1. Epilepsy surgery in a patient with a focal cortical dysplasia type 1 and a duplication in PCDH19 gene
Hartlieb, T. 1, Lübbig, A . 1,Pieper, T. 1, von Stülpnagel, C. 1,6, Holthausen, H. 1, Kudernatsch, M. 2, Winkler, P. 1, Blümcke, I. 3, Holinski-Feder, E. 5, Abicht, A. 5, Kluger, G. 1,6, Staudt, M. 1,4
1 Clinic für neuropediatrics and neurological rehabiltiation, epilepsy center for children and adolescens, Schön Klinik Vogtareuth
2 Clinic for neurosurgery and epilepsy surgery, Schön Klinik Vogtareuth,
3 Institute for neuropathology, University Erlangen
4 Department for neuropediatrics and developmental neurology, UniversityTübingen
5 MGZ Munich, Germany
6 Paracelsus Medical University, Salzburg, Austria
introduction
We report  a now 22 year old female patient suffering from a drug resistant focal epilepsy due to a focal cortical dysplasia who underwent epilepsy surgery at the age of 8 years. Postoperatively, 2 clusters of seizures occurred (follow up: 13 years). Genetic diagnostics due to persisting seizures revealed a de novo duplication in the PCDH 19 gene as coincident finding, which might be responsible for ongoing seizures.
case history
Age at onset of epilepsy: 13 month; the girl showed auras with panic, visual and somato-sensible symptoms evolving into focal tonic-clonic seizures with a left sided maximum, occurring in status-like clusters provoked by fever ( 6 times a year). Medication without sustained success (VPA, Ox-C, PHT, CLB, GBP, VGB).
The girl showed a movement disorder characterized by ataxia and mild left-sided hemiparesis.
Cognitive development was initially normal, decline and slowing of further development after onset of epilepsy, neuropsychological assessment at the age of 17 revealed a cognitive impairment with a FSIQ of 64.
hr-MRI
EEG-Monitoring
cor T2 1mm:
increased white matter signal with blurred cortico-medullary differentiation ( ), volume reduction of right temporo-occipital region ( )
> Characteristic MRI findings
of focal cortical dysplasia
type I
interictal: spikes non lateralized fronto-central,
intermittend slowing right fronto-central
Ictal: motoric seizures witch left sides maximum
SOZ right centro-parietal
Invasive diagnostics with subdural grids and strips due to discongruent findings in surface-EEG with widespread discharges in the right hemisphere showed an EEG status mesio-basal temporo-parieto-occipital and a right temporo-occipital resektion with amygdala-hippocampectomy and extension to the mesial precuneus was performed.
epilepsy surgery
histology
Cortical dyslamination with microcolumns and a increased number of ectopic neurons in the white matter.
> FCD ILAE Type 1A (Blümcke)
courtesy Prof. I. Blümcke, Erlangen
postoperative course
Postoperatively, only 2 febrile seizure clusters occurred (follow up:13 years). Patient is still on therapy with Ox-C and now ongoing seizure free.
genetic diagnostics in the pre-NGS/WES era
SCN1A single gene sequencing because of febrile status-like seizures with early onset and cognitive impairment : negative
PCDH19 MLPA analysis because of clustered febrile seizures in a mentally retarded female patient: de novo duplication in exon 3,4,5a
According to the ACMG guidelines the PCDH19 duplication in exon 3-5a in our patient is likely pathogenic (class 4). A review of the literature shows deletions or missense mutations in exon 1of PCDH19 gene to be responsible for most of the early infantile epileptic encephalopathies (EIEE9) due to interactions of two coexisting different PCDH19-assosiated neuronal populations. One case report of a duplication in exon 5 of PCDH19 (Dimova et al 2012) lead to a similar phenotype as in our patient with drug-resistant, febrile seizure clusters starting at the age of 5 months with moderate intellectual disability. Furthermore, two Mutations in exon 5 and one in exon 3 out of a cohort of 35 patients with typical PCDH19 associated phenotype have been reported (Marini et al reportet 2010). The predominant ictal feature in this group was fearful screaming in 70 %, which is close to fearful auras with panic in our patient.
There is no case of PCDH19 mutation and focal cortical dysplasia in the literature, most likely this is a coincident finding, and the epilepsy in our patient was a result of genetic and symptomatic components. Keeping in mind that seizures in PCDH19 patients become less frequent over time (i.e. 30% seizure free patients reportet by Marini et al.) it is unclear whether epilepsy surgery or normal time course of disease led to the dramatic improvement of our patient with ongoing seizure freedom.
MLPA-analysis PCDH19
red arrows show increased number of copies in patient (blue) exons 3-5 of PCDH19 gene in comparison to control (red)
MLPA-analysis PCDH19
red probes show increased number of copies in patients exons 3-5 of PCDH19 gene in comparison to control (blue)
discussion
conclusion:
Beside standard diagnostic procedures (e.g EEG, MRI) the evaluation of epilepsy surgery failures should take into account current genetic diagnostics if compatible phenotypical characteristics are associated with the epilepsy.
One should bear in mind that also a phenotype with a focal semiology and localized discharges does not contradict the coincidence of a genetic epilepsy syndrome. The proof of a genetic epilepsy syndrome, may have an impact on therapy and comprehensive care for the patient.
Literature: A novel PCDH19 mutation inherited from an unaffected mother; Dimova et al.: Pediatric Neurology 46 (2012)
Focal seizures with affective symptoms are a major feature of PCDH19 gene–related epilepsy; Marini et al.; Epilepsia 53 (12): , 2012