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Epilepsy in patients with pineal gland cyst
Clinical Neurology and Neurosurgery 165 (2018) 72–75
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Epilepsy in patients with pineal gland cyst a,⁎
b
T a
a
a
Jelena Bosnjak , Silva Soldo Butkovic , Snjezana Miskov , Lejla Coric , Ana Jadrijevic-Tomas , Vlatka Mejaski-Bosnjakc a b c
Department of Neurology, University Hospital, Sestre milosrdnice, Zagreb, Croatia Department of Neurology, University Hospital Osijek, School of Medicine, University of Osijek, Osijek, Croatia Department of Neuropediatrics, Children’s Hospital, School of Medicine, University of Zagreb, Zagreb, Croatia
A R T I C L E I N F O
A B S T R A C T
Keywords: Pineal gland cyst Pineal region Epilepsy Epileptic seizures
Objective: The aim of the study is to describe types of epileptic seizures in patients with pineal gland cyst (PGC) and their outcome during follow up period (6–10 years). We wanted to determine whether patients with epilepsy differ in PGC volume and compression of the PGC on surrounding brain structures compared to patients with PGC, without epilepsy. Patients and methods: We analyzed prospectivelly 92 patients with PGC detected on magnetic resonance (MR) of the brain due to various neurological symptoms during the period 2006–2010. Data on described compression of the PGC on surrounding brain structures and size of the PGC were collected. Results: 29 patients (16 women, 13 men), mean age 21.17 years had epilepsy and PGC (epilepsy group). 63 patients (44 women, 19 men), mean age 26.97 years had PGC without epilepsy (control group). Complex partial seizures were present in 8 patients, complex partial seizures with secondary generalization in 8 patients, generalized tonic clonic seizures (GTCS) in 10 and absance seizures in 3 patients. Mean PGC volume in epilepsy group was 855.93 mm3, in control group 651.59 mm3. There was no statistically significant difference between epilepsy and control group in PGC volume. Compression of PGC on surrounding brain structures was found in 3/ 29 patients (10.34%) in epilepsy group and in 11/63 patients (17.46%) in control group with no statistically significant difference between epilepsy and control group. All patients with epilepsy were put on antiepileptic therapy (AET). During the follow up period, 23 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, whereas 3 patients had no improvement in seizure frequency. Two patients from epilepsy group and 3 patients from control group were operated with histologically confirmed diagnosis of PGC in 4, and pinealocytoma in 1 patient. Conclusions: In patients with PGC, epileptic seizures were classified as: complex partial seizures (with or without secondary generalization), GTCS and absance seizures. All patients were put on AET. During follow up period 79.31% patients were seizure free. There was no difference in PGC volume, nor in described compression of the PGC on surrounding brain structures between epilepsy and control group. Based on our findings, pathomechanism of epileptic seizures in patients with PGC cannot be attributable solely to PGC volume or described compression on surrounding brain structures based on MRI findings.
1. Introduction Pineal gland cysts (PGC) occur in all ages, from the fetal period to senility, with predominance in adults in the fourth decade of life, mainly in women. Symptomatic PGC are most frequent in young women [1]. The incidence of PGC is up to 23% in healthy patients volunteering in imaging studies and up to 40% of cases in autopsy series [2]. A degenerative process in the gland has been suggested to be the origin of the cyst [3]. The diagnosis of PGC is usually established by magnetic resonance (MR) of the brain. Although there are radiological
⁎
criteria which define benign PGC from the tumors of this area, pathohystological analysis is the endpoint in the final diagnosis [1]. Usually PGC have no clinical implications and remain asymptomatic for years [1]. The most common symptoms are: headache of variable intensity, vertigo, visual and oculomotor disturbances and obstructive hydrocephalus [4–7]. Less frequently patients present with: ataxia [8], motor and sensory impairment [9], mental and emotional disturbances [7,10], circadian rhythm disturbances [7,11], hypothalamic disfunction of precocious puberty [7,12], secondary parkinsonism [13] and epilepsy [1,14–16]. A relationship between PGC size and appearance of the
Corresponding author. Present address: Polyclinic Medikol, Vocarska cesta 106, 10000 Zagreb, Croatia. E-mail address: [email protected] (J. Bosnjak).
https://doi.org/10.1016/j.clineuro.2017.12.025 Received 16 May 2017; Received in revised form 6 September 2017; Accepted 28 December 2017 Available online 04 January 2018 0303-8467/ © 2018 Elsevier B.V. All rights reserved.
Clinical Neurology and Neurosurgery 165 (2018) 72–75
J. Bosnjak et al.
2.2. Data collection
symptoms is generally postulated, but in many cases may be irrelevant [17]. The appearance of clinical symptoms is attributable to: rapid enlargement of PGC, rapid coalescence of pre-existing smaller cavities, increase of the fluid pressure gradient between the third ventricle and cyst cavity or direct inflow of the cerebrospinal fluid (CSF) to the PGC due to communication of the cyst with the third ventricle [1]. Possible complications related to PGC are: bleeding to the cyst lumen [18], development of papilloma of the choroid plexus [19], rapid rupture of the cyst with resulting aseptic cerebrospinal meningitis [20] or even sudden death [21]. Authors suggest observation of the PGC for many years [1]. The aim of this study is to describe types of epileptic seizures in patients with PGC and their outcome during follow up. We also wanted to determine whether patients with epilepsy differ in PGC volume and compression of the PGC on surrounding brain structures compared to patients with PGC, without epilepsy.
