Al XX-lea Congres SNPCAR,

Băile Felix, 18-21.09.2019

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A 42-a Conferinta Nationala de Neurologie − Psihiatrie si Profesiuni Asociate a Copilului si Adolescentului cu participare internationala


VARIABILITATEA MODELELOR CLINICO-ELECTROCEFALOGRAFICE ÎN ENCEFALOPATIILE EPILEPTICE LA COPIL

Autor:

Lucrarea a urmărit în partea sa generală (aşa cum se vede şi din cuprinsul anexat) să realizeze o sinteză a datelor cunoscute despre encefalopatiile epileptice (EE) ale copilului, iar în partea de cercetare propriu-zisă să verifice în ce măsură se întâlnesc în patologia internată în Clinica de Neurologie şi Psihiatrie Pediatrică din Târgu-Mureş modelele descrise în literatura de specialitate, cât şi dacă există particularităţi. Analiza a inclus aspectele clinice, electroencefalografice (EEG), alături de metodele moderne de investigaţie (imagistică, biochimie, oftalmologie). Lotul de pacienţi urmăriţi longitudinal pe parcursul a 10 ani de la data internării a inclus 30 copii, realizând corelaţii clinico-clinice (comorbidităţi, aspecte diferite pe parcursul evoluţiei), clinico-EEG, clinico-imagistice şi clinico-terapeutice. S-a insistat asupra importanţei diagnosticului precoce şi a introducerii imediate a terapiei. Bibliografia include 200 titluri, din care vom prezenta aici o selecţie strictă (date de referinţă şi cât mai moderne).

Introduction

 

The study of this group of disorders requires both a definition of terms and a delimitation from conditions to which there are convergence points, made ​​in Chapter 1 of the dissertation (thesis achieved under the guidance of Prof. Ion Pascu, PhD, Tg. Mures). Epileptic encephalopathy (EE ) is a heterogeneous group of epilepsies and epileptic syndromes characteristic to infants andchildren, who have some common features: a) polymorphic nature of the seizures that we define in terms of clinical aspects, b) electroencephalographic patterns (EEG) absolutely characteristic of almost every entity, pre-existing cognitive impairment or installed progressively, as a background producing seizures; resistance to treatment, in most cases requiring joint antiepileptic drug (AED), in bi-therapy or polytherapy (1,14,161). Encephalopathy (E) refers to a disorder of brain function , especially in the intellectual activity or in the higher brain functions (14, 173). Epileptiform encephalopathy’s (EEP) refers to disorders with EEG epileptiform activity recorded without critical clinical activity. Nonconvulsivant  epilepticus condition, which in most cases consists only of a light degree of alteration of consciousness, together with a focal electrographic epilepticus status aspect  is considered by some authors form of EE (14, 32, 173) . Epileptiform (Ep) is a term that refers to graphic-elements as spikes, spikes and-wave activity or other rhythmic waves, implying  epilepsy or not (173).

Note: Figures in brackets correspond to the bibliography, which, for lack of space, will appear in brackets in the bibliography. The Table of Contents is presented below because this summary includes only part of the  processed data.

 

Table of contents

I. GENERAL PART: Chapter 1. Definition of terms; Chapter 2. Epileptic encephalopathy place in the various classifications of ILAE; Chapter 3 . Variability of clinical symptoms in epileptic encephalopathy; Chapter 4 . The etiology and pathophysiology of epileptic encephalopathy. Hypothetical models; Chapter 5 EEG patterns in epileptic encephalopathy; Chapter 6. The value of modern methods in brain electrical activity exploration

 II. SPECIAL PART  Chapter 7. Material and Methods. Study group, Work equipment, Programs used in the study groups including cases of EE, Chapter 8 . Results; Chapter 9 . Discussions; Chapter 10 . Conclusions; Selective Bibliography.

