Abstract
To The Editor:
Priapism is a urological emergency and can lead to tissue necrosis and permanent impotence. Priapism is defined as complete or partial penile tumescence that persists for >4 hours beyond sexual stimulation, or is not associated with sexual stimulation. Ischemic priapism accounts for 95% of priapism, and is a compartment syndrome of the penis. Ischemic priapism is estimated to have an incidence of between 0.3 and 1.5 per 100,000 men per year. No apparent cause can be found in 60% of cases of ischemic priapism. However, 40% of cases are associated with hematological disorders, use of medications (systemic or intracorporeal vasoactive agents, antidepressants, antipsychotics, antihypertensives and recreational drugs), malignancy, and neurological disorders (Tay et al. 2012). Patients who use antipsychotic drugs should be informed about the complications of priapism, especially those with a history of prolonged erections associated with other α-adrenergic blocking agents, a history of substance abuse, or a history of sickle cell disease, all of which may induce a hypoxic state (Koirala et al. 2009). Here, we present a 21-year-old autistic male who developed priapism on an existing regimen of risperidone.
Case Report
The patient was a 21-year-old Caucasian male with a diagnosis of autistic disorder, limited verbal abilities, and intellectual disabilities. He was first evaluated in the Autism and Developmental Disabilities Clinic at Stanford University, at 15 years of age and was re-assessed at 21 years of age. Developmental history was normal, with typical verbal and nonverbal communication, until the age of 30 months. The patient's first meaningful words apart from “mama” and “dada” were spoken before he was 18 months old, and he was able to make two word combinations at the age of 21 months. He was able to identify animals and colors at the age of 24 months. He then had a fairly rapid regression in his social and cognitive abilities, with an inability to acquire new skills. At the age of 38 months, he was diagnosed with autistic disorder. He has been followed by a pediatric neurologist, as his electroencephalogram (EEG) showed epileptiform discharges; however, he has had no clinical seizures. An MRI of the brain, with contrast. obtained when he was 13 years of age, was normal. He had also been evaluated several times through medical genetic tests, and had high-resolution chromosome analysis, fragile X testing, and array comparative genomic hybridization, which were all within normal limits.
The patient's most challenging behaviors have been hitting himself because of poor frustration tolerance, boredom, and irritability; prominent vocal and motor stereotypies; hyperactivity, and sleep disturbances. Previous medication trials have included paroxetine, sertraline, clonazepam, clonidine, valproate, and carbamazepine. All of those medications caused a variety of side effects from gastrointestinal symptoms to irritability. In addition, a trial of carbamazepine led to thrombocytopenia with easy bruisability, which led to its discontinuation. The most satisfactory response was achieved with risperidone, which led to a decrease in disruptive behaviors and agitation. Risperidone was initially started when the patient was 10 years of age. He was treated with different dosages, and was on 6 mg/day of risperidone between 2002 and 2009. However, the dose was decreased in late 2009 to a steady dosage of 3 mg/day and was maintained at this dosage until July 2012, when risperidone was discontinued.
At the time of his most recent presentation to our clinic, the patient's risperidone had been discontinued for ∼3 months after several incidents of priapism for which he required emergency interventions. He had first developed priapism in August 2011 when he was on 3 mg/day of risperidone. He had previously used risperidone at 6 mg/day along with clonidine, a potent α2-agonist, without any significant side effects. After the first incident of priapism, risperidone was reduced to 1.5 mg Qpm; however, a recurrence of the priapism occurred ∼6 months later. With a further reduction in dose to 1 mg at night, he had another episode of priapism 1 week later. He was at that time switched from the generic form that he had been receiving to the brand form, while maintaining the same daily dosage of 1 mg daily. Ketoconazole was also added for its antiandrogenic properties. Unfortunately, the patient experienced two more episodes of priapism; in July and August of 2011. Risperidone was then decreased to 0.5 mg, which again led to another episode of priapism, and, therefore, its discontinuation in July 2012.