We collected data on described compression of the PGC on surrounding brain structures and size of the PGC on MR of the brain, measured in three dimensions (anteroposterior-AP; laterolateral-LL and craniocaudal-CC). The size of the PGC was expressed as volume AP × LL × CC in mm3. An electroencephalography (EEG) was done to all the patients with PGC and epilepsy according to standard protocol. Epileptic seizures were classified in accordance with the WHO's Epilepsy Dictionary and the WHO Commission on Classification and Terminology [22]. Informed consent was obtained from all patients or their parents/tutors if the patient was < 18 years old. Authorization was received from the Hospital's Ethical Committee, in accordance with the Helsinki Declaration. 2.3. Statistical analysis Kolmogorov-Smirnov test was used to asses normal distribution of variables (age and gender). Fisher's Exact test was used to compare existence of compression of the PGC on surrounding brain structures between epilepsy and control group. Kruskal-Wallis test was used to determine difference in PGC volume between epilepsy and control group. The statistical significance was taken at the level p < 0.05. SAS Entreprise Guide statistical Software Version 7.1. licensed to HZJZ (Croatian Institute for Public Health) was used for statistical analysis.
2. Patients and methods 2.1. General clinical data We examined 92 patients with PGC with no systemic disorders or other pathological changes described on MR of the brain. Patients had no history of head trauma, developmental delay, central nervous system infection, family hystory of seizures, alcohol or drug abuse. Patients were collected consecutivelly in Neuropediatric out-patient clinic (Department of Neuropediatrics, Children’s Hospital, School of Medicine, University of Zagreb, Croatia) and Neurology outpatient clinic (Department of Neurology, University Hospital, Sestre milosrdnice, Zagreb, Croatia) during the period 2006–2010. They were sent to MR of the brain due to headache, vertigo, visual disturbances, sensory symptoms, sleep disturbances, emotial disturbances and epilepsy as presenting symptom (Table 1). Mean duration of epilepsy was 5 months. Some of the patients were admitted to emergency room with first epileptic seizure, while the longest history of epileptic seizures was 4 years. During the follow up period (6–10 years) all the patients underwent MR in 6 months to 1 year, or depending on neurosurgical assessment.
3. Results 29 patients, mean age 21.17 ± 11.50 years (16 women, mean age 23.69 ± 11.20, 13 men, mean age 18.08 ± 11.54 years) had epilepsy and PGC (epilepsy group). 63 patients, mean age 26.97 ± 17.69 years (44 women, mean age 26.16 ± 16.42, 19 men, mean age 28.84 ± 20.69 years) had PGC without epilepsy (control group). Statistically, these two groups did not differ in age and gender. Types of epileptic seizures were: complex partial seizures in 8 patients, complex partial seizures with secondary generalization in 8 patients, GTCS in 10 and absance seizures in 3 patients. Mean volume of the PGC in epilepsy group was 855.93 ± 1080.70 mm3, in control group 651.59 ± 1011.10 mm3. There was no statistically significant difference between epilepsy and control group in PGC volume (χ2 = 1.3264, df = 1, p = 0.2494). Compression of the PGC on surrounding brain structures was found in 3/29 patients (10.34%) in epilepsy group and in 11/63 patients (17.46%) in control group (Fig. 1). We found no
Table 1 Patient data.
Sex
Epilepsy group (N = 29)
Control group (N = 63)
Male Female
13 16
19 44
Age (years) Symptoms
Pineal gland cyst volume
Compression on surrounding structures
21.17 ± 11.50
26.97 ± 17.69
Headache Epilepsy Vertigo Visual disturbances Parinaud's syndrome Sensory Emotional disturbances Obstructive hydrocephalus Sleep disturbances
15 29 5 3 0
57 0 18 9 2
0 0
2 1
0
1
1
1
0-100 mm3 101-600 mm3 601-2000 mm3 > 2000 mm3 Kruskal-Wallis test
7 9 9 4 p = 0.2494
20 24 14 5
3 p = 0.5360
11
Fisher's Exact test
Fig. 1. Pineal gland cyst with compression on superior colliculi in 18 year old male - MRI sagittal T2 image.
73
Clinical Neurology and Neurosurgery 165 (2018) 72–75
J. Bosnjak et al.
et al have found signs of disturbance of the CSF flow through the cerebral aqueduct with the presence of gliosis (areas of elevated signal level in vicinity of cerebral aqueduct) in about 50% of the cases [1]. In epidermoid cyst case study, mild to moderate hydrocephalus was present in all 24 patients. Perilesional edema was not identified in any case [23]. During the follow up period, 23/29 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, whereas 3 patients (13.04%) had no improvement in seizure frequency. One operated patient with PGC is seizure free, and another patient with pinealocytoma has refractory epilepsy. Other studies report partial to complete recovery of the symptoms after operation [1,14,16,23]. Current literature lists epilepsy as one of the symptoms of PCG. Based on our findings, except in cases of decribed hydrocephalus, acute intracystic haemorrhage or rupture of the cyst, pathomechanism of seizures cannot be solely attributable to PGC volume or described compression of the PGC on surrounding brain structures on MRI. Another possible pathomechanism of seizures in patients with PGC could be decreased levels of melatonin, sythesized by pinealocytes. Anticonvulsant properties of melatonin are attributable to its antioxydant activity, increase of brain GABA concentration, inhibition of calcium influx into neurons, and decreased neuronal nitric oxide generation [24]. The study by Jain S et al. did the literature search and revealed 26 papers reporting association between melatonin and epilepsy or seizures and concluded that in the majority of cases, melatonin might improve seizure control, but, in some cases, deterioration of seizures has been reported [25]. Mandera et al. found normal or slightly depressed melatonin levels in all analyzed children with PGC, while patients with pineocytomas had increase of melatonin secretion at night [1]. We did not measure the level of melatonin in our patients which is the limitation of our study and therefore emphasize the need for further research.
