Adult-onset mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): a diagnostic challenge

Abstract

Rare causes of stroke-like presentations can be difficult to diagnose. We report a case of a man in his 40s who first presented with stroke symptoms, but whose clinical course was not typical for a stroke. A detailed investigation of the patient’s medical history revealed bilateral sensorineural hearing loss which prompted a wider diagnostic assessment.

Furthermore, lack of vascular risk factors and a normal angiogram strengthened our suspicion of an unusual underlying condition. Raised lactic acid levels and genetic analysis confirmed a diagnosis of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.

Background

Thirty per cent of strokes have an undetermined origin, and after excluding common causes, a number of rarer causes remain.^{1 2} Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome belongs to a group of rare mitochondrial disorders that cause stroke-like presentations.³ The phenotypic variability, unpredictable clinical course and presentation of MELAS, can often lead to misdiagnosis.^4–8 We aim to highlight the importance of a thorough background history when consulting patients with stroke-like symptoms and create an awareness of bilateral deafness as a cardinal symptom of MELAS. This will facilitate a wider diagnostic assessment to identify rarer causes of stroke-like episodes in adult patients.

Case presentation

A man in his 40s presented with an acute onset weakness of his left arm, Medical Research Council (MRC) grade 4/5, dysarthria and left upper motor neuron facial palsy. He had no vascular risk factors and no family history of neurological disorders. On examination, there was muscle wasting in both hands, notably in the thenar and hypothenar muscles, in addition to left upper and lower limb pyramidal weakness. Reflexes were brisk globally, with normal muscle tone and an up-going plantar reflex on the left. There was no cerebellar or sensory ataxia. Review of his clinical records revealed long standing bilateral sensorineural deafness which had deteriorated significantly in the preceding 12 months.

Investigations

A CT of the head showed a right hemispheric cortical hypodensity (figure 1). Normal findings on the CT angiogram and venogram excluded large vessel occlusion, stenosis, vascular malformations and venous sinus thrombosis. The patient was admitted under the stroke team for further assessment. Laboratory investigations including full blood count, renal and liver function, C reactive protein, erythrocyte sedimentation rate, haematinics, lipid and autoimmune profile were all normal. An ECG was suggestive of left ventricular hypertrophy but a subsequent echocardiogram showed a normal ventricle and no significant valve disease. MRI on the head on the day after admission showed cortical and subcortical fluid-attenuated inversion recovery (FLAIR) signal abnormality as well as a diffusion restriction involving the right temporal lobe, parietal lobe and cerebellum compatible with cerebral ischaemia (figure 1). The patient’s conscious level then deteriorated. An electroencephalogram (EEG), performed to rule out status epilepticus, showed periodic lateralised epileptiform discharges in the right temporo-occipital region. No further seizures were recorded after treatment with levetiracetam was started. Given the atypical MRI findings, the patient’s symptomatology and history of deteriorating sensorineural deafness, a mitochondrial disorder was considered. Serum lactate was raised at 4.03 mmol/L (normal range 0.5–2.2 mmol/L) as was the cerebrospinal fluid lactate at 4.37. MR spectroscopy showed an inverted double lactate peak (figure 2) and ragged red fibres were seen on muscle biopsy. Genetic analysis confirmed the diagnosis of MELAS with a m.3243A>G mtDNA mutation in the MTTL1 gene.

Figure 1.

Non-contrast CT head with right hemispheric cortical low density reported as an acute right middle cerebral artery territory infarct (A). T2-weighted MRI demonstrating a FLAIR (fluid-attenuated inversion recovery) signal abnormality in the right temporal and parietal lobes (B). Apparent diffusion coefficient (C) and diffusion-weighted image (D) demonstrating cortical diffusion restriction in the right temporal lobe (indicated by arrows).

Figure 2.

MR spectroscopy showing an inverted double lactate peak at 1.28 and 1.33 ppm characteristic of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (indicated by white arrow). Long echo time (TE) of 135 ms.

Treatment

The patient was started on L-arginine to reduce the frequency of stroke-like episodes and the severity of symptoms associated with MELAS, and antiepileptic treatment was continued. He was not treated with antiplatelets or anticoagulants as they are not indicated for MELAS and he had no other indication for primary vascular prevention.

Outcome and follow-up

The patient was seen 3 and 9 months post discharge. Mild weakness remained in his left arm, but he was functionally almost back to normal and walking independently without the use of aids. The patient reported intermittent left-sided sensory deficit and headaches at 9 months, but no new neurological signs were noted on examination. He is due to be seen at 13 months post discharge and has been referred to a specialist mitochondrial disease centre for management of his condition.

