Epilepsia, 46(6):889–900, 2005Blackwell Publishing, Inc.C© 2005 International League Against Epilepsy

Early Thalamic Injury Associated with Epilepsy and ContinuousSpike–Wave during Slow Sleep

∗Francesco Guzzetta, ∗Domenica Battaglia, ∗Chiara Veredice, ∗Valeria Donvito, ∗Marika Pane,∗Donatella Lettori, ∗Francesca Chiricozzi, ∗Daniela Chieffo, †Tommaso Tartaglione,and ∗Charlotte Dravet

Departments of ∗Medical and Surgical Pediatrics and Developmental Neurosciences and †Radiology, Catholic University,Rome, Italy

Summary: Purpose: Mechanisms inducing continuous spike–wave during slow sleep (CSWS) in encephalopathy with elec-trical status epilepticus during sleep are still unclear. Recently,some sporadic cases with early thalamic injury associated withCSWS have been reported. The aim of the study was to investi-gate in a population of patients with an early thalamic injury thepresence of an activation of paroxysmal activities during sleep,their characteristics, and possible relations to neuroimaging andneuropsychological features.

Methods: Thirty-two patients with prenatal or perinatal tha-lamic injuries, mostly due to a vascular mechanisms, were fullyexamined, including neuroimaging, EEG monitoring, and cog-nitive follow-up.

Results and Conclusions: Twenty-nine of 32 patients showedmajor sleep EEG activation. Among these 29 patients, two dif-

ferent groups were distinguished: the first included the more orless typical CSWS (12 cases), generally with symmetry of spikeand waves (SWs) and often with no spindle at all. The othercases had an usual asymmetry of SWs and presence or reductionof spindles, plus other atypical features concerning synchronismand morphology of SWs. Behavioral disorders were significantlymore present in patients with a true CSWS; their improvement(and in one case of the three thoroughly followed the improve-ment of cognitive competence) paralleled the disappearance ofCSWS. The generally predominant injury of the lateral aspect ofthe thalamus included reticular nucleus and ventral nuclei. Animbalance of γ -aminobutyric acid (GABA)B- versus GABAA -mediated receptors may be evoked as a cofactor predisposing toCSWS.

Epilepsy with continuous spike–waves (SWs) dur-ing slow sleep (CSWS) is an acknowledged epileptic syn-drome characterized by a combination of focal epilepsy,neuropsychological impairment, and typical EEG find-ings with a pattern of diffuse SWs occurring in ≤85%of slow sleep (1). Recently, the possible role of primaryearly thalamic injury in generating CSWS has been sug-gested (2), and sporadic cases with similar lesions havebeen reported (3–8). Morphologic and metabolic thala-mic abnormalities have been described in CSWS as well(9). Our study aimed at clarifying (a) the possible pres-ence and eventually the characteristics of an activation ofparoxysmal activities during sleep in a population of pa-tients with an early thalamic injury; and (b) their relationto findings from neuroimaging, with thalamic injuries, andwith neuropsychological features.

Accepted January 23, 2005.Address correspondence and reprint requests to Dr. F. Guzzetta

at Division of Child Neurology and Psychiatry, School of Medicine,Catholic University, Largo Gemelli I-00168 Rome, Italy. E-mail:fguzzetta@rm.unicatt.it

PATIENTS AND METHODS

All the patients aged between 4 and 12 years (whenCSWS usually develops), showing at magnetic resonanceimaging (MRI) an early acquired thalamic lesion and con-sequently admitted to our hospital between 1999 and 2003,were enrolled in the study. Indication for MRI resultedfrom the clinical problems suggesting hospital admission[i.e., paroxysmal manifestations (19 cases) or follow-upof newborns at risk (13 cases)].

Brain injury co-involving thalamus was generally de-termined by an ischemic or hemorrhagic prenatal or peri-natal insult; in only three cases were brain lesions sequelaeof an infectious disease that occurred in the first monthsof life. All patients underwent a full clinical assessmentthat included a neuropsychological assessment, an EEGrecording session with at least two sleep recordings per-formed over a 1-month period, and MRI. In all cases, apartfrom two without epilepsy, the follow-up was calculatedfrom the onset of seizures to the last observation that hadbeen carried out in our department.

