Stroke in Duchenne Muscular Dystrophy
A Retrospective Longitudinal Study in 54 Patients
Background and Purpose—Duchenne muscular dystrophy (DMD) is the most frequent skeletal muscle myopathy. Nearly all patients develop cardiomyopathy in their second decade of life. The purpose of this study was to evaluate the frequency, cause, and outcome of stroke in a German cohort of patients with DMD.
Methods—Retrospective analysis of medical records of 54 DMD patients, who lived in a regional facility for handicapped people (Wichernhaus Altdorf, Germany) between 1963 and 2013.
Results—Fifty-four DMD patients were followed up for 7.4 years on average. Mean age at admission and discharge from the long-term care facility or death were 11.4 and 18.8 years, respectively. Covering a total observation period of 400 patient-years, we identified 4 DMD patients with juvenile arterial ischemic strokes. Off-label systemic thrombolysis in 2 patients resulted in a nearly complete regression of stroke-related symptoms, but 1 patient died of septic pneumonia and cardiac failure 24 days after thrombolysis therapy. In the other 2 patients, who had their ischemic strokes in 1994 and 1998, severe infarction-related symptoms persisted, and 1 patient died 13 days later. DMD-associated cardiomyopathy without evidence of atrial fibrillation was the only risk factor for ischemic stroke in all patients.
Conclusions—This study indicates an increased risk for ischemic strokes in DMD patients. Regular cardiological assessment of all DMD patients is mandatory to evaluate the individual risk profile for cardioembolic events and to adapt therapeutic strategies.
Duchenne muscular dystrophy (DMD) is the most frequent muscular dystrophy with an incidence of 1 in 3600 to 6000 male births.1 The disease usually manifests between the third and fifth year of life and leads to a steady decline in strength and motor function, contractures, and loss of ambulation between 9 and 13 years of age.1 Furthermore, the lack of dystrophin protein expression in cardiac tissue of DMD patients is frequently associated with cardiomyopathy.1 The diagnosis of DMD is nowadays established by mutation analysis of the dystrophin gene or lack of dystrophin protein expression in diagnostic muscle biopsies.1 In years previous to the identification of the underlying dystrophin gene defect, DMD was diagnosed on the basis of its typical clinical presentation, very high creatine kinase levels, and dystrophic muscle biopsy findings. To date, no curative therapy is available for DMD, and most patients die in the second to forth decade of life because of respiratory or cardiac failure. Although cardiomyopathy is a frequent and prognosis-defining feature of DMD, just a small number of cases with stroke in DMD patients has been reported to date (Table).2–7 In this study, we retrospectively analyzed the frequency, cause, and outcome of stroke in a German cohort of 54 DMD patients, who lived in a regional facility for handicapped people between 1963 and 2013.
To analyze the frequency, cause, and outcome of ischemic and hemorrhagic stroke in DMD, we retrospectively reviewed the clinical data of 59 male patients, who lived at the Wichernhaus in Altdorf, a specialized learning and living facility for handicapped children and young adults near Nuremberg in Germany, between 1963 and 2013. Data were collected from the DMD patients’ medical files obtained from the treating Department of Neurology and Department of Orthopedics of the Rummelsberg Hospital, a teaching hospital of the Friedrich-Alexander University of Erlangen-Nürnberg, Germany, and from a local general practitioner serving the facility. Data collection was authorized by the ethics committee of the Friedrich-Alexander University of Erlangen-Nürnberg. Informed consent from patients was not required based on the retrospective analyses of medical records.
Diagnosis of DMD was made according to the criteria at the respective time. Diagnostic criteria for likely DMD were (1) disease manifestation between the third and fifth year of life with proximal muscle weakness and calf hypertrophy; (2) loss of ambulation between 9 and 13 years; (3) death before the age of 25/35 years without/with ventilation support, respectively; (4) high creatine kinase levels (>15× upper limit of normal); and (5) dystrophic pattern in muscle biopsy if performed. Diagnostic criteria for definite DMD were additional (1) report of a DMD causing dystrophin gene mutation or (2) report of negative dystrophin immunostaining in a muscle biopsy.