statistically significant difference between epilepsy and control group in described compression of the PGC on surrounding brain structures on MR of the brain (Fisher's exact Test, p = 0.5360) (Table 1). In 19/29 patients with epilepsy, EEG showed: focal spikes, biphasic spikes, spike and wave complex or diffuse paroxysmal discharges of spike and wave complex 3 Hz or more, while remaining 10/29 patients had nonspecific changes: focal slowing and dysrrhytmic changes. Two patients from epilepsy group and 3 from control group were operated due to the cyst volume, Parinaud syndrome, obstructive hydrocephalus or PGC enlargement on follow-up, with histologically confirmed diagnosis of PGC in 4 patients, and pinealocytoma in 1 patient. Other patients did not have significant enlargement of the PGC on follow-up MR of the brain. All the patient with epilepsy were put on antiepileptic therapy (AET) (valproate, carbamazepine, oxcarbazepine, lamotrigine, topiramate, levetiracetam) (mono or polytherapy) and were regularly controlled. During the follow up period 23/29 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, whereas 3 patients (13.04%) had no improvement in seizure frequency. One operated patient with hystologically confirmed PGC is seizure free, and another patient with pinealocytoma has refractory epilepsy. 4. Discussion In our group of patients with PGC, 29 out of 92 patients had epilepsy. Types of epileptic seizures were: complex partial with or without secondary generalization, GTCS and absance seizures. Comparing epilepsy and control group, we did not find any statistically significant difference in the volume of the PGC, nor in described compression of the PGC on surrounding brain structures on MRI of the brain. Most of the patients were collected in epilepsy neuropediatrics and neurology outpatient clinic, therefore the prevalence of epilepsy in patients with PGC in our study is markedly high. Epilepsy is listed as one of the symptom of the PGC in several studies [1,14–16]. Mandera M et al. presented 24 patients with PGC, two of them with epilepsy, but without description of epileptic seizure types [1]. Of two case reports from the literature, one patient had seizure as a manifestation of pineal gland intracystic haemorrhage [14] and another patient with PGC and cavum septi pellucidi had reflex epilepsy induced by hot water bathing. Seizures were described as complex partial followed by generalized tonic seizures [15]. One larger retrospective study [16] on 84 patients described GTCS in 8/32, absance in 10/32, myoclonisms in 8/32 and combination of all three seizure types in 6/32 patients with PGC. The authors did not include the volume of the PGC, but pointed that 70/82 patients were operated, based on the size of the cyst (> 15 mm or more), with the signs of compression of the quadrigeminal plate and surrounding veins. In the retrospective study of 24 patients with pineal epidermoid cysts, another type of benign tumor in the pineal region, three patients had generalized convulsions as presenting symptom [23]. In 19/29 patients with epilepsy, EEG showed: focal spikes, biphasic spikes, spike and wave complex or diffuse paroxysmal discharges of spike and wave complex 3 Hz or more. In study by Hajnsek et al., EEG showed diffuse paroxysmal discharges of spike and wave complex 3 Hz or more [16]. In former studies, epilepsy was explained in several theories: 1. compressive effect of the PGC on quadrigeminal plate and aqueduct of the midbrain, 2. compression of surrounding veins (vermian vein, internal cerebral vein, basal veins of Rosenthal and the great cerebral vein) due to cyst size which affects normal perfusion and result in EEG changes, 3. changes in melatonin levels and 4. hemosiderine deposits in the cyst. According to our results, volume of the PGC, nor described compression on surrounding brain structures based on MR findings, cannot explain by itself the occurence of epileptic seizures in patients with PGC [16]. In our study one patient had described hydrocephalus. Mandera
5. Conclusion Epilepsy was presenting symptom in 29 out of 92 patients with PGC. Epileptic seizures in patients with PGC were classified as: complex partial seizures (with or without secondary generalization), GTCS and absance seizures. There was no difference in PGC volume between patients in epilepsy and control group. There was no difference in described compression of the PGC on the surrounding brain structures between epilepsy and control group. During the follow up period 23 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, 3 patients (13.04%) had no improvement in seizure frequency. Two patients from epilepsy group and 3 from control group were operated with histologically confirmed diagnosis of PGC in 3 patients, and pinealocytoma in 1 patient. Based on our findings, pathomechanism of epileptic seizures in patients with PGC cannot be attributable solely to PGC volume or described compression on surrounding brain structures on MRI. Conflict of interest The authors declare no conflict of interest. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement The authors would like to thank Ivan Pristas, MD, PhD for his assistance in data interpretation. 74
