Evidence for Cardioembolic Stroke in a Case of Kearns-Sayre Syndrome
Background Cerebral infarction is a known complication in patients with mitochondrial encephalomyopathies (MELAS, MERRF, Kearns-Sayre syndrome), but the etiology in the different types remains uncertain.
Case Description A 33-year-old woman who had suffered from ophthalmoplegia, bilateral ptosis, ataxia, retinitis pigmentosa, and epilepsy since childhood was diagnosed to have Kearns-Sayre syndrome. The diagnosis was confirmed by muscle biopsy when she was 17 years old. A pacemaker was implanted because of the occurrence of bradyarrhythmias when she was 24 years old. The patient was admitted to the hospital with left-sided hemiparesis of sudden onset due to right striatocapsular infarction. Results of Doppler sonography of the carotid arteries were normal; however, transesophageal echocardiography revealed a thrombus in the left atrial appendage.
Conclusions Stroke in Kearns-Sayre syndrome is likely to be due to cardiac embolism. Anticoagulant therapy should be considered even for mild forms of cardiomyopathies leading to left ventricular dysfunction.
Of the three types of mitochondrial encephalomyopathies, only the syndrome of mitochondrial myopathy, encephalopathy, lactate acidosis, and “strokelike episodes” (MELAS) is typically accompanied by cerebral infarction.1 2 The syndrome of myoclonus epilepsy with ragged red fibers (MERRF) is not associated with strokes. For Kearns-Sayre syndrome (KSS), there is to our knowledge only one other case report associated with cerebral infarction.3 In MELAS, mitochondrial angiopathy is thought to cause cerebral ischemia4 ; however, our case documents the occurrence of cardiogenic embolism in KSS.
When the patient was 3 years old, her first neurological symptom was the development of generalized seizures. Since then, a retardation in growth and mental development became evident. Ptosis of the right eye developed when the patient was 7 years old and at the left side when she was 13. At 16 years of age, she was only 1.40 m tall and was found to have bilateral ophthalmoplegia, bilateral hypacusis, pigmental degeneration of the retina, mild proximal muscle weakness of the upper limbs, and mild cerebellar ataxia. She had a pathological glucose tolerance test, and electrocardiography (ECG) revealed a right bundle-branch block. Histological examination and electron microscopy of a muscle biopsy revealed “ragged red fibers” with abnormal mitochondrias, and a diagnosis of mitochondrial encephalomyopathy with the clinical features of KSS was made. There was no family history of muscle or nervous system disorder.
At the age of 20 years, the patient’s diabetes mellitus became insulin dependent. At 24 years, she developed hemodynamic relevant bradyarrhythmias such that a ventricular demand pacemaker had to be implanted. Despite her severe illness, she was able to take care of herself and worked as a librarian.
At 33 years of age, she was admitted to our hospital because of a sudden-onset left-side weakness. On neurological examination, in addition to her earlier symptoms, she had a left-side hemiplegia, dysarthria, and severe dysphagia. Arterial blood gas analysis showed no evidence of metabolic acidosis. Cerebrospinal fluid was acellular, and protein was elevated to 120 mg% (normal range, 10 to 40 mg%). Intubation had to be performed to avoid aspiration, and she underwent tracheotomy 7 days later.
Three days after the onset of symptoms, CT scanning of the brain revealed a fresh right striatocapsular infarct with moderate mass effect (Fig 1⇓). Furthermore, severe cerebellar atrophy, moderate cortical atrophy, and a hypodense lesion in the splenium of corpus callosum indicated preexisting encephalopathy (Figs 1⇓ and 2⇓).
Because of the localization of the infarct, a thrombotic embolism seemed to be the most likely cause. Continuous-wave and transcranial Doppler sonography of the extracranial and intracranial arteries provided no evidence of stenosis or occlusion. Transthoracic echocardiography 2 days after the stroke showed mild left ventricular insufficiency (ejection fraction, 49%) and mild mitral regurgitation. Additionally, transesophageal echocardiography was performed, and a thrombus (1.4×0.8 cm) was detected in the left atrial appendage (Fig 3⇓). There was no evidence for an atrial septal aneurysm or of a patent foramen ovale. No thrombus formation could be detected on the pacemaker, which was functioning normally. Continuous ECG monitoring in the intensive care unit showed a sinus rhythm with no significant arrhythmias. A Holter ECG (24 hours) was also normal.