Chapter 1. Its content was summarized in the introduction

Chapter 2. After a review of different previous classifications of epileptic encephalopathies (EE), there are presented the current criteria for EE evaluation, established by the ILAE working group (the 2001 classification), which includes five axes as follows: Axis I – ictal phenomenology; Axis II – type or types of sezures; Axis III – specifying the syndrome; Axis IV etiology specification; Axis V – extent of neurological-psihological-social damage (optional). Following this approach, EE have gained a distinct, unitary position (9 entities) (14).

Chapter 3, entitled «The variability of clinical symptoms of epileptic encephalopathies” reviews the accepted criteria of definition, the nine EE  recognized by the majority of epileptologists, namely: 3.1 Early myoclonic encephalopathy, 3.2. Early infantileepilepticencephalopathy (Ohtahara syndrome}; 3.3West syndrome, 3.4 Dravet syndrome, 3.5 Myoclonic status in non-progressive encephalopathies, 3.6 Epilepsy with myoclonic – astatic sezures (Doose sdr.), 3.7 Lennox-Gastaut syndrome , 3.8.Landau – Kleffner syndrome, 3.9 Epilepsy with continuous spike-wave during slow-wave sleep (another syndrome. than LK).
In this short abstract we will describe briefly only the clinical characteristics of the West syndrome and the Lennox-Gastaut syndrome which was mainly considered in the study group.

3.3. West syndrome. The main clinical picture is infantile spasms. Based on concurrent studies, including EEG, EMG and imaging recordings, it has become possible to describe several types of spasms . Symmetrical spasms are those where both sides of the body are involved symmetrically. Asymmetrical spasms are those involving a single body part or one side is more heavily involved than the other. Asynchronous spasms, the spasms involvs one side before the other in the same spasm. Focal spasms consist of brief muscle contractions, accompanied by lateral deviation of the eyes or « jerks « side of the head and associated with EEG changes characteristic spasms. Spasms (S) combined with focal seizures (FS): a) FS followed after several seconds of S, in bursts ; b ) alternating FS and S in bursts debuted with FS; c) FS gradually replaced by epileptic bursts, with overlapping of the two: Spasms preceded by focal seizures in epilepsy evolution assume occurrence of FS before the onset of spasms; Subtle spasms consist of contractions of the face muscles, opening or closing of the eyes, eye movements (up, down, converged), raising the shoulders, grimacing, yawning; Spasms preceded by short atonia, lasting muscle inhibition between 100 and 400 milliseconds; Subclinical spasms are difficult or no clinically observable , their presence being observed on EEG which show decreased amplitude and increased frequency followed by slow waves of high amplitude rhythmic fast activity, each lasting 1-2 sec. It repeats at intervals of 10 seconds. Seizures of drop attacks occur in cases with late onset and may signify the presence of the epileptic encephalopathy contnuum (EEC) phenomenon. Ttransition to this kind of seizures is common in the Lennox-Gastaut syndrome (60, 78 , 143, 148, 188 ) .

3.5. Lennox-Gastaut syndrome From clinical epileptic point of view it is characterized by seizure polymorphism comprising: tonic seizures, atypical absences, atonic seizures, myoclonic seizures, drop attacks, in association with nonconvulsive status epilepticus (32, 58, 121).
Chapter 4 of the thesis develops proposed Hypothetical models  for mechanisms of these diseases, the areas involved, including the EE etiology and pathophysiology we will further enumerate, without going into details : 4.1. Brainstem pathology (102) ; 4.2 . Cortico-subcortical interactions (87, 100) 4.3. Hypothalamic-pituitary adrenal dysfunction, (96 , 160) 4.4  Imune system dysfunction (44, 70 ) ; 4.5 The development desyncronisation model (DD), (56, 181) ; 4.6. Sinaptogenesis (56); 4.7. Myelination ; 4.8. The glutamate neurotransmitter systems (GNT) (56); 4.9. The serotonin neurotransmitter system (SNT) (56); 4.10. Acetylcholine neurotransmitter systems (ANT) (56): 4.11. Neuronal migration (NM) (56 ) 4.12. Known genetic associations (but only 13 diseases with genetic determinism may be considered as etiologic or predisposing factor for infantile (IS.). They are: tuberous sclerosis, Aicardi syndrome, Down syndrome, phenylketonuria syndrome, PEHO, lissencefalia, neurofibromatosis type I, Angelman syndrome, pyruvate dehydrogenase deficiency, hemimegalencephaly, Hypomelanosis Ito, X –linked infantile spasms and cortical dysplasia (54, 56, 64 )

Chapter 5, entitled « EEG patterns in epileptic encephalopathies « reviews in detail the known and described aspects. Here we will briefly cover only the WS and LGS patterns.

