Prolactin levels in cerebrospinal fluid of patients with infantile spasms

Prolactin Levels in Cerebrospinal Fluid of Patients With Infantile Spasms Gu¨zide Burc¸a Aydln, MD*, Gu¨ls¸en Ko¨se, MD†, Aydan Deg˘erlı˙yurt, MD†, Necmettin Dı˙n, MD*, Deniz C ¸ amurdanog˘lu, MD‡, and Fatmanur C ¸ akmak, MD* Infantile spasms are an age-related epileptic syndrome of infancy and are characterized by the combination of clusters of epileptic spasms and specific electroencephalographic findings. The etiology and the pathogenesis of the disease is still unclear. Prolactin has been thought to be specifically related to epileptic seizures. To investigate the possible mechanism of prolactin secretion in infantile spasms cerebrospinal fluid prolactin levels were examined. Fifteen patients with infantile spasms (10 females and five males), 3-16 months of age, were evaluated and compared with age- and sex-matched control subject. Cerebrospinal fluid samples for prolactin were obtained before and after treatment. The mean prolactin levels in the cerebrospinal fluid of the patients before therapy (3.25 ⴞ 1.48 ng/mL) was higher than the control group (2.38 ⴞ 0.89 ng/mL), and the difference between the two groups was statistically significant (P < 0.001). The mean prolactin level in the cerebrospinal fluid of the patients after therapy (4.69 ⴞ 1.47 ng/mL) was demonstrated to be higher than the mean prolactin level before therapy (3.25 ⴞ 1.48 ng/mL) and the difference between the two groups was statistically significant (P ⴝ 0.037). Elevation of cerebrospinal fluid prolactin levels before and after treatment in patients with infantile spasms provided evidence that the cerebrospinal fluid prolactin level is related with neuronal injury. © 2002 by Elsevier Science Inc. All rights reserved. Gu¨zide Burc¸a Aydin, Gu¨ls¸en Ko¨se, Aydan Deg˘erliyurt, Necmettin Din, Deniz C ¸ amurdanog˘lu, and Fatmanur C ¸ akmak. Prolactin Levels in Cerebrospinal Fluid of Patients With Infantile Spasms. Pediatr Neurol 2002;27:267-270.

From the SSK Ankara Children’s Hospital; Departments of *Pediatrics and †Pediatric Neurology; and ‡Tunali Laboratories; Ankara, Turkey.

© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(02)00433-2 ● 0887-8994/02/$—see front matter

Introduction Infantile spasms are an age-related epileptic syndrome of infancy characterized by the combination of clusters of epileptic spasms and specific electroencephalography findings. Numerous synonyms for infantile spasms have been used, including salaam attacks, jackknife seizures, and massive myoclonic jerks. Infantile spasms are characterized by brief contractions of the muscles of the neck, trunk, and extremities, usually occurring bilaterally and symmetrically. Prenatal, natal, or postnatal hypoxia is the most frequently evident cause [1-5]. In utero infections, chromosomal abnormalities, cerebral dysgenesis, tuberous sclerosis, and some metabolic disorders can also cause infantile spasms. However, the etiology is unknown for a large percentage of patients (2-58.5%) [2,4,5]. Like the etiology the pathogenesis of the disease remains unclear [1-4]. In some epileptic syndromes, investigators demonstrated significant postictal elevation of some hormones, such as growth hormone, cortisol, and prolactin in serum. Prolactin has been thought to be specifically related to epileptic seizures [6-11]. It has been thought that prolactin levels may provide a useful adjunct in the identification of epileptic seizures [10]. Increased secretion of prolactin in cerebrospinal fluid may play a role in seizure clusters and neuronal dysfunction. To investigate the possible mechanism of prolactin secretion in infantile spasms we examined cerebrospinal fluid prolactin level before and after treatment and compared them with the control group. Patients and Methods Fifteen patients with infantile spasms (10 females and five males), 3-16 months of age, were evaluated. The clinical data are summarized in Table 1. All patients with infantile spasms had typical clinical spasms and electroencephalography changes of hypsarrhythmia or modified hypsarrhythmia. None of the patients had any other type of seizures.

Communications should be addressed to: Dr. Aydin; Angora evleri. Pusula Sok. No: 7 Beysakent 06800; Ankara, Turkey. Received August 23, 2001; accepted April 8, 2002.

Aydin et al: Liquer Prolactin in Infantile Spasms 267

Table 1.

