Forecasting stroke-like episodes and outcomes in mitochondrial disease

Abstract

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically-determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinic-radio-pathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA (mtDNA) variants (n = 23). The age of first stroke-like episode was available for 105 patients (mean [SD] age: 31.8 [16.1]); a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mtDNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82–0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration was more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% vs 44%, p < 0.001) and reduced mean brain weight [SD] (1044 g [148] vs 1304 g [142], p = 0.005). Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.

l -Arginine in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes

“…These findings highlight that methodologically robust clinical trials are imperative to address the remaining uncertainty relating to the treatment of l -arginine in patients with MELAS syndrome. Because stoke-like episodes are increasingly recognized as evolving brain syndromes driven by seizure activity, 1,50 seizure treatments, including infusions of AEDs or use of anesthesia agents, should be prioritized in these patients. While there are potential cultural differences in shared decision-making for medical practice in rare diseases globally, we would encourage mitochondrial experts to share this information about l -arginine with patients and colleagues to allow them to make an informed decision.…”

Pathogenic mitochondrial DNA 3243A>G mutation: From genetics to phenotype

“…Frontiers in Genetics frontiersin.org vascular distribution and demonstrate variable lesion reversibility (Chen et al, 2020;Ng et al, 2021b). A recent study reported mismatched hypometabolism in SLEs (Finsterer et al, 2021), which may be explained by a reduced ability of mitochondria to utilize glucose.…”

“…Nervous system symptoms are the most prominent phenotypes of m.3243A>G. 80% of MELAS syndrome cases are associated with m.3243A>G, and the most common age of onset is 2–40 years, although late-onset cases have been reported ( Ayman W El-Hattab, 2018 ). SLEs are a typical symptom of MELAS syndrome, which shows increased T2-weighted signal areas involving both cortical and subcortical areas on temporal, occipital and parietal lobes that do not correspond to the classic vascular distribution and demonstrate variable lesion reversibility ( Chen et al, 2020 ; Ng et al, 2021b ). A recent study reported mismatched hypometabolism in SLEs ( Finsterer et al, 2021 ), which may be explained by a reduced ability of mitochondria to utilize glucose.…”

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

“…Further, accumulation of ROS and subsequent mitochondrial permeability transition pore (mPTP) opening or activation of Hypoxia Inducible Factor (HIF)-1α pathways trigger apoptosis. Thereby, mPTP opening leads to elevated calcium release and even higher levels of ROS [105][106][107][108][109][110]. Especially high amounts of ROS drive a series of downstream effects and act as central regulator.…”