Pathogenesis Of Stroke-like Episodes Research Articles

Pathophysiology of Stroke-Like Episodes in MELAS: A Possible Role of Neuron-Astrocyte Uncoupling in Cellular Damage during Synaptic Activation under Primary Oxidative Phosphorylation Defect (P01.033)

Objective: To speculate the pathophysiological mechanism of stroke-like episodes (SEs) in MELAS based on clinical data and current concept of neuron-astrocyte communications. Background The pathogenesis of SEs remains unknown. We previously reported that SEs are non-ischemic neurovascular events presumably associated with neuronal hyperexcitability (Neurology 2002, Curr Neurovasc Res 2005, Future Neurology 2010), however, the basic molecular mechanism underlying neuronal hyperexcitability remains unknown. It has been demonstrated that astrocytic processes sense synaptic activity and transmit the signals to the arterioles. Astrocytes communicate with a number of neurons or astrocytes by releasing gliotransmitters. Thus, gliotransmitters are considered to control synaptic transmission, neuronal synchrony and neuronal excitability. During synaptic activation, neurons preferentially use lactate which is continuously supplied through astrocyte-neuron lactate shuttle. Design/Methods: Retrospective review of 30 consecutive SEs in 8 patients with MELAS (A3243G (n=7), G13513A (n=1)) who were admitted to our hospital since 1990. Results: Common presenting symptoms included headache, visual symptoms, altered levels of consciousness or seizure, and psychiatric symptoms. Seizure developed during the course of SEs (69%), suggesting sustained neuronal hyperexcitability. SEs were often accompanied by focal hyperperfusion, focal periodic epileptiform discharges, spreading cortical edema and cortical laminar necrosis. Focal lactate accumulation with leptomeningeal vasodilatation was seen at early stage. Calcitonin gene-related peptide (CGRP) was elevated in CSF. Conclusions: SEs are episodic events characterized by neuronal hyperexcitability, increased anaerobic glycolysis, vasogenic edema and vasodilatation. We speculate that 1) sustained astrocyte activation following synaptic activation contributes to focal periodic epileptiform discharges and hyperperfusion, 2) trigeminovascular activation causes headache, 3) limited availability of ATP impairs sodium-dependent glutamate transporter, resulting in decreased clearance of glutamate from the synaptic cleft, 4) low extracellular adenosine level due to decreased ATP production may cause disinhibition of synaptic activity, and 5) sustained release of lactate from activated astrocytes potentially abort glycolytic pathway. Neuron-astrocyte uncoupling may contribute to cellular damage during SEs. Disclosure: Dr. Iizuka has nothing to disclose. Dr. Hamada has nothing to disclose. Dr. Sakai has nothing to disclose.