Clinical data of the patients with infantile spasms

Patient Age No. Gender (mo)

Developmental History

History

CT or MRI of the Head

Etiology

1

F

6 1 mo of flexor spasms 8 8 mo of mixed spasms; HIE

Normal

Minimal cerebral atrophy

Cryptogenic

2

F

MMR

Diffuse cerebral atrophy Leukomalacia

Symptomatic (perinatal asphyxia)

3

M

3 10 days of flexor spasms 9 9 mo of mixed spasms; HIE 8 2 mo of flexor spasms 4 3 mo of mixed spasms

MMR

Cerebral atrophy prominent Cryptogenic in left lobe

4

F

MMR

Bilateral frontotemporal atrophy Cerebral atrophy

5

M

6

F

7

M

4 4 mo of flexor spasms

MMR

8

F

5 5 mo of flexor spasms

MMR

9

M

Normal

10

F

11

F

6 20 days of flexor spasms 16 8 mo of flexor spasms 8 8 mo of mixed spasms

12

F

5 2 mo of flexor spasms

MMR

13

F

10 7 mo of flexor spasms

MMR

Cerebral atrophy Subependymal calcification

Symptomatic (tuberosclerosis)

14

M

MMR

Cerebral atrophy

Cryptogenic

15

F

4 1 mo of mixed spasms 5 5 mo of mixed spasms

MMR

Dandy-Walker variant

Symptomatic (DandyWalker variant)

Normal MMR

Outcome

ACTH, B6, valproate Spasms controlled, patient retarded ACTH, B6, Spasms controlled; phenobarbital, patient retarded vigabatrin ACTH, B6 Spasms controlled, patient retarded

ACTH, B6, valproate Spasms controlled, patient retarded ACTH, B6 Spasms controlled, patient retarded Cerebral atrophy Cryptogenic ACTH, B6, Spasms valproate, uncontrolled, phenobarbital patient retarded Corpus callosum dysgenesis Symptomatic (corpus ACTH, B6, Spasms callosum dysgenesis) valproate, uncontrolled, vigabatrin, patient retarded primidone Cerebral atrophy Cryptogenic ACTH, B6, Spasms controlled, valproate, patient retarded clonazepam Normal Idiopatic ACTH, B6 Spasms controlled

MMR (PKU) Cerebral atrophy MMR

Treatment

Symptomatic (perinatal asphyxia) Cryptogenic

Symptomatic (PKU)

Cerebral atrophy, corpus Symptomatic (corpus callosum agenesis, callosum agenesis) ventricular dilatation Subependymal calcification Symptomatic (tuberosclerosis)

ACTH, B6, valproate Spasms controlled, patient retarded ACTH, B6, Spasms controlled, phenobarbital, patient retarded phenytoin ACTH, B6, Spasms controlled, valproate, patient retarded phenobarbital, vigabatrin ACTH, B6, Spasms controlled, valproate, patient retarded phenobarbital, vigabatrin ACTH, B6 Spasms controlled, patient retarded ACTH, B6, Spasms controlled, vigabatrin patient retarded

Abbreviations: HIE ⫽ Hypoxic-ischemic encephalopathy MMR ⫽ Mental and motor retardation PKU ⫽ Phenylketonuria

The etiologic factors associated with infantile spasms were examined on admission for every patient. Medical histories, ophthalmologic and detailed neurologic examination, electroencephalogram, computed tomography, and magnetic resonance imaging of the head, a metabolic screen (complete blood count, blood glucose, electrolytes, liver and renal functions, immune globulins, TORCH antibodies, plasma-urine amino acids, organic acids, cerebrospinal fluid, and blood lactic and pyruvic acids) were performed. Cerebrospinal fluid specimens were obtained twice in patients with infantile spasms (first before therapy, second after the spasms disappeared). All cerebrospinal fluid specimens were frozen and stored at ⫺20°C until they were analyzed. Cerebrospinal fluid prolactin levels were measured by radioimmunoassay method using the Immolate Automated Analyzer and commercially available kits. The control group consisted of 15 age- and sex-matched children who did not have any neurologic disease or seizures. Cerebrospinal fluid

268

PEDIATRIC NEUROLOGY

Vol. 27 No. 4

specimens were obtained from the course of diagnostic evaluation for fever. The specimens were stored and analyzed in the manner as was performed in the patient group. The data were expressed as means ⫾ S.D. Statistical comparison of the data were performed by using Student t test. Statistical significance was determined at the probability level of 0.05.

Results Fifteen patients (10 females and 5 males), 3-16 months of age (mean 6.7 ⫾ 3.3 months) with infantile spasms were evaluated. The clinical data of the patients are summarized in Table 1. The mean age of beginning to

Table 2. Prolactin levels in cerebrospinal fluid of the patients with infantile spasms and control group

Patient No.

