Thursday, January 27, 2011

PVC - What does it mean?

Motivation: On the first day of my first clinical clerkship, I was following in rounds during medicine when I was called to read an EKG.  The EKG looked normal enough except for this sudden huge depolarization in the middle of the EKG.  I did not know what it meant at the time, but I have since learnt to call these beats premature ventricular complexes (PVC).  Over time, I also learnt to ignore scattered PVC on an EKG as non-consequential.  But, the fact remains that they exist, and some apparently healthy people have more PVC than others.  Do PVC reflect heart pathology? The clinical relevance of PVC in apparently healthy athletes was studied and reported a few years ago.

Paper: Long-Term Clinical Significance of Frequent and Complex Ventricular Tachyarrhythmias in Trained Athletes.  Biffi, A. et. al. J. Am. Coll. of Card. (2002) 40: 446-52.  http://content.onlinejacc.org/cgi/content/full/40/3/446

Methods: The study was conducted at the Institute of Sports Science at Rome, Italy.  Between 1984 to 1999, 355 athletes were referred to the institute for either (1) more than 3 PVC on resting 12-lead EKG or (2) history of palpitations.  Mean age was 24.8 years (range 14-35).  Each of the athletes underwent 24 hour Holter EKG monitoring, cardiovascular exam, echo, and chest x-ray.  Some athletes with more frequent PVC underwent further testing.  The athletes selected in the study were in most cases highly trained with 70% of the participants competing at the national level.  Athletes were followed-up six to twelve months (mean follow-up: 8.4 years).

Results:
Holter Montior Results: The number of PVC varied widely on 24 hour Holter monitor data.  The authors divided the participants into three groups:  (A) 71 (20%) athletes had between 2000 to 43,000 (!) PVC in 24 hours monitoring (mean: 10,850).  38 of the athletes in this group also had bursts of non-sustained ventricular tachycardia.  Only 8 of the 71 complained of palpitations.  None lost consciousness.  (B)  153 (43.1%) athletes had between 100 to 1,890 PVC in 24 hour monitoring.  None had ventricular tachycardia.  (C) 131 (36.9%) athletes had between 3 to 98 PVC.  None had ventricular tachycardia.

Cardiovascular Abnormalities: Based on echo, EKG, and other indicated invasive testing, the presence of structural abnormalities varied widely among the groups.  In group A (more than 2000 PVC/24 hr), 30% had evidence of structural abnormalities.  The disorders found were arrhythmogenic right ventricular cardiomyopathy, mitral valve prolapse, myocarditis, and dilated cardiomyopathy.  In group B (100-2000 PVC/24 hr), only 3% had evidence of mitral valve prolapse.  In group C (<100 PVC/24 hour), no abnormlities were noted.

Follow-up: During follow-up time, one athlete died from sudden cardiac death (he was in group A).  Everyone else survived.

Discussion: I think the paper demonstrated very nicely that among patients with PVC, a wide spectrum exists.  While just the appearance of PVC did not predict structural pathology, a large number of PVC (>2000/24 hours) was associated with greater prevalence of structural pathology.  It is interesting to note, however, that even among athletes with the highest number of PVC, 70% turned out not to have any identifiable structural pathology.  On the other hand, many of the structural pathologies identified were serious requiring treatment.  One wonders if in longer term follow-up, the group with higher PVC would have increased incidence of cardiovascular diseases or sudden death.  Follow-up was too short in the study.

A big weakness of the study is, of course, its generalizability.  Given that most patients are neither in their 20s nor playing sports at a competitive level, the conclusions drawn in this study may not be more generalizable, and in other circumstances, PVC may be more predictive of structural pathology.  In the group of athletes, the general level of diseases burden is low.  In conclusion, however, for a young athlete with a few PVC caught on a screening Holter, the chances of structural pathology is low.

Tuesday, January 18, 2011

Epilepsy and Death

Motivation: Many children have epilepsy, and many look remarkably well otherwise.  They eat, play, fight, go to school, and do otherwise regular things.  But, I have always wondered what happens to the children in the future?  Do they live happily ever after?

Recently, a group in Finland published one of the longer prospective follow-ups on childhood onset epilepsy.

Paper: Long-Term Mortality in Childhood-Onset Epilepsy.  Sillanpaa, M. and Shinnar, S.  NEJM (2010) 363: 2522-9.  http://www.nejm.org/doi/pdf/10.1056/NEJMoa0911610

Methods: The study included all children younger than 16 living in Turku, Finland with epilepsy (at least two unprovoked seizures).  The study was restricted to children who were seen in Turku University Hospital between 1961-1964.  At that time, epilepsy was apparently a reason to hospitalize children.  Also excluded were children with febrile seizures, single episode of seizure, or seizure judged to be from acute causes (like hyponatremia or hypoglycemia).  Since the start of the study, a follow-up examination was conducted every five years till 2003!

Results: The study followed a cohort of 245 patients.  During the 40 year follow-up, only five subjects migrated out of Finland.  Of the rest, information on death and cause of death were ascertained from the national registry, which covers all patients in the country.  At the time of last follow-up, 45% were in 5-year remission without drugs, 11% were in remission with drugs, and 44% were not in 5-year remission.

Overall mortality: The overall mortality rate during the forty year follow-up was 24%.  The overall mortality rate in comparison to mortality rate of the general population was 5.5 (CI: 4.6 to 6.6) for patients who suffered their first episode of epilepsy between 1961-1964.  The median age of death was 23 years.  No significant difference was found between genders.  85% of the total deaths occurred in patients who were not in 5 year remission.  Among the 60 deaths in the overall group, 33 deaths (55%) were epilepsy related (including 18 patients suffering sudden, unexplained death, 13 from seizures, and 6 drownings).  The rest of deaths were non-epilepsy related.

Subgroup analysis: When the overall cohort was subdivided into two subgroups consisting of (1) idiopathic or cryptogenic seizures and (2) remote symptomatic causes such as developmental delay, cognitive impairment, cerebral palsy, or neurologic insult like stroke, clear differences emerged.  The overall mortality rate was 11.1 person per 1000 person-years in the group with remote symptomatic cause while the mortality rate was 3.2 per 1000 person-years in the group with idiopathic or cryptogenic seizures (p<0.001).  In multivariate analysis, the most consistent predictor of mortality was absence of 5-year remission of seizure.  

Discussion: The primary strength of the study was the long follow-up time.  This study paints a clear picture that children who particularly have long-term uncontrolled seizure are at significantly increased risk of mortality as adults.  While patients with remote symptomatic causes of seizure have higher overall mortality than idiopathic causes, both groups have higher overall mortality.  There are many interesting results of the study.  One that I found surprising is that a substantial number of patients die of sudden unexplained death.  The authors comment on the side that in most of these patients, pulmonary edema was found during autopsy.  I wonder why some patients who were apparently not having active seizures would die from pulmonary edema.

The most encouraging result clearly was that in patients in 5-year remission, the mortality rate was significantly less.  While the association cannot be taken for causality, the next question is whether more aggressive management such as with surgery can stop the trend.  I guess we would need another heroic 40 year study to answer that!