Are you Lackin’ Prolactin? The Role of Prolactin in Diagnosing Seizures

Case Presentation

• 56-year-old female with a past medical history of HTN, DM2, homelessness, and medication nonadherence presents to the ED for possible unwitnessed seizure.

• Seizure lasted 2 minutes and resolved on its own without any medications. Post seizure vitals and physical exam are all normal except for mild confusion.

• Chart review reveals that the patient has been in the ED on 5 occasions for unwitnessed seizures, and is diagnosed as “malingering” each time.

• To ensure the patient gets the best care possible, the ED team consults the neurology service, who recommends a prolactin level to confirm a true seizure.

Clinical Question:

• What is the clinical value of serum prolactin in differentiating psychogenic non-epileptic seizures (PNES) from true seizures?

Things to Understand First:

• The pathophysiology of prolactin increase in seizures is not well understood. The general belief is that when the temporal lobe of the brain is stimulated, it sends signals to the hypothalamus resulting in pituitary secretion of certain hormones including prolactin.

• Using the terms “prolactin” and “seizure” in a PubMed search, only 290 articles were found. When limiting dates to publications after the year 2000, 97 articles were found. The initial study was done in 1978, and looked at serum prolactin as a way to separate epileptic seizures from non-epileptic seizures.

Summary of Evidence:

• A prospective study of patients admitted to an epilepsy monitoring unit in 2001 showed serum prolactin level increases above twice the baseline level following a complex partial seizure or a generalized seizure. [1]

• A non-randomized study in 2004 looked at 200 patients who presented to the emergency department with clinical symptoms consistent with possible seizure. 109/200 (54.5%) patients were ultimately diagnosed with a true seizure. Of these patients, 46/109 (42.2%) had elevated prolactin level, and 63/109 (57.8%) had a normal prolactin level. The sensitivity for prolactin in the diagnosis of seizure was 42% with a specificity of 82%, a PPV of 74% and NPV of 54%. Therefore, the utility of prolactin for differentiating true seizure from PNES is limited. [2]

• Another 2004 study found that 26.3% of patients with PNES had prolactin levels >2x normal, while only 17.6% of patients with true seizures had levels >2x normal. This study concluded prolactin was not useful in differentiating PNES from true seizures. [3]

• The American Academy of Neurology completed a systematic review of 41 articles in 2005 where they found prolactin had 60.0% sensitivity in diagnosing generalized tonic-clinic seizures and 46.1% sensitivity in diagnosing complex partial seizures. Additionally, most studies in the literature review found that prolactin is elevated 10-20 minutes after suspected seizure, but returns to baseline after that. They concluded that while serum prolactin can be used as an adjunct to diagnose true seizures, it is limited by the need to get a measurement rapidly after suspected seizure and its poor specificity and sensitivity. [4]

• A paper in 2010 highlighted the limitations of using prolactin in diagnosing a true seizure, including:

• Prolactin cannot differentiate simple partial seizures or absence seizures from non-epileptic seizures.

• Given proposed pathophysiology of prolactin elevation, it is unclear if complex partial seizures that do not involve the temporal lobe would result in an increase in prolactin.

• False negative rates are 10-20% even among patients with tonic-clonic seizures.

• There is no consensus regarding what level of prolactin elevation is significant

• Prolactin level must be drawn 10-20 minutes after suspected seizure, which limits its effectiveness outside that window. [5]

• In 2016, a retrospective study looking at role of prolactin in differentiating PNES vs true seizure looked at 200 patients who presented with suspected seizure. 146/200 patients had PNES. Of those patients, 42/146 had elevated prolactin level, representing a false positive rate of 28.8%. 54/200 patients were diagnosed with a true epileptic seizure. 22/54 had generalized tonic-clonic seizure and 32/54 had complex partial seizures. All 22 patients with generalized tonic-clonic seizures had elevated prolactin levels. 5/32 patients with complex partial seizures did not have an elevated prolactin level (false negative of 15.6%). In conclusion, sensitivity of prolactin level in detecting generalized tonic-clonic seizure was 100%, but it was only 84.4% for, complex partial seizure, Specificity was 71.2%. This study concludes that prolactin is of limited utility in distinguishing true seizure from PNES. [6]

• A 2017 review article concluded that while no laboratory values can prove or disprove a true seizure, prolactin level can differentiate ES and PNES with high specificity and moderate sensitivity, a conclusion which is contrary to that of many other authors. [7]

• A study published in 2017 found that 100% of patients with generalized tonic clonic seizures had elevated prolactin only after presenting within the first hour after symptoms started. When patients presented after 1 hour, 37% had elevated prolactin levels. And when they presented after 5 hours, 14% had elevated prolactin levels. This study concluded that prolactin is very limited in its usefulness in diagnosing true seizures in the setting of delayed presentation. [8]

Recommendations:

• The role of serum prolactin in diagnosing a true seizure versus PNES is limited due to the fact that it must be drawn 10-20 minutes after a seizure in order to have optimal diagnostic utility. For patients with witnessed seizures in the ED and those who present quickly following seizure symptoms, prolactin level may potentially be a useful adjunct in the diagnoses of true seizure.

• For patients presenting >20 minutes after seizure, prolactin levels have high false negative rates. Therefore, it is not recommended to use serum prolactin level when there is a significant delay between symptoms and ED presentation.

• Even when drawn rapidly after sympotoms, prolactin has inadequate sensitivity and specificity to reliably differentiate between PNES and true seizures. EEG video monitoring remains the gold standard in the diagnosis of true seizure.

References:

1. Shah A, Shein N, Fuerst D, et al. Peripheral WBC count and serum prolactin level in various seizure types and non-epileptic events. Epilepsia. November 2011;42(11):1472-1475.

2. Vukmir R. Does serum prolactin indicate the presence of seizure in the emergency department patient? Journal of Neurology. June 2004;251(6):736-739.

3. Shukia G, Bhatia M, Vivekanandhan S, et al. Serum prolactin levels for differentiation of non-epileptic versus true seizures: limited utility. August 2004;5(4):517-521.

4. Chen D, So Y, Fisher R. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. September 2005;65(5):668-675.

5. McCorry D, Cavanna A. New thoughts on first seizure. Clinical Medicine. August 2010;10(4):395-398.

6. Abubakr A, Wambacq I. Diagnostic value of serum prolactin in PNES in the epilepsy monitoring unit. Neurology: Clinical Practice. April 2016;6(2):100.

7. Nass R, Sassen R, Elger C, et al. The role of postictal laboratory blood analyses in the diagnosis and prognosis of seizures. Seizures. April 2017;47(1):51-65.

8. Javali M, Acharya P, Shah S, et al. Role of biomarkers in differentiating new-onset seizures from psychogenic non-epileptic seizures. Journal of Neuroscience in Rural Practice. December 2017;8(4):581-584.