Clinical Neurology and Neurosurgery 165 (2018) 72–75
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References
[13] J.T. Morgan, A.J. Scumpia, T.M. Webster, M.A. Mittler, M. Edelman, S.J. Schneider, Resting tremor secondary to a pineal cyst: case report and review of the literature, Pediatr. Neurosurg. 44 (2008) 234–238. [14] R. Mehrzad, S. Mishra, A. Feinstein, M.G. Ho, A new identified complication of intracystic hemorrhage in a large pineal gland cyst, Clin. Imaging 38 (4) (2014) 515–517. [15] Y. Tajima, N. Minami, K. Sudo, F. Moriwaka, K. Tashiro, Hot water epilepsy with pineal cyst and cavum septi pellucidi, Jpn. J. Psychiatry Neurol. 47 (1) (1993) 111–114. [16] S. Hajnsek, J. Paladino, Z.P. Gadze, S. Nanković, G. Mrak, V. Lupret, Clinical and neurophysiological changes in patients with pineal region expansions, Coll. Antropol. 37 (1) (2013) 35–40. [17] A.C. Mamourian, J. Towfighi, Pineal cysts: MR imaging, Am. J. Neuroradiol. 7 (1986) 1081–1086. [18] K.K. Mukherjee, D. Banerji, R. Sharma, Pineal cyst presenting with intracystic and subarachnoid haemorrhage: report of a case and review of the literature, Br. J. Neurosurg. 13 (2) (1999) 189–192. [19] D.A. Steven, G.J. McGinn, B.M. McClarty, A choroid plexus papilloma arising from an incidental pineal cyst, AJNR Am. J. Neuroradiol. 17 (5) (1996) 939–942. [20] J. Kitayama, K. Toyoda, K. Fujii, S. Ibayashi, H. Sugimori, S. Sadoshima, M. Fujishima, Recurrent aseptic meningitis caused by rupture of a pineal cyst, No To Shinkei 48 (12) (1996) 1147–1150. [21] C.M. Milroy, C.L. Smith, Sudden death due to a glial cyst of the pineal gland, J. Clin. Pathol. 49 (1996) 267–269. [22] Commission on classification and terminology of the international league against epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures, Epilepsia 22 (1981) 489–501. [23] K.I. Desai, T.D. Nadkarni, S.C. Fattepurkar, A.H. Goel, Pineal epidermoid cysts: a study of 24 cases, Surg. Neurol. 65 (2) (2006) 124–129. [24] H. Goldberg-Stern, H. Oren, N. Peled, B.Z. Garty, Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study, J. Child Neurol. 27 (12) (2012) 1524–1528. [25] S. Jain, F.M. Besag, Does melatonin affect epileptic seizures? Drug Saf. 36 (4) (2013) 207–215.
[1] M. Mandera, W. Marcol, G. Bierzynska-Macyszyn, E. Kluczewska, Pineal cysts in childhood, Childs Nerv. Syst. 19 (2003) 750–755. [2] Y. Pu, S. Mahankali, J. Hou, J. Li, J.L. Lancaster, J.H. Gao, D.E. Appelbaum, P.T. Fox, High prevalence of pineal cysts in healthy adults demonstrated by highresolution, noncontrast brain MR imaging, AJNR Am. J. Neuroradiol. 28 (9) (2007) 1706–1709. [3] A.J. Patel, G.N. Fuller, D.M. Wildrick, R. Sawaya, Pineal cyst apoplexy: case report and review of the literature, Neurosurgery 57 (5) (2005) E1066. [4] A. Taraszewska, E. Matyja, W. Koszewski, A. Zaczynski, K. Bardadin, Z. Czernicki, Asymptomatic and symptomatic glial cysts of the pineal gland, Folia Neuropathol. 46 (2008) 186–195. [5] G. Michielsen, Y. Benoit, E. Baert, F. Meire, J. Caemaert, Symptomatic pineal cysts: clinical manifestations and management, Acta Neurochirurgica (Wien) 144 (2002) 233–242. [6] J. Bosnjak, M. Budisic, D. Azman, M. Strineka, M. Crnjakovic, V. Demarin, Pineal gland cysts-an overview, Acta Clin. Croat. 48 (2009) 355–358. [7] C. Rousselle, V. des Portes, P. Berlier, C. Mottolese, Pineal region tumors: clinical symptoms and syndromes, Neurochirurgie 61 (2-3) (2015) 106–112. [8] J.S. Fain, F.H. Tomlinson, B.W. Scheithauer, J.E. Parisi, G.P. Fletcher, P.J. Kelly, G.M. Miller, Symptomatic glial cysts of the pineal gland, J. Neurosurg. 80 (1994) 454–460. [9] H. Mena, R.A. Armonda, J.L. Ribas, S.L. Ondra, E.J. Rushing, Nonneoplastic pineal cysts: a clinicopathologic study of twenty-one cases, Ann. Diagn. Pathol. 1 (1997) 11–18. [10] N. Tamaki, K. Shirataki, T.K. Lin, M. Masumura, S. Katayama, S. Matsumoto, Cysts of the pineal gland. A new clinical entity to be distinguished from tumors of the pineal region, Childs Nerv. Syst. 5 (1989) 172–176. [11] U. Engel, S. Gottschalk, L. Niehaus, R. Lehmann, C. May, S. Vogel, W. Jänisch, Cystic lesions of the pineal region-MRI and pathology, Neuroradiology 42 (2000) 399–402. [12] R.D. Dickerman, Q.E. Stevens, J.A. Steide, S.J. Schneider, Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis? Neuro Endocrinol. Lett. 25 (2004) 173–175.
