besides nonspecific degenerative changes in the muscle, the transmission electron microscope may reveal sarcoplasmic accumulation in both normal and abnormal mitochondrial morphology or large/swollen mitochondria with or without abnormal cristae.
Treatment / Management
Currently, there is no cure for subacute necrotizing encephalomyelopathy. Treatment strategies depend on the mode of inheritance and include both correcting underlying metabolic disturbances and supportive care. Supportive care targets mainly acidosis, seizures, and dystonias. Acute exacerbations of acidosis can be treated with either sodium bicarbonate or sodium citrate.[7] Antiseizure medication can be tailored based on seizure type but should exclude sodium valproate and barbituates, due to their negative effect on the mitochondrial respiratory chain.[9] Finally, dystonias can be managed as single-agent therapy or combination therapy with benzhexol, baclofen, tetrabenazine, and gabapentin. In refractory cases of dystonia, botulinum toxic injections can also be considered.[7] In SNE cases where nuclear DNA is involved, treatment is based on the subtype. For instance, in the case of thiamine transporter-2 and biotinidase deficiency, patients have responded well to lifelong treatment with a combination of thiamine and biotin or biotin therapy alone, respectively. Furthermore, coenzyme Q10 biosynthesis deficiency shows a positive response to coenzyme Q10 supplementation.[10] Novel therapies for SNE are also on the rise. An open-label phase 2A trial conducted in 2012 evaluated the use of a novel therapeutic agent, EPI-743, in pediatric cases of SNE. The results demonstrated statistically significant improvement and reversal in disease progression, compared to untreated children.[11](B3)
Differential Diagnosis
Many diseases can mimic subacute necrotizing encephalomyelopathy. It is, therefore, important to build a broad differential diagnosis during work-up. Several diseases affecting the mitochondria can mimic both nuclear DNA and mt-DNA variants, including mitochondrial depletion syndrome, mitochondrial translation defect, and MEGDEL syndrome.[7]
Prognosis
The prognosis of subacute necrotizing encephalomyelopathy is poor. The median age at death is just over 2 years, with the main cause of death is respiratory complications. Respiratory and heart failure have been shown to cause mortality in 50% of affected individuals by the age of three.[7] Similar to other mitochondrial diseases, SNE also demonstrates a median survival of approximately 90 days.[12] Disease onset prior to 6 months of age, failure to thrive, brainstem lesions, and intensive care unit (ICU) admissions have been associated with poor survival. Though the adult-onset disease is rare, affected individuals are thought to have a less severe form of the disease.[13]
Complications
Most complications from subacute necrotizing encephalomyelopathy are related to the central and peripheral nervous system and include deafness, retinitis pigmentosa, developmental delay, and dysphagia.[14] Nervous system deficits may extend into the peripheral nervous system to include polyneuropathy and myopathy. Less frequently, non-nervous system organs are affected, and SNE individuals may develop hypertrophic cardiomyopathy and hormonal imbalances.[14]
Deterrence and Patient Education
Due to the high mortality and rarity of SNE, mothers, and fathers of affected individuals must be screened for any genetic abnormalities. In addition, the risk of having additional children should be discussed with each family. Once the disease has manifested, it is imperative to diagnose the disease subtype, since this can affect both the course and efficacy of treatment.[10]
Enhancing Healthcare Team Outcomes
Subacute necrotizing encephalomyelopathy is a multifactorial disease, affecting many different organ systems in the body. Information sharing of evidence-based medical research and collaborative care has proven both pragmatic and cost-effective at improving patient outcomes.[Level 1][15] The potential to improve morbidity and mortality in SNE, therefore, lies in physicians' abilities to disseminate new information regarding best practices.[Level 1][16] In addition to working together, it is also essential the interprofessional team come to agreements on the final message being sent to the patient.[17] This can include primary care providers, neurologists, palliative care, pharmacists, and specialty trained nurses. A 2012 qualitative study found that, due to a perceived divide amongst health care professionals in different fields, patients received more mixed messages from providers.
The potential for such a phenomenon to negatively impact patient care cannot be ignored. Providers must reach out to other specialties of medicine when feelings of incomplete knowledge on a disease or organ system arise.[17][Level 5] Due to high mortality, end of life palliative care is the final critical step in a patient affected with SNE. By informing patients and their families about end of life and palliative care comfort options, unnecessary suffering is avoided both in the patient and their caregivers.[Level 2][18]
References
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Level 1 (high-level) evidenceSousa JS, D'Imprima E, Vonck J. Mitochondrial Respiratory Chain Complexes. Sub-cellular biochemistry. 2018:87():167-227. doi: 10.1007/978-981-10-7757-9_7. Epub [PubMed PMID: 29464561]
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Rahman J, Noronha A, Thiele I, Rahman S. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Annals of neurology. 2017 Jan:81(1):9-16. doi: 10.1002/ana.24835. Epub [PubMed PMID: 27977873]
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Level 1 (high-level) evidence