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 Table of Contents  
CASE REPORT AND REVIEW OF THE LITERATURE
Year : 2021  |  Volume : 38  |  Issue : 3  |  Page : 194-198

Refractory temporal lobe epilepsy in patients with mosaic turner syndrome: two case reports and literature review


1 Department of Neurology, School of Medicine, University of Hacettepe, Ankara, Turkey
2 Department of Pediatric Genetics, School of Medicine, University of Hacettepe, Ankara, Turkey

Date of Submission28-Feb-2021
Date of Decision13-May-2021
Date of Acceptance03-Jun-2021
Date of Web Publication20-Sep-2021

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/nsn.nsn_37_21

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  Abstract 


Turner syndrome (TS) is one of the most common sex chromosome abnormalities in women, but there are only a few case reports of patients with TS who have epilepsy or seizures. Here, we report two additional cases with drug-resistant temporal lobe epilepsy (TLE) and TS mosaicism. Patient #1 is a 22-year-old female with drug-resistant TLE whose karyotype analysis showed that 84% of interphase cells had (45,X) genotype and brain magnetic resonance imaging (MRI) initially reported as normal showed developmental left temporal lobe encephalocele. She underwent left temporal lobectomy, and she is seizure free for 10-year postoperative follow-up period. Patient #2 is a 49-year-old female who has TLE with normal brain MRI. The karyotype analysis showed that 2/30 of metaphase cells had (45, X) genotype. In addition, 11 cases of epilepsy associated with TS were determined through PubMed. The clinical characteristics of all are reviewed.

Keywords: Brain development, encephalocele, epilepsy, temporal lobe, Turner syndrome


How to cite this article:
Arslan D, Ütine E, Saygı S. Refractory temporal lobe epilepsy in patients with mosaic turner syndrome: two case reports and literature review. Neurol Sci Neurophysiol 2021;38:194-8

How to cite this URL:
Arslan D, Ütine E, Saygı S. Refractory temporal lobe epilepsy in patients with mosaic turner syndrome: two case reports and literature review. Neurol Sci Neurophysiol [serial online] 2021 [cited 2021 Oct 18];38:194-8. Available from: http://www.nsnjournal.org/text.asp?2021/38/3/194/326290




  Introduction Top


Turner syndrome (TS) is one of the most common sex chromosome abnormalities in women and can be defined as the combination of characteristic physical features and complete or partial absence of one of the X chromosomes. Typical characteristics of TS, such as short stature, webbing of the neck, gonadal dysgenesis, cardiovascular abnormalities, and other typical stigmata, help clinicians to point out this syndrome easily.[1] TS occurs in 1 in 2500–1 in 3000 newborn females. Almost half of them have monosomy X (45, X), 5%–10% have isochromosome, and the rest have mosaicism for (45, X) with one or more additional cell lineages, more than half being mosaics with the normal female karyotype.[2],[3] While there are only 11 cases of TS who also have epilepsy or seizures reported in the literature, among all only 7 of those cases of TS mosaicism associated with epilepsy have been published [Table 1]. Now, we report two new cases of TS mosaicism associated with drug-resistant temporal lobe epilepsy (TLE), one with developmental temporal encephalocele (TE) and the other with normal brain magnetic resonance imaging (MRI).
Table 1: The clinical characteristics of Turner syndrome cases associated with epilepsy

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  Case Reports Top


Patient #1 is a 22-year-old female with drug-resistant TLE who has been referred to our clinic as a candidate for epilepsy surgery. The first seizure episode occurred when she was 19 years old as a seizure with focal onset evolving into bilateral tonic–clonic seizure. She had no family history of epilepsy or any other neurological disease. No problems occurred during her delivery, and she did not have any other risk factor for epilepsy. She graduated from college a year ago, and no signs of intellectual disability or cognitive impairment were reported. She had menarche at 14 years of age spontaneously; her menstrual cycles were generally regular until the previous year. Due to menstrual irregularity, peripheral blood karyotype analysis was performed in another medical center. In the examination, 84% of the interphase cells were found to have the genotype (45,X). There were no other significant findings in her medical history. A physical examination showed that her weight and height were below the age- and sex-matched average values of population without any other significant finding. Her seizures have persisted once or twice a week despite the therapy with oxcarbazepine and topiramate with the dosages 1200 mg/day and 125 mg/day, respectively. She had been put on a number of different antiepileptic regimens for seizures such as valproic acid, levetiracetam, topiramate, oxcarbazepine, pregabalin, and their combinations, all of which proved to be inadequate in ending her seizures. Brain MRI was reported as normal initially. During long-term video electroencephalography (EEG) monitoring, her seizures began with right arm dystonic posture and unresponsiveness, followed by oral automatisms, some of which evolved into bilateral tonic–clonic seizures. Left temporal electrodes showed spiking activity during interictal EEGs and rhythmic sharp theta activities during ictal EEGs. Positron emission tomography (PET) showed left temporal hypometabolism. Because of the concordant findings of EEGs, seizure semiology, and brain PET showing the left temporal lobe responsible for seizures, the patient underwent left temporal lobectomy. She was seizure free for 10-year postsurgical follow-up. When all brain MRIs of our patients who underwent temporal lobectomy were reevaluated as a part of another project, we noticed that she had a left temporal lobe encephalocele [Figure 1].
Figure 1: Left temporal lobe encephalocele on brain magnetic resonance imaging of patient #1