Carotid dissection in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare, genetic etiology of stroke in young individuals. The most commonly associated genetic mutation is an adenine to guanine transition at nucleotide 3243 in the mitochondrial genome [1]. The pathogenesis of stroke-like episodes is not fully understood, but is believed to be due to mitochondrial angiopathy, metabolic defects, or neuronal hyperexcitability [2]. Mitochondrial angiopathy has largely been attributed to small vessel disease. In this report, we describe a patient with MELAS who presented with multiple strokes and was also found to have bilateral pseudoaneurysm formation of the internal carotid arteries with accompanying dissection. A 47-year-old female originally presented to an outside hospital with a two day history of word finding difficulties, headache, and right upper extremity weakness. Imaging confirmed a left middle cerebral artery (MCA) stroke. Her past medical history is significant for an episode of eclampsia complicated by bilateral visual and hearing loss. Her vision gradually improved but her hearing loss became progressively worse with time. Her family medical history includes adult onset hearing loss and diabetes in her mother. Initial stroke evaluation included magnetic resonance angiography (MRA) of the head and neck that demonstrated minimal atherosclerotic changes in the left middle cerebral artery with otherwise normal vessels, a normal transesophageal echocardiogram, and a normal cerebrospinal fluid profile. She had mildly elevated cholesterol and heterozygous inheritance of the prothrombin gene mutation. She initially recovered partially, but one week later, she had progressive decline in her mental status and subsequently decreased oral intake, prompting transfer to our facility for further evaluation. At presentation, she was found to be encephalopathic with infrequent, non-sensical speech. Initial labs were significant for a bicarbonate of 19 mmol/L with an anion gap of 13 mmol/L, hemoglobin A1c of 6.1%, and normal serum lactate (Table 1). A head CT showed bilateral basal ganglia and thalamic calcifications in addition to her stroke, and an EEG revealed bilateral slowing. Her vessels were re-examined with a CT angiogram of the head and neck that revealed a right internal carotid artery dissection with pseudoaneurysm and evidence of chronic dissection on the left carotid artery (Fig. 1a). The outside hospital MRA was reviewed and did not reveal any dissections. A lumbar puncture was performed and revealed an elevated lactic acid of 5.4 mmol/L. Repeat MRI/MRA with spectroscopy revealed a normal lactate peak and extension of the left MCA stroke involving the full MCA territory, new left PCA stroke, and a new right hemisphere infarct consistent with a right embolic phenomenon, possibly to the anterior choroidal artery, or an atypical lipohyalinosis of the lenticulostriates from the right MCA (Fig. 1b). A muscle biopsy was performed showing ragged red fibers. MELAS genetic testing was ordered and was positive for the mtA3243G mitochondrial mutation. In the setting of bilateral carotid dissections, genetic test for Ehlers–Danlos Syndrome Type IV was also ordered and was negative. No history of head or neck trauma was elicited. CT angiogram of the chest, abdomen and pelvis did not reveal any other R. C. C. Ryther Department of Child Neurology, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, USA

Regional cerebral blood flow and cerebrovascular reactivity during chronic stage of stroke-like episodes in MELAS — Implication of neurovascular cellular mechanism

Background Ischemic vascular hypothesis as a causative role in the pathogenesis of stroke-like episodes in MELAS remains to be debated. Methods This study consisted of two parts. Part 1 is a clinicoradiological study during acute stage of 18 consecutive stroke-like episodes in six patients with MELAS. Part 2 is a SPECT study to assess the regional cerebrovascular reactivity (rCVR) to acetazolamide during chronic stage in five patients with MELAS. Results Headache and epileptic seizure were the most common presenting symptoms. Unique features of acute stroke-like lesions included progressive spread of cortical lesions with vasogenic edema, focal periodic epileptiform discharges, focal hyperperfusion, and cortical laminar necrosis during subacute stage. During chronic stage, SPECT showed hypoperfusion in non-affected occipital cortex in three patients as well as in previously affected regions in four. The rCVR was preserved in three patients, focally impaired in one, and extensively impaired in one, but relatively preserved in the occipital cortex in all patients. Conclusions Stroke-like episodes could be non-ischemic neurovascular events initiated by neuronal hyperexcitability. Once neuronal hyperexcitability develops in a focal brain region, epileptic activities depolarize adjacent neurons, leading to a propagation of epileptic activities into the surrounding cortex, and resulting in energy imbalance. The mechanisms for neuronal hyperexcitability remain to be elucidated.

Pathogenesis of Stroke-Like Episodes in MELAS: Analysis of Neurovascular Cellular Mechanisms