5.3. West syndrome . Hypsarrhythmia is the inter- ictal archetypal pattern and is present in two thirds of patients with WS. In one third of cases occur hypsarrhythmia variants (asymmetric HA, modified HA, atypical HA, fragmented HA, sided HA). In the West syndrome whose etiology is tuberous sclerosis, there is a pattern of atypical hypsarrhythmia. Ictal EEG patterns are variable, amounting to at least 11 different types with a duration of 0.5 sec to 2 min. Infants with WS can be identified several weeks before the appearance of typical HA (49, 123).

5.5 Lennox-Gastaut syndrome (LGS) Inter – ictal EEG abnormalities in the beginning can be represented by background abnormalities with or without generalized discharges of slow spike and wave complexe. Ictal EEG recordings involve different aspects, depending on the type of seizures. Atypical absences are associated with generalized discharges of spike and slow wave complex (frequency below 2.5 Hz) Tonic seizures, accelerate the rapid paroxysmal activity. Atonic attacks mainly appear with generalized discharge of slow spike and wave complex (GDSSWC) and fast paroxysms, alone or in combination. Myoclonic attacks are mainly accompanied by generalized discharges of polispikes with or without slow waves and fast rhythms (13, 98, 171)

Chapter 6, entitled «The value of modern exploration methods of the brain electrical activity in the EE  electrical-clinical diagnosis « includes two chapters that describe:6.1. Modern techniques of automatic recording and interpretation of EEG, with EEG maping (197), special recording computer programs (digital EEG with creating automatic detection programs of ongoing events and their quantification), quantitative EEG (QEEG) including screening for possible epileptic spikes or seizures and long-term EEG monitoring or outpatient records in ICU (82.143) EEG monitoring of known or suspected seizures refers to continuous EEG recording for 24 hours to support the diagnosis and treatment. It can be performed on out or in- patients (127). Ambulatory EEG new digital models (EEGA) reduce review time by sequencing and have automatic detection programs for spike and seizures; they identify epileptiform discharges on the basis of changes in amplitude, frequency and regularity. They have some clinical application: a) confirm the clinical suspicion of epilepsy, b) evaluate interictal epileptiform activity; c) prove the presence of seizures in patients surprised by this fact; d) assess response to therapy; e) assess nocturnal sleep events or related to it; f) assess suspicion of pseudoseizures; g) assess syncope (194) Improvement of records followed in real time by the video EEG opportunity to highlight subclinical seizures or subtle ones, such as different types of infantile spasms, absence, very short myoclonic seizures (144). Long time monitoring video – EEG involves 24 hours recordings in those cases in which there is suspicion of the presence of seizures, but there is insufficient data. MEG source imaging creates the possibility of locating the source of epileptic spikes, even if they are several sources and will involve surgical approach divided into several stages (83) Subchapter 6.2. presents Combined methods of exploring brain activity. One is the EEG recording while exploring functional MRI. The result of this technique is to « map « the hemodynamic changes associated with epileptic activity performed by recording the BOLD (blood oxygen level dependent) signal ( 190).