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Patient #2 is a 49-year-old female who was referred to our clinic for further investigation of drug-resistant TLE. She has suffered from temporal lobe seizures with abdominal pressure, nausea, manual automatisms, and lateralized dystonic posture, which started at the age of 30 and usually occurred once a week with nocturnal predominance. Some of the seizures were followed by deviation of the head and eyes to the right side and ended with bilateral tonic–clonic seizures. She was on valproate therapy with a dosage of daily 1000 mg. She had been put on a number of different antiepileptic regimens, that she could not recall. Her mother and aunt also suffered from epilepsy. In her medical history, pituitary insufficiency with hypothyroidism and diabetes insipidus stood out. Her age of menarche was 14 and she did not complain of any menstrual irregularities, but she had no child even though she did not use any contraception. The patient's neurological examination was normal; however, her height was below the age- and sex-matched average values of population and she had a low posterior hairline. On physical examination, there was no other remarkable dysmorphic feature and developmental anomaly. The interictal EEG of the patient showed very active left temporal spikes. Brain MRI was reported as normal; however, adenohypophysis was thin compared to normal appearance. Taking the short stature and pituitary insufficiency into the consideration, a peripheral blood karyotype analysis was performed on GTG-banded (trypsin-Giemsa G-band) metaphase chromosomes, revealing 45, X (2) /46, XX (28). Her seizures still persist with the combination of levetiracetam and topiramate therapy.

Our patients' clinical data, EEG, and brain MRI findings are summarized in [Table 1], including other published cases with TS and epilepsy.


  Review of Literature Top


Epilepsy is not frequent in TS, and reports on epilepsy are very rare. It is mostly described as symptomatic focal epilepsy due to developmental malformations.[2] In 1985, Tsubo and Nielsen showed epileptogenic activity in 1 of 64 TS patients' EEG, suggestive of idiopathic epilepsy, without radiological documentation.[15] In a more recent study in 2004 by Grosso et al., no epileptiform activity in EEGs was noted in 11 patients with TS.[16] In 2014, Saad et al. reviewed the clinical, neuropsychiatric, and EEG data of 53 TS females. The EEGs have revealed abnormalities in seven patients. In one patient who was a 4-year-old girl and suffered from generalized tonic–clonic seizures, EEG has shown generalized epileptiform activity. She has had no abnormalities in brain MRI. The other six patients presenting with intellectual disabilities have shown abnormal EEG background activity.[17] Taking these studies into consideration, hormonal insufficiency or other unknown pathophysiological mechanisms appear to be relevant in many abnormal neurological features in TS patients with normal brain MRI.[18]