Infantile Spasm Before Therapy After Therapy (ng/mL) (ng/mL)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

5.8 2.3 1.71 2.7 4.81 5.52 3.5 2.58 0.95 2.78 4.33 4.61 1.5 2.3 3.5

6 5.48 2.5 4.69 5.8 6 5.52 5.52 1.4 4.81 6 5.8 3.54 2.7 4.69

Control Group (ng/mL) 3.8 1.4 1.4 2.53 2.8 2.6 1.46 3 1.33 1.33 1.73 2.4 3.8 3 3.2

exhibit spasms was 4 ⫾ 2.7 months. Spasms appeared at the first day of life in 2 patients and at 12 months. The mean time course between the onset of spasms and admission to the hospital was 2.6 ⫾ 2.5 months (the shortest time was the same day of beginning the spasms, whereas the longest was 8 months). Cerebrospinal fluid levels of prolactin were measured in 15 patients with infantile spasms before and after therapy and in 15 children in the control group (Table 2). The mean prolactin level in the cerebrospinal fluid of the patients before treatment (3.25 ⫾ 1.48 ng/mL) was higher than the control group (2.38 ⫾ 0.89 ng/mL), and the difference between the two groups was statistically significant (P ⬍ 0.001). The mean prolactin level in the cerebrospinal fluid of the patients after treatment (4.69 ⫾ 1.47 ng/mL) was found to be higher than the mean prolactin level before treatment (3.25 ⫾ 1.48 ng/mL), and the difference between the two groups was statistically significant (P ⫽ 0.037). Discussion Elevated plasma prolactin levels have been documented during and after certain seizure types in adults [8-12] and in children [6,7,11]. The data obtained in these studies indicate that elevation of plasma prolactin is a specific phenomenon related to seizure discharges. The knowledge about the association of prolactin and seizure activity might be considered a tool to distinguish between epileptic and nonepileptic phenomena in patients [10,13]. It is known that prolactin is increased in stress, hypoglycemia, and arousal [14]. Its secretion is inhibited by dopamine and is enhanced by various prolactin-releasing factors. The physiologic significance of prolactin-releasing factors in humans is unknown [15-17]. In animal models, it is demonstrated that electrochemical stimulation of the medial basal hypothalamus increases prolactin

secretion [6,18]. It is thought that abnormal electrical activity may lead to suppression of dopamine thus resulting in a rise in prolactin [19-21]. In addition, this ␤-endorphin concentration is reported to increase rapidly after seizures, and it is also thought that postictal rise in prolactin levels might be opioid mediated [22]. Infantile spasms have an overwhelmingly poor prognosis. In most patients, developmental delay or arrest is observed at the beginning of disease, and in the remaining patients, it usually develops soon after the onset [1-4]. The pathogenesis of infantile spasms and the development of mental retardation remain unclear. Several neurotransmitters (including serotonin, amino acids, monoamine metabolites, neuron-specific enolase, and ␥-aminobutyric acid) and hormones (including cortisol and growth hormone) are considered to have a role in the pathogenesis [9,20,23-28]. As yet no biochemical factor has been identified as the cause of the spasms and neuronal dysfunction in these patients. In the present study, elevation of prolactin levels in cerebrospinal fluid were demonstrated in newly diagnosed patients with infantile spasms. The mean prolactin levels in cerebrospinal fluid were elevated in the patients with infantile spasms, compared with the control group. Results also provide evidence for an increase of cerebrospinal fluid prolactin levels despite treatment. Prolactin levels in cerebrospinal fluid were still higher after treatment, suggesting that neuronal dysfunction process is ongoing. In our study, one patient (Patient 9) was classified into an idiopathic group. The interesting finding in this patient was the lower prolactin values than those of the other patients at diagnosis and after therapy. He was followed until 6 years of age, and his mental development was excellent. His prolactin values also support the relationship between high prolactin values and neuronal dysfunction. Prolactin levels in cerebrospinal fluid might have a direct relationship with the degree of neurodevelopmental status. Prolactin seems to have an important role in the pathogenesis of infantile spasms. Whether hormonal discharges occur in response to stimulation of specific neurogenic pathways remains unknown. These pathways might also be responsible for clusters of spasms that are described in infantile spasms and neuronal dysfunction. Cerebrospinal fluid prolactin values may help in differentiating idiopathic infantile spasms from the cryptogenic form. These values may also allow us to predict mental status at the time of diagnosis. In a search of the literature, we could not find any study about changes in prolactin values in cerebrospinal fluid of patients with infantile spasms. Additional studies comparing patients with idiopathic and cryptogenic spasms are required to elucidate the physiopathogenesis of infantile spasms. Our special thanks are given to Sag˘ lık-I˙s¸ Tade Union for their contribution to laboratory research.