Chapter 7. The material and the method include:
7.1. The group under study The group of patients under study consisted of 30 patients who were hospitalized with the Clinic of Pediatric Neuropsychiatry in Tîrgu-Mureş from 1999 to 2009 (for 10 years). On the date when they were admitted to the group the patients’ageranged from 2 months to 6 years. The patients were surveyed for 10 years as of the date when they were admitted.Given the heterogeneous character of the clinical and electroencephalographic entities belonging to the EE group, we included only 4 EE forms in the group, corresponding to the established inclusion criteria, namely the West syndrome, the Lennox-Gastaut syndrome, the Landau-Kleffner syndrome and the Dravet syndrome. In many cases we found this phenomenon of epileptic encephalopathy continuum(EEC) that involved two of the most common forms of EE, namely the West syndrome (WS) and the Lennox-Gastaut syndrome (LGS). Of the four clinical forms of EEG, the largest number of patients (28, i.e. 90.3%) was diagnosed as suffering from the West syndrome (20, i.e. 70%) and from the Lennox-Gastaut syndrome (8, i.e. 20.3 %); with 10.6 % of them we have managed to seize the phenomenon of „epileptic encephalopathy continuum” described in the first part of the paper. Basically, 90 % of the included pathology fell within the first two syndromes mentioned, and this is why we will give a brief presentation of their inclusion criteria.

Inclusion criteria for the West syndrome: Types ofseizures: spasms (s) in flexion or in extension, combined spasms (in flexion and in extension), asymmetric spasms, asynchronous spasms, spasms preceded by short atony, spasms preceded by partially asymmetric seizures during the epileptic attack, focal spasms, subtle spasms and subclinical spasms; / The onset of seizures: from 3 to 7 months / EEGpattern: hypsarrhythmia, with its different variants (asymmetric, modified, atypical, fragmented, unilateral); / Evolution of EEGabnormalities: the rhythms are being organized during the process, and from 2 to 4 years the HA pattern is replaced by the pattern of slow spike and wave complex (SWC) of LGS; / Psychomotordevelopment: Delayed per primam or only set in (regression) after the onset of spasms and maintained in most cases due to the lack of control or to the poor control of seizures; /Neurologicalsyndrome: variable (spastic or hypotonic forms of quadriparesis, hemiparesis, paraparesis or dystonic-dyskinetic forms).

 The inclusion criteria for the Lennox-Gastaut syndrome: Types of seizures: tonic seizures, atonic seizures, epileptic seizures, myoclonic seizures, drop attacks, status epilepticus (sometimes persistent infantile spasm); / Onset of seizures: after 1 year of age; / EEG patterns: • paroxysms of rapid rhythms or rapid rhythmic spikes characterizing tonic seizures, the most frequently observed in slow wave sleep;
• general discharges of slow spike and wave complexes, bilaterally, synchronously, symmetrically and with high amplitude on the frontal derivations characteristic to atypical absences; • inter-ictal spikes and multifocal spikes or slow spike and waves complexes, prevalent in the frontal and occipital areas; • foci of multiple independent spikes in the transition from the HA pattern to the slow SWC pattern; / Psychomotor development: sometimes delayed at the onset of seizures (there are only symptomatic forms), sometimes set in after the seizure started (regression); / The neurological syndrome: variable (spastic, hypotonic or dystonic-dyskinetic forms of quadriparesis, hemiparesis and paraparesis).

 7. 2. Method (Work equipment): For efficiently monitoring the patients they had to be periodically re-evaluated, clinically and paraclinically.
Clinically, the patients received a thorough medical history (anamnesis). The data were recorded on diseases related to the family medical history and to the personal pathological history and a synthesis of the data is summarized in the table titled “Pre- and peri-natal antecedents, family history and personal pathology.” We also insisted on the stages of psychomotor development and on the epileptic seizures onset and their type. All types of seizures were organized in the table titled “Age of admission to the study, types of seizures, and ophthalmic and imaging investigations.” All the patients received general clinical examination, an assessment of their neurological and reflexo-psycho-motor development, using transient reflex examination and psychomotor development scales, as well as neurological examination, also highlighting existing cranial malformations. A data synthesis is shown in the tables called “The neurological syndrome and the psychomotor development of language” andTypes of epileptic encephalopathies and comorbidities.”