75
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Epilepsy in patients with pineal gland cyst a,⁎
b
T a
a
a
Jelena Bosnjak , Silva Soldo Butkovic , Snjezana Miskov , Lejla Coric , Ana Jadrijevic-Tomas , Vlatka Mejaski-Bosnjakc a b c
Department of Neurology, University Hospital, Sestre milosrdnice, Zagreb, Croatia Department of Neurology, University Hospital Osijek, School of Medicine, University of Osijek, Osijek, Croatia Department of Neuropediatrics, Children’s Hospital, School of Medicine, University of Zagreb, Zagreb, Croatia
A R T I C L E I N F O
A B S T R A C T
Keywords: Pineal gland cyst Pineal region Epilepsy Epileptic seizures
Objective: The aim of the study is to describe types of epileptic seizures in patients with pineal gland cyst (PGC) and their outcome during follow up period (6–10 years). We wanted to determine whether patients with epilepsy differ in PGC volume and compression of the PGC on surrounding brain structures compared to patients with PGC, without epilepsy. Patients and methods: We analyzed prospectivelly 92 patients with PGC detected on magnetic resonance (MR) of the brain due to various neurological symptoms during the period 2006–2010. Data on described compression of the PGC on surrounding brain structures and size of the PGC were collected. Results: 29 patients (16 women, 13 men), mean age 21.17 years had epilepsy and PGC (epilepsy group). 63 patients (44 women, 19 men), mean age 26.97 years had PGC without epilepsy (control group). Complex partial seizures were present in 8 patients, complex partial seizures with secondary generalization in 8 patients, generalized tonic clonic seizures (GTCS) in 10 and absance seizures in 3 patients. Mean PGC volume in epilepsy group was 855.93 mm3, in control group 651.59 mm3. There was no statistically significant difference between epilepsy and control group in PGC volume. Compression of PGC on surrounding brain structures was found in 3/ 29 patients (10.34%) in epilepsy group and in 11/63 patients (17.46%) in control group with no statistically significant difference between epilepsy and control group. All patients with epilepsy were put on antiepileptic therapy (AET). During the follow up period, 23 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, whereas 3 patients had no improvement in seizure frequency. Two patients from epilepsy group and 3 patients from control group were operated with histologically confirmed diagnosis of PGC in 4, and pinealocytoma in 1 patient. Conclusions: In patients with PGC, epileptic seizures were classified as: complex partial seizures (with or without secondary generalization), GTCS and absance seizures. All patients were put on AET. During follow up period 79.31% patients were seizure free. There was no difference in PGC volume, nor in described compression of the PGC on surrounding brain structures between epilepsy and control group. Based on our findings, pathomechanism of epileptic seizures in patients with PGC cannot be attributable solely to PGC volume or described compression on surrounding brain structures based on MRI findings.
1. Introduction Pineal gland cysts (PGC) occur in all ages, from the fetal period to senility, with predominance in adults in the fourth decade of life, mainly in women. Symptomatic PGC are most frequent in young women [1]. The incidence of PGC is up to 23% in healthy patients volunteering in imaging studies and up to 40% of cases in autopsy series [2]. A degenerative process in the gland has been suggested to be the origin of the cyst [3]. The diagnosis of PGC is usually established by magnetic resonance (MR) of the brain. Although there are radiological
⁎
criteria which define benign PGC from the tumors of this area, pathohystological analysis is the endpoint in the final diagnosis [1]. Usually PGC have no clinical implications and remain asymptomatic for years [1]. The most common symptoms are: headache of variable intensity, vertigo, visual and oculomotor disturbances and obstructive hydrocephalus [4–7]. Less frequently patients present with: ataxia [8], motor and sensory impairment [9], mental and emotional disturbances [7,10], circadian rhythm disturbances [7,11], hypothalamic disfunction of precocious puberty [7,12], secondary parkinsonism [13] and epilepsy [1,14–16]. A relationship between PGC size and appearance of the
Corresponding author. Present address: Polyclinic Medikol, Vocarska cesta 106, 10000 Zagreb, Croatia. E-mail address: [email protected] (J. Bosnjak).
https://doi.org/10.1016/j.clineuro.2017.12.025 Received 16 May 2017; Received in revised form 6 September 2017; Accepted 28 December 2017 Available online 04 January 2018 0303-8467/ © 2018 Elsevier B.V. All rights reserved.
Clinical Neurology and Neurosurgery 165 (2018) 72–75
J. Bosnjak et al.
2.2. Data collection
symptoms is generally postulated, but in many cases may be irrelevant [17]. The appearance of clinical symptoms is attributable to: rapid enlargement of PGC, rapid coalescence of pre-existing smaller cavities, increase of the fluid pressure gradient between the third ventricle and cyst cavity or direct inflow of the cerebrospinal fluid (CSF) to the PGC due to communication of the cyst with the third ventricle [1]. Possible complications related to PGC are: bleeding to the cyst lumen [18], development of papilloma of the choroid plexus [19], rapid rupture of the cyst with resulting aseptic cerebrospinal meningitis [20] or even sudden death [21]. Authors suggest observation of the PGC for many years [1]. The aim of this study is to describe types of epileptic seizures in patients with PGC and their outcome during follow up. We also wanted to determine whether patients with epilepsy differ in PGC volume and compression of the PGC on surrounding brain structures compared to patients with PGC, without epilepsy.