This 21-year-old male had had five total interventions for priapism over a period of 1 year. Attempts to decrease the dose and to switch patient to different forms of risperidone led to the reccurrence of priapism. He has not sustained any permanent tissue damage and the urologist has determined that he is not impotent. Ketoconazole was discontinued in August 2012, at which time the patient was put on leuprolide depot 3.75 mg monthly injections by his urologist as a cautionary measure. He has had no recurrences of priapism since then. In October 2012, leuprolide was discontinued, and no priapism was noted at 4 months' follow-up. The patient's behaviors have now escalated as expected; caregiver reports an increase in disruption, agitation, irritability, and insomnia.
Discussion
The mechanism of antipsychotic-induced priapism is thought to be related to blockade of α1-adrenergic receptors (Andersohn et al. 2010). Ziprasidone and risperidone have the highest affinity, followed by clozapine and quetiapine. Olanzapine has the lowest affinity for the adrenergic receptors (Sood et al. 2008). To our knowledge, there is only one case report of risperidone-paroxetine associated priapism in a 13-year-old boy with autism (Yang and Tsai 2004). Kem et al. (2002) reported a case of priapism associated with trazodone in an adolescent with autism. Despite the frequent use of risperidone in individuals with autism, there is a scarcity of literature regarding the occurrence of priapism in this clinical population.
Stuttering priapism is a variant of the ischemic type of priapism that is characterized by repetitive, transient, painful, self-limiting episodes of priapism. This variant is known to progress to major episodes of ischemic priapism in 28% of cases. Irreversible corporal damage occurs after 4–6 hours of ischemia. Corporal tissue necrosis develops after an extended period of ischemia and the tissue eventually becomes fibrotic. Patients with ischemic priapism with a duration of <24 hours have a 50% chance of retaining some degree of erectile function whereas beyond 24 hours, the risk of penile deformity and loss of complete erectile function is >90% (Tay et al. 2012). Guidelines or recommendations are currently lacking with respect to the use of any agent that is effective, safe, and tolerable for reducing or preventing episodes of stuttering priapism. The preferred mainstay of managing ischemic priapism is prevention. Medical prophylaxis is quite distinct from treatment of acute major episodes of priapism, which involves surgical decompression of the penis and pharmacological stimulation of cavernosal tissue contraction. Chronic androgen ablation with estrogens, antiandrogens, or gonadotropin-releasing hormone analogues have been previously described, to prevent stuttering episodes of priapism (Dahm et al. 2002). Short-term regimens of ketoconazole in combination with prednisone have also been recently used (Abern and Levine 2009). The overarching goal of these therapies is to reduce serum testosterone levels to hypogonadal levels, which then suppresses androgen-associated mechanisms conjectured to be involved in triggering recurrent priapism episodes. Hormonal agents, however, have not always been successful in prophylaxis, and the risk of their administration includes substantial side effects, such as erectile dysfunction, low libido, and gynecomastia. Therefore, despite their seeming efficacy, these hormonal agents do not have the characteristics of ideal prophylactic agents (Morrison and Burnett 2012).
Conclusions
In summary, this case report illustrates the risk of priapism caused by risperidone for individuals with autism. It also highlights the possibility of its occurrence while the patient is on a stable dose, and after lowering the total daily dosage. These observations add to the literature on the emergence of priapism from risperidone in combination with other medications, during rapid dose escalation, and when there is concurrent to substance use. This case emphasizes further the importance of considering the dynamic properties of each drug, while being aware of rare but potentially serious complications of antipsychotic drugs. This is particularly important when dealing with patients with autism who might have limited expressive abilities to communicate their distress and discomfort.
Footnotes
Disclosures
Dr. Hardan has received research funding from Forest Research Institute and Bristol Meyers Squibb. He is also a consultant for Forest Research Institute and Integragen. Dr. Pradhan has no competing financial interests.