In terms of paraclinical tests the serial EEG recordings were of utmost importance. The recordings were made ​​with a 16-channel device, the Nyhon Koden brand. Longitudinal and transverse assemblies were used in the system 10 to 20, with a paper speed of 15 mm / sec. and a calibrated amplitude of 50 microV.
There was a large variability in the EEG patterns typical with the EE group, given the level of effectiveness of the anti-epileptic drugs (AED) associated according to the rigorous principles of rational polytherapy, however there have been cases when despite a “very good” seizure control, the EEG appearance remained significantly altered. There have also been cases when despite a poor control of the seizures the EEG appearance was improved.
All these findings related to the variability of EEG patterns and their variants and to the treatment formulas used for each monitored treatment, and last but not least the measurable quantitative parameters for the evolution of the seizure frequency were included in the table titled „EEG aspects, antiepileptic treatments and seizure development under treatment.”

 The imaging evaluations performed consisted of ultrasound examinations (mainly transfontanellar ultrasound, abdominal or targeting other locations, too), skull radiography, computer tomography examinations and magnetic resonance imaging (MRI) of skull and brain, all included in a previously mentioned table.
The eye fundus examination revealed aspects suggestive of the acute and chronic stages of the intracranial hypertension syndrome and aspects typical with phakomatoses. Laboratory analyses mainly required that blood samples should be taken. The blood parameters were determined periodically, i.e. every 3 months, mainly targeting the liver and kidney, and the titer of the antibodies anti CMV, HSV and Toxoplasma Gondii. In rare situations the serum concentrations were determined of antiepileptic drugs.

7.3. Programs used in the studied groups including cases of EE. We have processed all available medical information. After processing the data we drew up the 5 tables previously mentioned. The statistical analysis was made using the SPSS program version 19 and GRAPH PAD PRISM. For univariate analysis of the data the x2 test (dichotomous variables) was used. Frequency tables were used in order to obtain numerical and percentage data. We calculated the mean values and the standard deviation (SD). The differences were considered as statistically significant with a value of the p parameter smaller than 0.05.

Chapter 8. Results: We found correlations between the parameter values ​​obtained by statistical processing of the data, which clearly demonstrates the variability of the clinical and electroencephalographic patterns for the forms of epileptic encephalopathy studied. They showed statistically significant data, proving close links between the etiological factors, the comorbidities EE, represented in a large number of cerebral palsies (CPs) or, in a smaller number, by neurocutaneous syndromes (tuberous sclerosis, neurofibromatosis, trigeminal encephalopathy) and the tendency in most of the cases towards severe, mixed (motor, mental and language) development delay.

As concerns the personal physiological history, more frequently occurred the following: first trimester pregnancy symptoms (FTPS), primary asphyxia syndrome (PAS) of various degrees (PAS I, II, III), threat abortion (TA), neonatal seizures (NNS), Apgar score (AS) at 1 and 5 minutes (see Table no. XII). In Fig. No. 14 we presented the correlations between the Apgar score and the West syndrome, with a significantly lower score (Apgar 1 for about ¼ of the cases). The age of admission to study, i.e. the age of seizure onset shows features which will be discussed below. We have insisted on cases of WS which turn into LGS (“secondary” LGS) and the “de novo” LGS with early or very early onset.

 

Table XII FTPS and SAG III frequency in WS (multivariate regression)with statistically significant p: 0.05 and 0.034 respectively

A particular aspect stands out with LGS, which shows a high incidence of the onset of the seizures within 1 to 4 months (most unusual!), with a spike representative of the third month and with consistent possibility of onset from 1 to 5 years of age, which corresponds to literature data. The explanation for the spike of incidence in the third month is the phenomenon of transition from WS to LGS, even if the first seizures occurring are not the infantile spasms.

As seen in the disease history, the types of seizures that occurred more frequently, such as infantile spasms and generalized seizures, especially generalized tonic seizures were subjected to statistical analyses. The methods used did not reveal a statistically significant p coefficient. Unsurprisingly, some generalized seizures showed a statistically significant frequency with the WS, even when present in very few cases, as shown in Fig. 20.