We collected data on described compression of the PGC on surrounding brain structures and size of the PGC on MR of the brain, measured in three dimensions (anteroposterior-AP; laterolateral-LL and craniocaudal-CC). The size of the PGC was expressed as volume AP × LL × CC in mm3. An electroencephalography (EEG) was done to all the patients with PGC and epilepsy according to standard protocol. Epileptic seizures were classified in accordance with the WHO's Epilepsy Dictionary and the WHO Commission on Classification and Terminology [22]. Informed consent was obtained from all patients or their parents/tutors if the patient was < 18 years old. Authorization was received from the Hospital's Ethical Committee, in accordance with the Helsinki Declaration. 2.3. Statistical analysis Kolmogorov-Smirnov test was used to asses normal distribution of variables (age and gender). Fisher's Exact test was used to compare existence of compression of the PGC on surrounding brain structures between epilepsy and control group. Kruskal-Wallis test was used to determine difference in PGC volume between epilepsy and control group. The statistical significance was taken at the level p < 0.05. SAS Entreprise Guide statistical Software Version 7.1. licensed to HZJZ (Croatian Institute for Public Health) was used for statistical analysis.
2. Patients and methods 2.1. General clinical data We examined 92 patients with PGC with no systemic disorders or other pathological changes described on MR of the brain. Patients had no history of head trauma, developmental delay, central nervous system infection, family hystory of seizures, alcohol or drug abuse. Patients were collected consecutivelly in Neuropediatric out-patient clinic (Department of Neuropediatrics, Children’s Hospital, School of Medicine, University of Zagreb, Croatia) and Neurology outpatient clinic (Department of Neurology, University Hospital, Sestre milosrdnice, Zagreb, Croatia) during the period 2006–2010. They were sent to MR of the brain due to headache, vertigo, visual disturbances, sensory symptoms, sleep disturbances, emotial disturbances and epilepsy as presenting symptom (Table 1). Mean duration of epilepsy was 5 months. Some of the patients were admitted to emergency room with first epileptic seizure, while the longest history of epileptic seizures was 4 years. During the follow up period (6–10 years) all the patients underwent MR in 6 months to 1 year, or depending on neurosurgical assessment.
3. Results 29 patients, mean age 21.17 ± 11.50 years (16 women, mean age 23.69 ± 11.20, 13 men, mean age 18.08 ± 11.54 years) had epilepsy and PGC (epilepsy group). 63 patients, mean age 26.97 ± 17.69 years (44 women, mean age 26.16 ± 16.42, 19 men, mean age 28.84 ± 20.69 years) had PGC without epilepsy (control group). Statistically, these two groups did not differ in age and gender. Types of epileptic seizures were: complex partial seizures in 8 patients, complex partial seizures with secondary generalization in 8 patients, GTCS in 10 and absance seizures in 3 patients. Mean volume of the PGC in epilepsy group was 855.93 ± 1080.70 mm3, in control group 651.59 ± 1011.10 mm3. There was no statistically significant difference between epilepsy and control group in PGC volume (χ2 = 1.3264, df = 1, p = 0.2494). Compression of the PGC on surrounding brain structures was found in 3/29 patients (10.34%) in epilepsy group and in 11/63 patients (17.46%) in control group (Fig. 1). We found no
Table 1 Patient data.
Sex
Epilepsy group (N = 29)
Control group (N = 63)
Male Female
13 16
19 44
Age (years) Symptoms
Pineal gland cyst volume
Compression on surrounding structures
21.17 ± 11.50
26.97 ± 17.69
Headache Epilepsy Vertigo Visual disturbances Parinaud's syndrome Sensory Emotional disturbances Obstructive hydrocephalus Sleep disturbances
15 29 5 3 0
57 0 18 9 2
0 0
2 1
0
1
1
1
0-100 mm3 101-600 mm3 601-2000 mm3 > 2000 mm3 Kruskal-Wallis test
7 9 9 4 p = 0.2494
20 24 14 5
3 p = 0.5360
11
Fisher's Exact test
Fig. 1. Pineal gland cyst with compression on superior colliculi in 18 year old male - MRI sagittal T2 image.
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et al have found signs of disturbance of the CSF flow through the cerebral aqueduct with the presence of gliosis (areas of elevated signal level in vicinity of cerebral aqueduct) in about 50% of the cases [1]. In epidermoid cyst case study, mild to moderate hydrocephalus was present in all 24 patients. Perilesional edema was not identified in any case [23]. During the follow up period, 23/29 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, whereas 3 patients (13.04%) had no improvement in seizure frequency. One operated patient with PGC is seizure free, and another patient with pinealocytoma has refractory epilepsy. Other studies report partial to complete recovery of the symptoms after operation [1,14,16,23]. Current literature lists epilepsy as one of the symptoms of PCG. Based on our findings, except in cases of decribed hydrocephalus, acute intracystic haemorrhage or rupture of the cyst, pathomechanism of seizures cannot be solely attributable to PGC volume or described compression of the PGC on surrounding brain structures on MRI. Another possible pathomechanism of seizures in patients with PGC could be decreased levels of melatonin, sythesized by pinealocytes. Anticonvulsant properties of melatonin are attributable to its antioxydant activity, increase of brain GABA concentration, inhibition of calcium influx into neurons, and decreased neuronal nitric oxide generation [24]. The study by Jain S et al. did the literature search and revealed 26 papers reporting association between melatonin and epilepsy or seizures and concluded that in the majority of cases, melatonin might improve seizure control, but, in some cases, deterioration of seizures has been reported [25]. Mandera et al. found normal or slightly depressed melatonin levels in all analyzed children with PGC, while patients with pineocytomas had increase of melatonin secretion at night [1]. We did not measure the level of melatonin in our patients which is the limitation of our study and therefore emphasize the need for further research.