Discussion

First described in 1984, MELAS syndrome is a maternally inherited rare disorder most commonly caused by a mutation in the MTTL1 gene encoding tRNA found in the mitochondria.^{3 9 10} Cases of MELAS in Europe are estimated to be between 16:10 000 and 236:100 000,^11–13 with 1%–6% of presentations thought to occur after the age of 40.¹⁰ The disease manifests in childhood with headaches, vomiting and seizures. In adults, symptoms similar to strokes, such as hemiparesis and visual disturbances, as well as deafness and peripheral neuropathy, are more common.^{3 14}

The pathogenesis of MELAS is not clearly understood; however, the m.3243A>G mutation is most commonly associated with the disease. The mutation results in dysfunctional mitochondria, which reduces the synthesis of electron transport chain complexes impairing mitochondrial energy production.^{10 15 16} This results in insufficient ATP generation to meet the demands of the various organ systems in the body, leading to multiple organ system disturbance.¹⁰ Therefore, MELAS predominantly affects highly metabolic active tissues such as the brain, inner ear, skeletal and heart muscles.³

MELAS is difficult to diagnose because, like other mitochondrial myopathies, signs can be difficult to recognise.¹⁷ Adult-onset MELAS is more frequently missed than childhood-onset disease, because the index of suspicion is lower than in children, who generally lack vascular risk factors and thus are less likely to develop vascular infarcts.¹⁸ Also, taking into account the variable clinical course and presentation of the disease, this could explain why mitochondrial myopathies such as MELAS are thought to be underdiagnosed.¹⁷

When patients in their 40s present with sudden onset of focal neurological symptoms such as hemiparesis and hemisensory loss, stroke is the most likely diagnosis, as demonstrated by the case presented here. However, it is important to maintain a wider differential diagnosis if the subsequent clinical course is atypical. Unusual features in our case were the reduced level of consciousness, with mild hemiparesis, the absence of vascular risk factors, as well as an identification of a background history of bilateral sensorineural hearing loss and atypical radiological findings. While the muscle wasting in the patient’s hands was not initially linked with MELAS, peripheral neuropathy is associated with the disease and is the most likely explanation for this finding.^{14 19} Comparatively, the patients’ globally brisk reflexes, normal tone and muscle wasting suggest a degree of mixed upper and lower motor neuron signs. This could be due to mitochondrial heteroplasmy, which could determine severity of disease or phenotypic variability.^{3 20 21} The reduced level of consciousness seen could have been due to impaired mitochondrial oxidative phosphorylation, hence encephalopathy presenting as reduced consciousness associated with stroke-like episodes rather than a seizure.³

Historically, diagnosing MELAS required specific criteria including stroke-like episodes before the age of 40, encephalopathy characterised by seizures and presence of lactic acidosis or ragged red fibres on muscle biopsy, in addition to two or more features of abnormal early psychomotor development, recurrent headaches or recurrent vomiting.^{14 22} However, these criteria are not useful for cases of adult-onset disease where the first presentation of stroke-like episodes occurs after the age of 40. Here, neuropathic symptoms such as deafness can be a key pointer to the diagnosis.^{14 23}

Specialist consensus suggests a diagnostic approach using a combination of clinical findings, MRI head and EEG, which then prompts consideration of mitochondrial myopathies and further genetic testing if clinically indicated.²⁴ MELAS is not included in the National Institute for Health and Care Excellence guidance on differential diagnosis of stroke.^{25 26} Greater awareness of rare stroke mimics such as MELAS, as well as a thorough evaluation of a patient’s medical history, could prevent misdiagnosis in adult patients and help clinicians identify rare causes of stroke presentations.^{17 18} The UK has dedicated specialist centres for the management of mitochondrial diseases with online resources for managing MELAS.²⁷

Learning points.

• A reduced level of consciousness with relatively mild hemiparesis is unusual in patients with stroke and requires review of the differential diagnosis.

• Absence of vascular risk factors in patients with stroke should prompt a wider diagnostic assessment.

• Identification of early-onset sensorineural hearing loss should prompt consideration of genetic aetiologies such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in patients experiencing stroke-like episodes and exhibiting atypical radiological findings.

• Diagnosis of stroke mimics may not be possible on the day of admission and requires critical reassessment, especially if the clinical course is not as expected.

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