Figure 20. CTCG frequency in SW.

Caption: 0= first examination, 1= during the progress

A situation similar to the tonic-clonic seizures is seen in the case of amyotonic seizures (AS). One explanation could be the confusion caused by the similarity between the seizures of head falling on the thorax and the spasms in flexion (without upper limb flexion) suggestively known as the Salaam tic (twitch) (see Figure 21)

Figure 21. CA frequency inn SW.Caption: 0 = at the beginning of the study; 1 = on a later examination

 

As expected, one of the types of generalized seizures representative for LGS, the generalized tonic-clonic seizure, is represented in a proportion very close to 50%. Unlike this kind of seizure, generalized tonic seizures are present in much higher, almost double, proportions.

Figure 23. CTG frequency in SLGCaption: 0=first examination, 1= during the progress

Figure 24. CTCG frequency in SLGCaption: 0=first examination, 1= during the progress

 

 

The progress of motor, mental and language development highlighted with WS values ​​of p less than 0.05, both for motor retardation existing before the onset of epileptic seizures and where regression occurred after the onset of seizures and was exacerbated by the lack of control over them. Also statistically significant associations were found with the hypotonic and spastic forms of CPs, and the multivariate regression analysis showed the same phenomenon with the dystonic-dyskinetic forms.

Analyzing the cases made it clear to what extent the initial motor retardation is present with the West syndrome and the fact that it increases with persistent seizures. The phenomenon is more obvious and stronger with the symptomatic forms of WS where the cerebral structural changes in the substrate can be identified by neuroimaging. Hypotonic forms of CP are associated with SW in most of the cases, i.e. in nearly 60% of the cases.

The comorbidities most strongly associated with epileptic encephalopathies are cerebral palsies (CPs) and congenital microcephaly with the West syndrome, and in different proportions with LGS. The results were presented in tables and figures, highlighting the predominance of neurological forms / symptoms, differentiated in the two EE forms analyzed, an aspect changing during the evolution, probably under the influence of medication (see Fig. 30).

Figure 30.  Frequency of the association between CP and LGSCaption: 0 = at the study onset; 1=  on a later examination (during the progress)

 

The imaging aspects captured by computer tomography (CT) and by magnetic resonance imaging (MRI) showed several types of changes. Of these, the most frequently observed was the cortical atrophy, followed by migration disorders and other brain malformations. Such modifications (massive and associated with a high titer of anti-CMV antibodies, present in a patient with WS, 8 months of age) are shown in Fig. 31 (see Fig. 31).

 

The imaging aspects captured by computer tomography (CT) and by magnetic resonance imaging (MRI) showed several types of changes. Of these, the most frequently observed was the cortical atrophy, followed by migration disorders and other brain malformations. Such modifications (massive and associated with a high titer of anti-CMV antibodies, present in a patient with WS, 8 months of age) are shown in Fig. 31 (see Fig. 31).

Of the whole studied group, all the 30 patients received eye fundus examination, and in 14 cases the EF examination revealed papillary pallor (PP), and 12 of them looked normal.

The types of seizures have largely fallen within the nosological markers, but there were situations when certain types of seizures characteristic of a certain syndrome were also present in a statistically significant proportion of another syndrome (eg, generalized seizures, both tonic and tonic-clonic and amiotonic with the West syndrome). However, infantile spasms were present in all cases of West syndrome or LGS evolved from the WS under study.

Electroencephalographic anomalies: we have found the well-known characteristic patterns with four of the EE forms, but they showed great variability during monitoring. These patterns are not typical with a single form; they are the classic pattern or variants thereof that can be found in other forms of EE. Thus, the hypsarrhythmia pattern can be found both with Ohtahara syndrome (but in an altered form), and in the forms of transition to the Lennox-Gastaut syndrome, in which the slow spike and wave complex pattern usually evolves from the alternative pattern of fragmented hypsarrhythmia. All these phenomena of a pattern transforming into another are part of the epileptic encephalopathy continuum (EEC) electrographic phenomenon.