statistically significant difference between epilepsy and control group in described compression of the PGC on surrounding brain structures on MR of the brain (Fisher's exact Test, p = 0.5360) (Table 1). In 19/29 patients with epilepsy, EEG showed: focal spikes, biphasic spikes, spike and wave complex or diffuse paroxysmal discharges of spike and wave complex 3 Hz or more, while remaining 10/29 patients had nonspecific changes: focal slowing and dysrrhytmic changes. Two patients from epilepsy group and 3 from control group were operated due to the cyst volume, Parinaud syndrome, obstructive hydrocephalus or PGC enlargement on follow-up, with histologically confirmed diagnosis of PGC in 4 patients, and pinealocytoma in 1 patient. Other patients did not have significant enlargement of the PGC on follow-up MR of the brain. All the patient with epilepsy were put on antiepileptic therapy (AET) (valproate, carbamazepine, oxcarbazepine, lamotrigine, topiramate, levetiracetam) (mono or polytherapy) and were regularly controlled. During the follow up period 23/29 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, whereas 3 patients (13.04%) had no improvement in seizure frequency. One operated patient with hystologically confirmed PGC is seizure free, and another patient with pinealocytoma has refractory epilepsy. 4. Discussion In our group of patients with PGC, 29 out of 92 patients had epilepsy. Types of epileptic seizures were: complex partial with or without secondary generalization, GTCS and absance seizures. Comparing epilepsy and control group, we did not find any statistically significant difference in the volume of the PGC, nor in described compression of the PGC on surrounding brain structures on MRI of the brain. Most of the patients were collected in epilepsy neuropediatrics and neurology outpatient clinic, therefore the prevalence of epilepsy in patients with PGC in our study is markedly high. Epilepsy is listed as one of the symptom of the PGC in several studies [1,14–16]. Mandera M et al. presented 24 patients with PGC, two of them with epilepsy, but without description of epileptic seizure types [1]. Of two case reports from the literature, one patient had seizure as a manifestation of pineal gland intracystic haemorrhage [14] and another patient with PGC and cavum septi pellucidi had reflex epilepsy induced by hot water bathing. Seizures were described as complex partial followed by generalized tonic seizures [15]. One larger retrospective study [16] on 84 patients described GTCS in 8/32, absance in 10/32, myoclonisms in 8/32 and combination of all three seizure types in 6/32 patients with PGC. The authors did not include the volume of the PGC, but pointed that 70/82 patients were operated, based on the size of the cyst (> 15 mm or more), with the signs of compression of the quadrigeminal plate and surrounding veins. In the retrospective study of 24 patients with pineal epidermoid cysts, another type of benign tumor in the pineal region, three patients had generalized convulsions as presenting symptom [23]. In 19/29 patients with epilepsy, EEG showed: focal spikes, biphasic spikes, spike and wave complex or diffuse paroxysmal discharges of spike and wave complex 3 Hz or more. In study by Hajnsek et al., EEG showed diffuse paroxysmal discharges of spike and wave complex 3 Hz or more [16]. In former studies, epilepsy was explained in several theories: 1. compressive effect of the PGC on quadrigeminal plate and aqueduct of the midbrain, 2. compression of surrounding veins (vermian vein, internal cerebral vein, basal veins of Rosenthal and the great cerebral vein) due to cyst size which affects normal perfusion and result in EEG changes, 3. changes in melatonin levels and 4. hemosiderine deposits in the cyst. According to our results, volume of the PGC, nor described compression on surrounding brain structures based on MR findings, cannot explain by itself the occurence of epileptic seizures in patients with PGC [16]. In our study one patient had described hydrocephalus. Mandera
5. Conclusion Epilepsy was presenting symptom in 29 out of 92 patients with PGC. Epileptic seizures in patients with PGC were classified as: complex partial seizures (with or without secondary generalization), GTCS and absance seizures. There was no difference in PGC volume between patients in epilepsy and control group. There was no difference in described compression of the PGC on the surrounding brain structures between epilepsy and control group. During the follow up period 23 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, 3 patients (13.04%) had no improvement in seizure frequency. Two patients from epilepsy group and 3 from control group were operated with histologically confirmed diagnosis of PGC in 3 patients, and pinealocytoma in 1 patient. Based on our findings, pathomechanism of epileptic seizures in patients with PGC cannot be attributable solely to PGC volume or described compression on surrounding brain structures on MRI. Conflict of interest The authors declare no conflict of interest. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement The authors would like to thank Ivan Pristas, MD, PhD for his assistance in data interpretation. 74