We have reviewed the literature through a PubMed search from 1985 until 2020 by using keywords “epilepsy” and “Turner syndrome.” Eleven cases of epilepsy associated with TS were determined through PubMed. The clinical characteristics of the 11 cases and our additional 2 cases are reviewed (n = 13). In about 69% of the cases (n = 9), karyotype analysis showed mosaicism.[4],[5],[6],[7],[8],[9],[10] The age at onset of seizures in 77% of the patients (n = 10) was below 19.[4],[5],[6],[7],[8],[9],[11],[12],[13],[14] Only 23% of the patients (n = 3) suffered from adult-onset epilepsy.[10] There was no specific seizure type determined in these patients. About 38% of the cases (n = 5) had a mixed seizure type.[9],[12],[14] Among all, one patient suffered from absence epilepsy and one from reflex epilepsy.[7],[11] The most common type was generalized seizures, which occurred in 76% of the patients (n = 10).[5],[6],[7],[8],[9],[12],[13],[14] They all showed EEG abnormality, and 69% of them (n = 9) showed spike-and-wave complexes.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] Almost all, 92% of them (n = 12), were treated with multiple antiepileptic drugs in a range between 2 and 11 different AEDs.[4],[5],[6],[7],[8],[9],[10],[12],[13],[14] However, in 77% of the patients (n = 10), epilepsy had a poor prognosis.[4],[5],[7],[8],[10],[11],[12],[13],[14] One of these who had a multidrug-resistant epilepsy was seizure free after temporal lobectomy (Patient #1). Among all, MRI findings of 30% of the patients (n = 4) were evaluated as normal.[7],[10],[13] However, MRI screening of 15% of the patients (n = 2) was not included in the articles.[4],[14] In the remaining 54% of the patients (n = 7), the presence of symptomatic epilepsy can be mentioned. Symptomatic epilepsy in TS is usually associated with cortical developmental malformations. Lissencephaly, bilateral frontal polymicrogyria, bilateral perisylvian hypoplasia, partial agenesis of the corpus callosum, blurring of the boundary between gray and white matter in the right parietal lobe and prominent smaller right lateral ventricles are the reported neuroimaging findings of TS cases with symptomatic epilepsy.[5],[6],[8],[9],[11],[12] In addition, MRI of one of our patients showed developmental TE. TEs are herniation of the brain parenchyma through the dura mater and skull that involve the temporal lobe. Although spontaneous TEs are thought to be rare, the real prevalence is probably higher than expected. Recently, an increase in TE cases has been observed in patients with drug-resistant epilepsy reported in the literature. Despite the increased awareness of TEs in patients with refractory epilepsy, the frequency of overlook of TEs in patients with drug-resistant TLE is not clear. However, it is known that TEs not reported in the first MR imaging interpretation of a large number of drug-resistant TLE patients are noticed by retrospective examinations.[19]


  Discussion Top


The pathophysiology of epilepsy in TS is still unclear. The X chromosome plays an important role in cerebral development. The absence of one of the X chromosomes may cause differences of gray matter volumes and alterations in neuronal networks.[20] Most of the reported cases have been presented with cortical malformations. Therefore, loss of biallelic gene expression from unsilenced segments of X chromosome might be causative for developmental or functional abnormalities in cortical neurons. In addition to brain malformations, hormonal insufficiency or metabolic abnormalities might be relevant in many abnormal neurological features in TS and epilepsy. A study showed that hormones may alter seizure thresholds by affecting neuronal excitability.[18] However, it seems to us that there are so many unknown pathophysiological mechanisms contributing to the development of abnormal neurological features in TS patients that remain to be revealed. Several recent studies reported autosomal copy number changes in patients with temporal lobe epilepsies, however, no X-linked genomic copy number changes have been linked to these types of seizures yet. On the other hand, epilepsy may affect up to 1% of normal population, and the frequency of epilepsy in TS may be considered unchanged.[21],[22],[23]


  Conclusion Top


Neurologists may also overlook TS mosaicism in some of the patients with epilepsy because of the subtle clinical findings of mosaic TS patients. We hope that our reports will raise awareness and will be instructive for further investigations and large-scale studies to elucidate the underlying pathogenesis and management of epilepsy in patients with TS.

Acknowledgments

We had no additional assistance in the writing and publishing process of the article.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Tombini M, Marciani MG, Romigi A, Izzi F, Sperli F, Bozzao A, et al. Bilateral frontal polymicrogyria and epilepsy in a patient with Turner mosaicism: A case report. J Neurol Sci 2003;213:83-6.  Back to cited text no. 9
    
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Zeng YJ, Yang XS, Tian FF, Xiao L, Liu W, Yang X. A case of Tunner syndrome combined with epilepsy. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2004;29:364.  Back to cited text no. 13
    
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[PUBMED]  [Full text]  
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Tsuboi T, Nielsen J. Electroencephalographic examination of 64 Danish Turner girls. Acta Neurol Scand 1985;72:590-601.  Back to cited text no. 15
    
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Grosso S, Farnetani MA, Di Bartolo RM, Berardi R, Pucci L, Mostardini R, et al. Electroencephalographic and epileptic patterns in X chromosome anomalies. J Clin Neurophysiol 2004;21:249-53.  Back to cited text no. 16
    
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Catarino CB, Kasperavičiūtė D, Thom M, Cavalleri GL, Martinian L, Heinzen EL, et al. Genomic microdeletions associated with epilepsy: Not a contraindication to resective surgery. Epilepsia 2011;52:1388-92.  Back to cited text no. 22
    
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