Figura 31.  MRI of an 8 months’ male patient, diagnosed with the West syndrome

 

The graphical representations (see Fig. 34-39) of the dynamics of classical EEG pattern anomalies and of the variants thereof during the monitoring were summarized, selecting five stages considered to be significant, for each of the studied EE (WS, LGS, LGS evolved from SW).

Fig. 34. Frequency of the patterns  EEG_1 to SLG

Fig. 35.  Frequency of the patterns  EEG_5 to SLG

Caption: We have chosen the first (EEG_1) and the fifth stage (EEG_5), considered to be significant for demonstrating the dynamic and variable character of changes, especially as concerns the hypsarrhythmia pattern.

Fig.36. . Frequency of the patterns  from EEG_1 to SW

Fig.37. Frequency of the patterns from EEG 5 to SW

Caption: HA = hypsarrhythmia, SSWC = slow spike and wave complexes PPD = periodic pseudo-rhythmic discharges.

 

Comparing the evolution of patterns for the both syndromes we have found out a better control of the hypsarrhythmia pattern than the one of slow pike and wave complexes, during evolution.

Fig. 38. Frequency of patterns from EEG_1

Fig.39. Frequency of patterns from EEG_5

 

With the transitional forms from WS to LGS (WS LGS), we first recorded, at a rate close to 50%, the presence of the hypsarrhythmia pattern, intricate with SSWC and PPD (the first pattern being half of the hypsarrithmic pattern, while PPD is half of SSWC), as can be seen in figure 51. Comparing this form of transition from WS to LGS with the other two forms analyzed, in terms of EEG there are consistent similarities with the West syndrome, at least in terms of irregular periodic survey of the hypsarrhythmia pattern and the lack of sufficient control over the SSWC pattern. In this context one can conjecture a favorable development of these cases if the transition from WS to LGS occurs later on. 

 The therapeutic-evolutive characteristics have shown reactivity changes during the evolution, depending on the variability of clinical seizures. The results have been presented in detail in this thesis. We only wish to note that by averaging the drug control over the three main types of seizures in the three syndromes, it appears that the least controllable are the focal seizures, i.e. 25% on average, while the generalized seizures and the infantile spasms have shown a high degree of control in a substantially equal proportion of 50%, with each of the representative syndromes.

Chapter 9.  The discussions on the results are grouped by categories:

 9.1. The age of onset of the seizures: we found values similar to those in the scientific literature, with one exception: With LGS (onset of seizures from 1 to 7 years, with a peak from 3 to 5 years), surprisingly and unlike the current data on incidence, the “peak” in the studied group is attained from 3 to 4 months, an interval similar to the onset of infantile spasms in the West syndrome. The explanation could be that the percentage (57.1%) of LGS de novo forms are less represented than the forms of LGS evolved from WS, which explains the “too early” onset of the generalized seizures, most of them tonic ones (see figure 18).

9.3. the etiological factors – our results correspond to the literature data, but we found out that a significant contribution to the generation of these syndromes have had the opportunistic infections, of which the herpesviridae (cytomegalovirus and herpes viruses) are significantly represented by percent and in almost equal proportions, as compared the other viruses (see fig.67).

9.4. The comorbid disorders identified are those found in the literature studied. We will not go into detail here, noting only that we frequently found disabling comorbidities such as cerebral palsy – CP present in 25 cases, accounting for 83%, with different p values ​​of the two syndromes studied and that the spastic forms of CP are commonly associated with the Lennox-Gastaut syndrome, whereas the hypotonic forms are commonly associated with West syndrome.

9.5. The imaging investigations revealed pathological aspects in a significant proportion: different degrees of cortical atrophy with a number of 18 cases, totalling 60% and other aspects totalling 10%, consisting of: ventriculomegaly / hydrocephalus, intracranial calcifications, cerebellar hypoplasia, porencephaly cysts. The eye fundus appearance was normal in 14 of the cases studied (46.6%) and the papillary pallor was found with 12 patients (40%).