Medical records were analyzed with regard to the diagnosis of ischemic or hemorrhagic stroke. Stroke was defined as acute onset of a focal neurological deficit with proof of infarction or hemorrhage in a corresponding brain territory by computed tomographic imaging or magnetic resonance imaging (MRI).
The 95% confidence interval for incidence rate was calculated based on the Byar method.8
Our retrospective analysis of the medical records of 59 male individuals identified 54 patients fulfilling the diagnostic criteria for definite (n=11) or likely (n=43) DMD. In the remaining 5 individuals, at least 1 DMD-defining criterion was not fulfilled, resulting in exclusion from further analysis.
The analysis of the 54 DMD patients covered a total observation time of 400 patient-years with a mean follow-up period of 7.4 (range, 0.2–17.3) years. Mean age at admission and discharge from the long-term care facility or death were 11.4 (range, 3.8–22.1) and 18.8 (range, 12.1–35.0) years, respectively. In this cohort, we identified 4 individuals with arterial ischemic strokes, yielding an incidence rate of 1 in 100 patient-years (95% confidence interval, 0.3339–2.3751; Table). None of the patients had any evidence for hemorrhagic stroke.
Patient 1 is a 16-year-old DMD patient, who was admitted because of acute dysarthria, left-sided central facial weakness, and complete loss of motor function of his left hand in September 2013. He received systemic thrombolysis using recombinant tissue-type plasminogen activator (0.9 mg/kg) 2.5 hours after onset of symptoms. Subsequent cerebral MRI demonstrated an infarction in the territory of the right middle cerebral artery (Figure IA in the online-only Data Supplement), whereas magnetic resonance angiography (Figure IB in the online-only Data Supplement) and neurovascular ultrasound were unremarkable. Transthoracic echocardiography revealed dilated cardiomyopathy with severe global hypokinesis and markedly reduced left ventricular systolic function. Relevant valve disease and atrial size were not recorded. Assuming a cardioembolic stroke, oral anticoagulation with phenprocoumon was initiated. Although stroke-related symptoms regressed nearly completely within a few days, his cardiac function quickly deteriorated, and he died from septic pneumonia and cardiac failure 24 days after the manifestation of stroke. Patient 2 is a 16-year-old male patient, who developed acute aphasia, right-sided central facial weakness, and plegia of his right hand in November 2012. He also received systemic thrombolysis using recombinant tissue-type plasminogen activator (0.9 mg/kg), which led to a full recovery of his language skills but not of his acute motor symptoms. Subsequent cerebral MRI demonstrated a territorial infarction predominantly involving the left basal ganglia (Figure IC in the online-only Data Supplement) because of partial occlusion in the M1 segment of the left middle cerebral artery (Figure ID in the online-only Data Supplement). Transthoracic echocardiography demonstrated reduced left ventricular systolic function (ejection fraction 42%) without evidence of atrial or ventricular enlargement, thrombus formation, septal defect, or relevant valve disease. He was put on platelet antiaggregation therapy with acetylsalicylic acid for secondary stroke prevention. Patient 3 is a 13-year-old DMD patient, who developed acute right-sided hemiparesis in June 1998. He had previously been diagnosed with severe dilated cardiomyopathy with enlarged left atrium and ventricle but no relevant valve disease. He died 13 days after his ischemic stroke. Unfortunately, no further information on the stroke workup and cause of death are available. Patient 4 is a tetraparetic 16-year-old DMD patient, who developed acute severe aphasia and worsening of his preexisting left arm pareses. Cerebral MRI demonstrated an infarction in the territory of the right middle cerebral artery. Transthoracic and transesophageal echocardiography revealed reduced left ventricular systolic function without evidence of atrial or ventricular enlargement, thrombus formation, septal defect, or relevant valve disease. He had an unfavorable clinical outcome with persistence of his central nervous system–related symptoms.