Anticoagulant therapy, first with intravenous heparin and later with warfarin, was administered. With physical therapy and phoniatric training, there was slow recovery in dysphagia and dysarthria. After 3 months, the tracheostoma could be closed, and the patient could start swallowing again. Seven months later, the patient still had a severe left-side hemiparesis and required help for all activities of daily living. She remained wheelchair dependent and was not able to return to work.
KSS is characterized by the triad of onset before the age of 20 years, progressive external ophthalmoplegia, pigmental degeneration of the retina, in addition to at least one of the following: heart block, cerebellar signs, or cerebrospinal fluid protein above 100 mg%.5 6 Our patient displayed all these features of KSS as well as hearing loss, short stature, and diabetes mellitus, which are commonly associated with KSS. The presence of red ragged fibers on muscle biopsy confirmed the diagnosis of mitochondrial disease. In addition, the patient had generalized seizures since early childhood, which is more frequent in MERRF and MELAS. This does not, however, exclude the diagnosis of KSS in our case, since overlapping features of the three traditionally distinct clinical entities are frequent.7
Mitochondrial encephalomyopathies are often associated with heart disease, ie, heart block on ECG, diffuse left ventricular hypokinesis or left ventricular hypertrophy on echocardiography, and mitral valve regurgitation or prolapse.8 Various forms of cardiac conduction disturbances are found in all KSS patients; however, signs of left ventricular dysfunction seem to be rare.
The etiology of cerebral infarcts in mitochondrial encephalomyopathies is still uncertain. In two patients with mitochondrial encephalomyopathy, Ohama et al4 found structural changes in the mitochondria of cerebral arterioles. They suggested that this mitochondrial angiopathy might be responsible for ischemia. Lach et al9 described a patient with an overlap syndrome (MELAS/MERRF) who had a noninflammatory vasculopathy with microaneurysms and small thrombi. We have been able to detect only one case of cerebral infarction in KSS in the literature.3 The authors assumed that the patient had a cardiogenic embolism due to left ventricular dysfunction, but a cardiac thrombus was not detected, and pacemaker control and Holter ECG gave no evidence of arrhythmias.
Since a genetic classification of the mitochondrial disease was not performed, it cannot be excluded that this patient harbored the nt3243 mutation of mitochondrial DNA. This mutation is found in 80% of MELAS patients2 and occasionally in KSS patients10 and predisposes to cerebral ischemia. In our case of KSS with cerebral infarction, a cardiac thrombus was demonstrated by transesophageal echocardiography. The CT scan showed a striatocapsular infarction, which is classified as a territorial type of ischemia due to an embolus.11 In the presence of an intracardiac thrombus, the diagnosis of a cardiogenic stroke can be made. The localization and size of the infarct are atypical for vascular cerebral encephalopathy, which is the presumed pathophysiology of infarcts in MELAS.1 4
Despite the thrombus detected by transesophageal echocardiography, there was only mild left ventricular dysfunction and no evidence for significant arrhythmias similar to those in the case previously reported.3 Even in the absence of previous risk factors (arrhythmias, severe left ventricular dysfunction, valve insufficiency), patients with KSS seem to have an elevated risk of developing cardiac thrombi. Cardiac embolism might also be an important cause of stroke in other forms of mitochondrial encephalomyopathies, such as MELAS, in which the incidence of structural cardiac change is also high.8 Transesophageal echocardiography should therefore be included in the diagnostic management of patients with mitochondrial encephalomyopathies.
Our patient had only a poor outcome after striatocapsular infarction, despite her young age, because stroke rehabilitation was complicated by preexisting encephalopathy and myopathy. To prevent cardiogenic cerebral infarction in KSS, antithrombotic therapy with aspirin should be considered in the early stages of the disease. Anticoagulation with warfarin has to be considered if left ventricular dysfunction or cardiac thrombus is detected by echocardiography.
Corrrespondence to Christoph Kosinski, Department of Neurology, Technical University of Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany.
- Received February 21, 1995.
- Revision received June 26, 1995.
- Accepted June 29, 1995.
- Copyright © 1995 by American Heart Association
DiMauro S, Tonin P, Servidei S. Metabolic myopathies. In: Handbook of Clinical Neurology. New York, NY: Elsevier Science Publishers BV. 1992;62:479-523.
Anan R, Nakagawa M, Miyata M, Higuchi I, Nakao S, Suehara M, Osame M, Tanaka H. Cardiac involvement in mitochondrial diseases. Circulation. 1995;91:955-961.
Lach B, Preston D, Servidei S, Embree G, DiMauro S, Swierenga S. Maternally inherited mitochondrial encephalomyopathy: a vasculopathy. Muscle Nerve. 1986;9(suppl 5)180. Abstract.