The pathogenesis of stroke-like episodes in mitochondrial encephalopathy, myopathy, lactic acidosis and stroke-like episodes (MELAS) is not fully understood although two main theories have been proposed; ischemic vascular hypothesis caused by "mitochondrial angiopathy" and generalized cytopathic hypothesis caused by "mitochondrial cytopathy". Crucial molecular mechanism includes the lack of taurine modification at the wobble uridine of mutant transfer RNAsLeu(UUR) resulting in defective translation of cognate codons due to a defect in codon-anticodon interaction. Whereas recent clinical studies have shed light on the neuronal hyperexcitability, which may potentially initiate a cascade of stroke-like events. Stroke-like episodes are characterized by neuronal hyperexcitability, neuronal vulnerability, increased capillary permeability, and focal hyperaemia. It is recognized that stroke-like lesions not only evolve in the area incongruent to a vascular territory, but also potentially spread into the surrounding cortex with concomitant vasogenic edema presumably provoked by prolonged epileptic activities. Based on the clinical observations, we speculate that stroke-like episodes appear to be non-ischemic neurovascular events; once neuronal hyperexcitability developed in a localized brain region as a result from either mitochondrial dysfunction in the capillary endothelial cells, or in neurons or astrocytes, epileptic activities may depolarize the adjacent neurons leading to propagation of epileptic activities in the surrounding cortex. Increased capillary permeability provoked by epileptic activities in the presence of mitochondrial capillary angiopathy may cause unique edematous brain lesions predominantly involving the cortex. As a consequence, susceptible neuronal population in the cortex may result in neuronal loss with a laminar or pseudo-laminar distribution.

Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome.

The pathogenesis of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) remains unknown. Fourteen stroke-like episodes in six patients with MELAS were studied using clinical, neuroradiologic, and electrophysiologic approaches. In two patients postmortem examination was done. Headache and epileptic seizure were the most common presenting symptoms. In 13 of 14 episodes the cerebral cortex was primarily involved with variable subcortical edema particularly in the temporal, occipital, and parietal cortex. Repeated MRI performed in two episodes revealed progressive spread of the cortical lesion to the surrounding cortex for a few weeks after the onset of symptoms. In 6 of 11 episodes T1-weighted hyperintense cortical signal compatible with cortical laminar necrosis was seen during subacute stage of the episode. Fat-suppression MRI confirmed intracortical gyral hemorrhage in one episode. Petechial gyral microhemorrhages were also pathologically confirmed in the autopsy of another patient. In 9 of 11 episodes focal epileptiform discharges on EEG were noted in the acute brain lesion. In seven of nine episodes focal cortical hyperperfusion was seen in SPECT studies. The stroke-like episodes in MELAS may reflect neuronal hyperexcitability, which increases energy demand and creates energy imbalance between energy requirement and adequate availability of adenosine triphosphate due to oxidative phosphorylation defect particularly in the susceptible neuronal population, causing cortical necrosis. The episodic nature of stroke-like episodes is unexplained.

Adult-Onset MELAS

We report a 46-year-old woman with implications regarding pathogenesis of strokelike episodes in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). She had a 10-month history of episodic seizures, strokes, cognitive decline, vomiting, and ileus. She also had sensorineural hearing loss, insulin-dependent diabetes mellitus of several years' duration, and persistent lactic acidosis. Family history was pertinent for a similar syndrome in her deceased mother (onset in her sixties), for hearing loss and diabetes mellitus in two brothers, and for hearing loss in her only child, a son. Serial MRIs of the brain revealed severe but evanescent cerebral cortical abnormalities. A left temporal brain biopsy was performed to exclude encephalitis. Light microscopy revealed a diffuse fibrillary gliosis with abundant reactive gemistocytes, focal evidence of ischemic neuronal injury, and edema. Electron microscopy revealed bizarre enlarged mitochondria and changes consistent with cellular edema. Succinate dehydrogenase staining was strongly reactive within cerebral blood vessels and within neurons. A point mutation was subsequently found at nt 3243 of the mitochondrial tRNA(Leu(UUR) gene in peripheral leukocytes and in brain, confirming the clinical diagnosis of MELAS. Quantitation revealed that 82% of brain mitochondria carried the disease mutation, indicating that most, if not all, tissues were affected. Our findings suggest that strokelike episodes in MELAS result from defects in neuronal metabolism, as well as in cerebral vasculature.