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References
[13] J.T. Morgan, A.J. Scumpia, T.M. Webster, M.A. Mittler, M. Edelman, S.J. Schneider, Resting tremor secondary to a pineal cyst: case report and review of the literature, Pediatr. Neurosurg. 44 (2008) 234–238. [14] R. Mehrzad, S. Mishra, A. Feinstein, M.G. Ho, A new identified complication of intracystic hemorrhage in a large pineal gland cyst, Clin. Imaging 38 (4) (2014) 515–517. [15] Y. Tajima, N. Minami, K. Sudo, F. Moriwaka, K. Tashiro, Hot water epilepsy with pineal cyst and cavum septi pellucidi, Jpn. J. Psychiatry Neurol. 47 (1) (1993) 111–114. [16] S. Hajnsek, J. Paladino, Z.P. Gadze, S. Nanković, G. Mrak, V. Lupret, Clinical and neurophysiological changes in patients with pineal region expansions, Coll. Antropol. 37 (1) (2013) 35–40. [17] A.C. Mamourian, J. Towfighi, Pineal cysts: MR imaging, Am. J. Neuroradiol. 7 (1986) 1081–1086. [18] K.K. Mukherjee, D. Banerji, R. Sharma, Pineal cyst presenting with intracystic and subarachnoid haemorrhage: report of a case and review of the literature, Br. J. Neurosurg. 13 (2) (1999) 189–192. [19] D.A. Steven, G.J. McGinn, B.M. McClarty, A choroid plexus papilloma arising from an incidental pineal cyst, AJNR Am. J. Neuroradiol. 17 (5) (1996) 939–942. [20] J. Kitayama, K. Toyoda, K. Fujii, S. Ibayashi, H. Sugimori, S. Sadoshima, M. Fujishima, Recurrent aseptic meningitis caused by rupture of a pineal cyst, No To Shinkei 48 (12) (1996) 1147–1150. [21] C.M. Milroy, C.L. Smith, Sudden death due to a glial cyst of the pineal gland, J. Clin. Pathol. 49 (1996) 267–269. [22] Commission on classification and terminology of the international league against epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures, Epilepsia 22 (1981) 489–501. [23] K.I. Desai, T.D. Nadkarni, S.C. Fattepurkar, A.H. Goel, Pineal epidermoid cysts: a study of 24 cases, Surg. Neurol. 65 (2) (2006) 124–129. [24] H. Goldberg-Stern, H. Oren, N. Peled, B.Z. Garty, Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study, J. Child Neurol. 27 (12) (2012) 1524–1528. [25] S. Jain, F.M. Besag, Does melatonin affect epileptic seizures? Drug Saf. 36 (4) (2013) 207–215.
[1] M. Mandera, W. Marcol, G. Bierzynska-Macyszyn, E. Kluczewska, Pineal cysts in childhood, Childs Nerv. Syst. 19 (2003) 750–755. [2] Y. Pu, S. Mahankali, J. Hou, J. Li, J.L. Lancaster, J.H. Gao, D.E. Appelbaum, P.T. Fox, High prevalence of pineal cysts in healthy adults demonstrated by highresolution, noncontrast brain MR imaging, AJNR Am. J. Neuroradiol. 28 (9) (2007) 1706–1709. [3] A.J. Patel, G.N. Fuller, D.M. Wildrick, R. Sawaya, Pineal cyst apoplexy: case report and review of the literature, Neurosurgery 57 (5) (2005) E1066. [4] A. Taraszewska, E. Matyja, W. Koszewski, A. Zaczynski, K. Bardadin, Z. Czernicki, Asymptomatic and symptomatic glial cysts of the pineal gland, Folia Neuropathol. 46 (2008) 186–195. [5] G. Michielsen, Y. Benoit, E. Baert, F. Meire, J. Caemaert, Symptomatic pineal cysts: clinical manifestations and management, Acta Neurochirurgica (Wien) 144 (2002) 233–242. [6] J. Bosnjak, M. Budisic, D. Azman, M. Strineka, M. Crnjakovic, V. Demarin, Pineal gland cysts-an overview, Acta Clin. Croat. 48 (2009) 355–358. [7] C. Rousselle, V. des Portes, P. Berlier, C. Mottolese, Pineal region tumors: clinical symptoms and syndromes, Neurochirurgie 61 (2-3) (2015) 106–112. [8] J.S. Fain, F.H. Tomlinson, B.W. Scheithauer, J.E. Parisi, G.P. Fletcher, P.J. Kelly, G.M. Miller, Symptomatic glial cysts of the pineal gland, J. Neurosurg. 80 (1994) 454–460. [9] H. Mena, R.A. Armonda, J.L. Ribas, S.L. Ondra, E.J. Rushing, Nonneoplastic pineal cysts: a clinicopathologic study of twenty-one cases, Ann. Diagn. Pathol. 1 (1997) 11–18. [10] N. Tamaki, K. Shirataki, T.K. Lin, M. Masumura, S. Katayama, S. Matsumoto, Cysts of the pineal gland. A new clinical entity to be distinguished from tumors of the pineal region, Childs Nerv. Syst. 5 (1989) 172–176. [11] U. Engel, S. Gottschalk, L. Niehaus, R. Lehmann, C. May, S. Vogel, W. Jänisch, Cystic lesions of the pineal region-MRI and pathology, Neuroradiology 42 (2000) 399–402. [12] R.D. Dickerman, Q.E. Stevens, J.A. Steide, S.J. Schneider, Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis? Neuro Endocrinol. Lett. 25 (2004) 173–175.
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