Additionally, all documented 12-lead ECGs (all patients) and Holter ECGs (just patients 1 and 2) showed sinus rhythm. Stroke workup of patient 1, 2, and 4 did not reveal any further general vascular risk factors. Laboratory screening for coagulation disorders and vasculitis in patient 1 and 2 were unremarkable.
Ischemic strokes in DMD have previously been described in a small number of patients,2–7 but epidemiological data on cerebral infarction in DMD and in primary myopathies in general are scarce.9 In a prospective observational study published in Stroke 1987,10 none of 52 DMD patients were reported as having cerebral infarction. A Japanese questionnaire-based study published in 1996 reported 5 cerebral infarctions among 665 DMD patients within the year 1993, yielding a stroke incidence rate of 0.75 per 100.6 Covering 54 DMD patients and a total observation period of 400 patient-years, our study identified 4 patients with arterial ischemic strokes manifesting between 13 to 16 years of age, yielding an incidence rate of 1 per 100 patient-years. This is much higher than the overall arterial ischemic stroke incidence in childhood, which is quoted as 1.6 per 100 000.11
Off-label thrombolysis with recombinant tissue-type plasminogen activator in 2 boys led to a swift and marked remission of their stroke-related deficits. In line with previously reported data about safety of alteplase in childhood ischemic stroke,12 systemic thrombolysis in both juveniles was without adverse events. MRI along with stroke workup point to a thromboembolic cause of their stroke. The other 2 13- and 16-year-old DMD patients had major ischemic strokes in 1998 and 1994, respectively. Both had severe and persistent ischemia-related symptoms; 1 patient died 13 days after his stroke and the other survived gravely handicapped by severe motor aphasia. Analyses of the medical files of these 4 stroke patients revealed (1) no history of previous cerebrovascular episodes; (2) no preexisting anticoagulant or platelet antiaggregation therapy; and (3) no evidence for common cerebrovascular risk factors, coagulation disorders, vasculitis, or other stroke-related vascular pathologies. However, all 4 had a documented history of cardiac dysfunction ranging from impaired left ventricular systolic function (patients 2 and 4) to severe dilated cardiomyopathy (patients 1 and 3). Although none had evidence of atrial fibrillation, the occurrence of juvenile ischemic stroke in our DMD boys seems likely because of cardioembolic events on the basis of their preexisting cardiomyopathy. In this context, it is noteworthy that the majority of previously reported DMD patients with strokes showed evidence of dilated cardiomyopathy (Table). In contrast, atrial fibrillation is a rather rare condition in DMD cardiomyopathy.13
Although almost all DMD patients, who benefit from major improvements in symptomatic multidisciplinary care, will have cardiomyopathy in adulthood,14 there are currently no standard guideline recommendations for preventive anticoagulation or antiplatelet therapy in juvenile and adult DMD patients. Thus, regular cardiological assessment of all DMD patients is mandatory to evaluate the individual risk profile for cardioembolic events and to adapt therapeutic strategies.15
We are grateful to the residents and staff of the Wichernhaus Altdorf, who supported this study. This work was performed in partial fulfillment of the requirements for obtaining the academic degree, Dr. med. (C.H.).
S. Dittrich is a principal investigator of the multicenter study “Effect and Safety of Preventive Treatment With ACE Inhibitor and Beta Blocker on the Onset of Left Ventricular Dysfunction in Duchenne Muscular Dystrophy,” which is funded by the German Ministry of Health (support code 01KG0912, Eudra CT number 2009-009871-36). The other authors report no conflicts.
Presented in part as a poster at the 22nd Congress of the German Society for Muscle Diseases, Bochum, Germany, June 2015.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.013678/-/DC1.
- Received April 6, 2016.
- Revision received May 11, 2016.
- Accepted May 19, 2016.
- © 2016 American Heart Association, Inc.
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