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Re: Use of serum prolactin in diagnosing epileptic seizures: Report of the TTA Subcommittee of the AAN

A recent AAN Practice Parameter concluded that postictal prolactin (PRL) elevation is useful in differentiating generalized tonic-clonic and complex partial seizures from psychogenic nonepileptic seizure. [1] This observation was previously suggested by Trimble. [2] An interesting finding is that serum PRL does not increase during status epilepticus (SE). [3,4] As stated in the parameter, “on the basis of inconsistent studies, no conclusion can be established regarding serum PRL changes following termination of SE.” The purpose of this monograph is to shed light on this paradox and to suggest clues to the pathophysiology and treatment of SE.

Normally, seizures spontaneously stop as the cortical inhibitory mechanisms extinguish the abnormal neuronal electric activity. [5] The postictal EEG slowing, Todd’s paralysis, and postictal psychological depression are examples of manifestations of the cortical inhibition. Various mechanisms have been proposed to contribute to the post-ictal state. [6] One hypothesis is that the cortical activity in SE does not reach the threshold to initiate the shut-off mechanism. Thus the inhibitory process may not be fully activated in SE leading to failure of seizure termination. Because SE often is the first clinical seizure of an epileptic patient it has been proposed that the naïve brain must be trained to harness its built-in antiseizure mechanism. [7]

GABA(A) receptors undergo functional changes during prolonged SE perhaps further compounding the deficiency in cortical inhibition. [8] The longer SE continues the more refractory to treatment it becomes. It is rare that a prolonged seizure is induced during electroconvulsive therapy (ECT), and typically another electric shock at higher or maximum energy levels will terminate the seizure. [9] Can it be that status epilepticus really is “status hypoepilepticus?” This hypothesis may change our view regarding the treatment algorithm for SE that conventionally aims at inhibition of the seizure activity. This is generally achieved by administration of serial anticonvulsants or induction of pharmacological coma or generalized anesthesia that carry a considerable morbidity. [10] Instead, a full generalized seizure using ECT may be able to reach the threshold required for effective cortical depression in refractory SE. [11]

The spread of ictal activity from the hippocampus or amygdala to the hypothalamus can elicit pituitary PRL release. [12,13] Complex partial seizures involving the temporal lobes and high-frequency simple partial seizures involving limbic structures increase PRL release. [14] A study of PRL response to ECT demonstrated that suprathreshold and bilateral stimulations yielded more robust PRL rise than threshold and unilateral stimulations, respectively. [15] According to one study, the shorter the interictal period the smaller the PRL release. [16]

In repetitive or continuous seizures, the postictal PRL release may decrease, and in SE it does not increase. [3] PRL stores may be exhausted and not sufficiently replenished during SE. However, this hypothesis has been refuted by at least two experiments that were able to induce a PRL surge during SE using metoclopramide or TRH as a PRL-releasing factor. [17,18]

Another possible explanation for the decremental PRL release in SE is that the intensity of ictal discharges gradually diminishes during the course of SE. This is supported by the common clinical observation that motor phenomena usually decrease during SE.

References

1. Chen DK, So YT, Fisher RS. Use of serum prolactin in diagnosing epileptic seizures. Neurology 2005;65:668-675.

2. Trimble M. Serum prolactin in epilepsy and hysteria. BMJ 1978;2:1682.

3. Bauer J. Epilepsy and prolactin in adults: a clinical review. Epilepsy Research; 1996;24:1-7.

4. Tomson T, Lindbom U, Nilsson BY, Svanborg E, Anderson DE. Serum prolactin during status epileptics. J Neurol Neurosurg Psychiatry 1989;52:1435-1437.

5. Lowenstein D, Alldredge BK. Status epilepticus. The New England Journal of Medicine 1998; 338:970-976.

6. Fisher RS, Schachter SC. The postictal state: a neglected entity in the management of epilepsy. Epilepsy and Behavior 2000;1:52-59.

7. Niedermeyer E. Epileptic Seizure Disorders. In: Niedermeyer E, Lopes da Silva F. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields, Fifth Edition, Chapter 27. Lippincott Williams & Wilkins, 2005.

8. Lowenstein D, Alldredge BK. Status epilepticus: new concepts. Curr Opin Neurol 1999;12:183-90.

9. Fink M. ECT in Neurology. In: The Psychiatric Times 2001.

10. Anschel D, Fink M. Use of pharmacologic coma for status epilepticus. Epilepsy and Behavior 2005;6:292.

11. Fink M, Kellner C, Sackeim HA. Intractable seizures, status epilepticus, and ECT. J ECT 1999;15:282-284. Letter.

12. Parra A, Velasco M, Cervantes C, Munoz H, Cerbon MA, Velasco F. Plasma prolactin increase following electric stimulation of the amygdala in humans. Neuroendocrinology 1980;31:60-65.

13. Renaud LP. An electrophysiological study of amygdalahypothalamic projections to the ventromedial nucleus of the rat. Brain Res 1976;105:45- 58.

14. Sperling MR, Pritchard PB 3rd, Engel J Jr, Daniel C, Sagel J. Prolactin in partial epilepsy: an indicator of limbic seizures. Ann Neurol 1986;20:716-722.

15. Lisanby SH, Devanand DP, Prudic J, et al. Prolactin response to electroconvulsive therapy: effects of electrode placement and stimulus dosage. Biol Psychiatry 1998;43:143-155.

16. Malcovicz DE. Prolactin secretion following repetitive seizures. Neurology 1995;45:448-452.

17. Lindbom U, Tomson T, Nilsson BY, Anderson DE. Serum prolactin response to metoclopramide during status epilepticus. J Neurol Neurosurg Psychiatry 1992;55:685-687.