Aydin et al: Liquer Prolactin in Infantile Spasms 269

References [1] Hrachovy RA, Frost JD. Infantile spasms. Ped Clin North Am 1989;36:311-29. [2] Cowan LD, Hudson LS. The epidemiology and natural history of infantile spasms. J Child Neurol 1991;6:355-64. [3] Lombroso CT. A prospective study of infantile spasms: Clinical and therapeutic correlations. Epilepsia 1983;24:135-58. [4] Hrachovy RA, Frost JD, Kellaway P. Hypsarrhytmia. Variations on the theme. Epilepsia 1984;25:317-25. [5] Wong M, Trevathan E. Infantile spasms. Pediatr Neurol 2001; 24:89-98. [6] Bye AME, Nunn KP, Wilson J. Prolactin and seizure activity. Arch Dis Child 1985;60:848-51. [7] Zelnik N, Kahana L, Rafael A, Besner I, Iancu TC. Prolactin and cortisol levels in various paroxysmal disorders in childhood. Pediatrics 1991;88:486-89. [8] Sperling MR, Pritchard PB, Engel JJ, Daniel CBS, Sagel J. Prolactin in partial epilepsy: An indicator of limbic seizures. Ann Neurol 1986;20:716-21. [9] Culebras A, Miller M, Bertram L, Koch J. Differential response of growth hormone, cortisol and prolactin to seizures and to stress. Epilepsia 1987;28:564-70. [10] Pritchard PB, Wannamaker BB, Sagel J, Daniel CM. Serum prolactin and cortisol levels in evaluation of pseudoepileptic seizures. Ann Neurol 1985;18:87-89. [11] Molaie M, Culebras A, Miller M. Nocturnal plasma prolactin and cortisol levels in epileptics with complex partial seizures and primary generalized seizures. Arch Neurol 1987;44:699-702. [12] Rao ML, Stefan H, Bauer J. Epileptic but not psychogenic seizures are accompanied by simultaneous elevation of serum pituitary hormones and cortisol levels. Neuroendocrinology 1989;49:33-39. ¨ , C¸ evik N. Serum cortisol and prolactin [13] Dirik E, S¸ en A, Anal O in childhood paroxysmal disorders. Acta Paediatr Jpn 1996;38:118-120. [14] Noel GL, Suh HK, Stone JG, Franz AG. Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab 1972;35:840-51. [15] Lam KS, Lechan RM, Minamitani N, Segerson TP, Reichlin S. Vasoactive intestinal peptide in the anterior pituitary is increased in hypothyroidism. Endocrinology 1989;124:1077-84.

270

PEDIATRIC NEUROLOGY

Vol. 27 No. 4

[16] Nagy G, Mulchahey JJ, Neill JD. Autocrine control of prolactin secretion by vasoactive intestinal peptide. Endocrinology 1988;122:36466. [17] Hagen TC, Arnaut MA, Scherzer WJ, Martinson DR, Garthwaile TL. Antisera to vasoactive intestinal polypeptide inhibit basal prolactin release from dispersed anterior pituitary cells. Neuroendocrinology 1986;43:641-45. [18] Clemens JA, Shaar CJ, Kleber JW, Tandy WA. Reciprocal control by the preoptic area of LH and prolactin. Exp Brain Res 1971;12:250-3. [19] Thorner MO, Logis IS. Prolactin secretions as an index of brain dopaminergic function. Adv Biochem Psychopharmacol 1981;28:50320. [20] Dana-Haeri J, Trimble MR, Oxley J. Prolactin and gonodotropin changes following generalized and partial seizures. J Neurol Neurosurg Psychiatry 1983;46:331-5. [21] O’Dea JPK, Gould D, Hallberg M, Weiland RG. Prolactin changes during electroconvulsive therapy. Am J Psychiatry 1978;135: 609-11. [22] Aminouf MJ, Simon RP, Wiedemann E. The hormonal responses to generalized tonic-clonic seizures. Brain 1984;107:569-78. [23] Langlais PJ, Wardlow ML, Yamamoto H. Changes in CSF neurotransmitters in the infantile spasms. Pediatr Neurol 1991;7:440-5. [24] Ince E, Karago¨ l U, Deda G. Excitatory amino acid levels in CSF of patients with infantile spasms. Acta Paediatr 1997;86:1333-6. [25] Airaksinen E, Tuomisto L, Riikonen R. The concentrations of GABA, 5-HIAA and HVA in the cerebrospinal fluid of children with infantile spasms and the effects of ACTH therapy. Brain Dev 1992;14: 386-90. [26] Silverstein F, Johnston MV. Cerebrospinal fluid monoamine metabolites in patients with infantile spasms. Neurology 1984;34:102-5. [27] Suzuki Y, Toribe Y, Goto M, Kato T, Futagi Y. Serum and CSF neuron-specific enolase in patients with west syndrome. Neurology 1999;53:1761-64. [28] Siemens H, Rating D, Hanefeld F. Infantile spasms: CSF proteins before and during treatment with ACTH. Dev Med Child Neurol 1981;23:384-6.