Figura  67.  Frequency of the opportunistic infections in percentage

 

9.6. As concerns the types of seizures and their frequency during the monitoring, the aspect noted which drew our attention as being particular to the studied group was the surprising percentage of generalized seizures (tonic and tonic-clonic) in patients with WS. The same aspect was found in patients with LGS developed from WS. The longitudinal follow-up and the repetitive investigations allowed us to discover the transformation of one syndrome into another (WS LGS) both clinically and paraclinically, thus highlighting the events known as the epileptic encephalopathy continuum. During the analysis the seizures were grouped into three distinct categories: generalized seizures, focal seizures and infantile spasms, in order to facilitate the approach to the therapeutic-evolutive characteristics. 9.7. EE treatment is a very complex process, mainly due to the polymorphism of the seizures identified with each entity and it involves polytherapy with all the clinical forms, which thus becomes a rule, monotherapy remaining but an untouchable target. Our results are consistent with those in literature. Pharmacological treatment is ineffective in about 20% of the cases, which is seen as an unacceptable quality of life. These cases are termed as resistant / refractory epilepsy. After repeated attempts to define the disease, the following definition was accepted in 2009: “the failure of adequate tests with one or two carefully chosen, well tolerated, commonly used antiepileptic drug, to obtain total seizure control.&rdqurdquo; Seizure control – another controversial term, defined by the experts’ consensus, consists of: “a control over all the types of seizures for a period of 12 months or the equivalent of a period three times larger than the interval between seizures before further therapeutic intervention, however long it may be.” (109, 143). As monotherapy remains a unattainable target, the rule should be rational polytherapy, which relies on clear principles and rules, described in the general section. Tables on first and second choice drugs, the pharmacokinetics and side effects of the AED, including data on the interaction of the AED with other drugs are included in the thesis. They are comprehensive and contain updated information.

 

Chapter 10. Conclusions
Epileptic encephalopathies in our study are clearly dominated by two clinical forms: WS and LGS. We divided the casuistry of the second in LG syndrome “de novo” and LG caming  from WS. The peak incidence of the onset West syndrome was found at the age of 3 months (50% of patients studied), with a significant share in the first and fourth month (30%), while at the second and fifth months it was 15%. The incidence of the onset  in the Lennox-Gastaut syndrome showed a constant rate between the ages of 1 and 5 years, mentioning that in our study we found a notable exception: major debut in third month (40%) and at the age of 6 years (25 %).

 The known etiologic factors were also identified in our control group: especially causes acting during immediate pre, peri and postnatal, producing some asphyxia syndromes of different degrees, which have the effect of weakening i.e. anyway immature brain, providing conditions for the development of  serious, often irreversible conditions. We also found in our control group significant strong correlations between Apgar score values, asphyxia syndromes and their significance as predictors for EE in general and for WS and LGS, in particular.

Regarding EE causative factors, our results show that opportunistic infections have a decisive role. The most significant data revealed almost equal percents for the cytomegalovirus and herpes viruses (26 and 23%) and lower (13%) for Toxoplasma gondii/

Co-morbidities occurring in EE are multiple, at our control group prevailed cerebral palsies /chronic encephalopathy (various neurological syndromes: spastic and hypotonic forms in more than 60% but also in ataxic and dyskinetic ones), which was associated with a highly severe retardation in development. The respective developmental delay preceded the onset of encephalopathy in 64 % of cases, mostly in WS , whereas regression was installed after the onset of seizures and was present in 34 % of the observed patient , mostly in LGS. Other important comorbidities found were neurocutaneous syndromes, autistic syndrome, microcephaly , and craniosynostosis.

Polymorphism seizures is a rule, even in  classic WS where  infantile spasms , as revealed in this study, can coexist, with generalized seizures , not to mention focal seizures that may occur in early clinical spasm or as onset clinical manifestation. I also found that in LGS infantile spasms may persist in association with generalized seizures representative for LGS.

 

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