18. Lindbom U, Tomson T, Nilsson BY, Anderson DE. Serum prolactin response to thyrotropin-releasing hormone during status epilepticus. Seizure 1993;2:235-239.

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Re: Reply from the authors

We appreciate the interest by Sandstrom and Anschel in our review of the utility of serum prolactin in the diagnosis of seizures. [1] They raise several interesting concepts about status epilepticus but since our paper was focused on prolactin, we will direct our response to the failure of prolactin to increase with status epilepticus.

The detailed time course of serum prolactin changes at multiple time points during status epilepticus is not yet documented in a population of humans. In an animal model produced by microinjection of kainic acid into hippocampus of rat [19], serum prolactin peaked in about 15 minutes, and returned to baseline by about 30 minutes. The authors speculated that the elevated prolactin release might inhibit further prolactin release, but no direct evidence is available to support or refute this mechanism.

One hour of seizures induced by pilocarpine reduce D1 and D2 receptors in rat striatum. [20] It is plausible that dopamine function in the hypothalamic-pituitary axis, which controls prolactin release, might be altered by prolonged seizures. Since prolactin release can be stimulated during the time when it is no longer elevated in the course of status epilepticus [17], we agree with Sandstrom and Anschel that the lower serum prolactin levels during status cannot be explained by exhaustion of prolactin stores.

Prolactin serum assays should not be necessary for the diagnosis of status epilepticus, since a clinical-EEG correlation usually will be more informative. The important message from past literature and the remarks of Sandstrom and Anschel is that status epilepticus should not be considered less likely because serum prolactin is normal.

References

19. Lin YY, Yen SH, Pan JT, Su MS, Wu ZA, Chan SH. Transient elevation in plasma prolactin level in rats with temporal lobe status epilepticus. Neurology. 1999;53:885-7.

20. Nascimento VS, Oliveira AA, Freitas RM, Sousa FC, Vasconcelos SM, Viana GS, Fonteles MM. Pilocarpine-induced status epilepticus: monoamine level, muscarinic and dopaminergic receptors alterations in striatum of young rats. Neurosci Lett. 2005;383:165-70.

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Re: Use of serum prolactin in diagnosing epileptic seizures

The AAN Therapeutics and Technology Assessment Subcommittee recently reported on the use of serum prolactin (PRL) in differentiating epileptic seizures from nonepileptic seizures (NES). [1] The authors addressed two main concerns: whether serum PRL is useful in distinguishing individual epileptic seizures from psychological NES; and whether serum PRL is useful in distinguishing individul epileptic seizures from other paroxysmal neurological conditions.

The diagnosis and treatment of patients with psychological NES has long confounded neurologists, psychiatrists, and emergency department physicians. Currently, no randomized double blind, placebo controlled trial (RCT) has been completed for NES. [2] A common concern with diagnoses in the DSM-IV is that psychiatric diagnoses have no physiological correlates. While aggregate data on depression and anxiety states have revealed alterations in the HPA axis, these findings are not applicable to the diagnosis of those with major depressive disorders or post traumatic stress disorders. NES are the exception to this rule, with diagnosis validated by a physiologic measure - the gold standard, video-EEG, and with adjunctive differentiation from epilepsy using serum PRL assay.

Trimble first showed that generalized tonic clonic seizures (GTC), but not NES, raised serum PRL. [3] Pooling the available data of the ten studies meeting inclusion criteria, the subcommittee authors found a sensitivity of 60% for GTC and 46% for complex partial seizures (CPS), and a specificity of ~ 96% for both. They found a positive predictive value of 93 to 99%.

Cragar et al similarly found lack of PRL elevation has an average 89% sensitivity to psychological NES. [4] Clinically, this translates into a strong confirmation of a diagnosis of epileptic seizures when an elevated PRL is found in patients with GTC or CPS-like events suspected of being NES. The authors concluded that serum PRL rise is probably a useful adjunct to differentiate GTC or CPS from NES.

This report is timely in light of the difficulty in management of patients with NES. Harden found that neurologists and psychiatrists differ significantly in their opinion, with psychiatrists believing video-EEG was inaccurate in NES diagnosis, compared to neurologists. [5]

The committee from the recent NINDS/NIMH/AES sponsored NES Treatment Workshop is preparing a multi-site RCT for NES treatment. The AAN subcommittee's report on PRL as an adjunctive diagnostic measure for seizures bolsters the validity of the video-EEG established NES diagnosis. Hopefully this will increase the confidence of psychiatrists, psychologists, and other providers in treating patients with NES.

References

1. Chen DK, So YT, Fisher RS. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005;65:668-675.

2. LaFrance WC, Jr., Devinsky O. The treatment of nonepileptic seizures: Historical perspectives and future directions. Epilepsia 2004;45(suppl.2):15-21.

3. Trimble MR. Serum prolactin in epilepsy and hysteria. Br Med J 1978;2:1682.

4. Cragar DE, Berry DT, Fakhoury TA, Cibula JE, Schmitt FA. A review of diagnostic techniques in the differential diagnosis of epileptic and nonepileptic seizures. Neuropsychol Rev 2002;12:31-64.

5. Harden CL, Burgut FT, Kanner AM. The diagnostic significance of video- EEG monitoring findings on pseudoseizure patients differs between neurologists and psychiatrists. Epilepsia 2003;44:453-456.

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Re: Reply from authors

We are grateful to Dr. LaFrance for his kind comments about our prolactin therapeutics and technology assessment article. As he points out, it was a critical compendium of prior work, and we prepared it in part because this potentially useful physiological marker has never really “caught on” in clinical practice. Although the test can have excellent specificity and positive predictive value, this is true only in a setting of high suspicion for epileptic generalized tonic-clonic or complex partial seizures, and in the absence of several confounding factors.