889

890 F. GUZZETTA ET AL.

Seizure types and epilepsies were classified accordingto current international classifications (10,11). To assessthe severity of epilepsy, we considered both the frequencyand the intensity of seizures, as well as the seizure typeand the duration of the active period. The most severe de-gree (+++) consisted of: daily seizures, drop attacks, sec-ondary generalization, status, and polymorphic seizures.The degree immediately below (++) consisted of: weeklyto monthly seizures, absence of drop attacks, no status, andpossible polymorphic seizures. When the second degree(++) lasted <1 year, we rated epilepsy with only one plus(+)

MRIAll patients underwent MRI on a 1.5-Tesla MR system

(Horizon Echospeed/Excite; General Electric, Milwau-kee, WI, U.S.A.). MRI was performed in all patients byusing a high-resolution protocol, consisting of: (a) sagit-tal spin-echo T1-weighted sequence (TR, 650 ms; TE, 15ms; two excitations; 24-cm field of view; 4-mm thickness;10% intersections gap; 256 × 256 acquisition matrix); (b)axial and coronal fast spin–echo T2-weighted sequences(TR, 2,750 ms; TE, 100 ms; two excitations; 24-cm fieldof view; 3-mm thickness; 10% intersections gap; 256 ×320 acquisition matrix).

MRI was repeated several times (from two to fivetimes), especially when the first examinations did not al-low us to evaluate the lesions properly. Neuroimagingrecords included the description of thalamic lesions ac-cording to the involvement of different nuclei, as well asregarding any other possible brain lesion. An analysis ofthe thalamus was performed by defining, whenever pos-sible, the ischemic and/or hemorrhagic character of thelesion and its location. Because of possible image distor-tions caused by the different types of destructive injury,especially when hydrocephalus was present, the locationwas only grossly defined as regarding (a) the lateral as-pect of the thalamus including the reticular nucleus (nRT),(b) the medial nuclear mass, including the mediodor-sal nucleus, (c) the ventral nuclear mass comprising theventral posterior, lateral and anterior nuclei; and (d) thelateral-posterior nuclear mass (the pulvinar). The lasttwo categories may possibly include the intralaminarnucleus.

EEG recording and polysomnographyVideopolygraphic study was performed by using 21

EEG electrodes according to the 10/20 International Sys-tem. In the youngest infants, 11 electrodes were used. Del-toid surface electromyogram (EMG) also was recorded.

Every patient underwent numerous recordings whenawake (≤24) and repeated, sometimes prolonged, sleeprecordings (≤16); 14 patients had at least one nocturnalpolysomnography video-EEG recording lasting ≥24 h.

Two groups of patients on the base of the duration ofslow sleep abnormalities were distinguished: those with

>85% SWs (CSWS) and those with <85% (not classifi-able as CSWS). The former were separated into typicaland atypical CSWS. Typical CSWS was characterized bya pattern persisting for more than a month, consisting ofdiffuse, rhythmic, synchronous, and symmetrical SWs oc-curring in >85% of slow sleep, with typical morphologyand with the absence of physiologic sleep figures (Fig. 1).In atypical CSWS, the morphology of the anomalies wasvariable, consisting of SWs associated with spikes (S),polyspikes (SS), sharp waves, often being asynchronous,asymmetrical, or even unilateral and nonrhythmic(Fig. 2). In the group without CSWS, the anomalies weremore heterogeneous, often multifocal, noncontinuous (oc-cupying ≥50% of slow sleep), and sometimes similar tothose seen in Lennox–Gastaut syndrome; the physiologicsleep elements were usually present. We named these as-pects “sleep overactivation” of epileptic paroxysms (Fig.3).

Neuropsychological assessmentNeuropsychological skills and cognitive development

were assessed with techniques relevant to the age of thechildren examined [Griffiths developmental scales (12),WPPSI (13), WISC-R (14)], as well as with tests concern-ing specific abilities. Patients were classified according tothe following criteria:

IQ or DQ >85, normal mental developmentBetween 75 and 85, borderline mental developmentBetween 50 and 75, mild mental retardationBetween 25 and 50, moderate mental retardation<25, severe mental retardation.

The behavioral disturbances were defined as (a) severe(+++) when associated with major disorders in com-munication and in social interaction, with restricted andstereotyped patterns of behavior as well as severe symp-toms such as extreme hyperactivity and aggressiveness orself-injurious behavior; (b) moderate (++) when charac-terized by a lesser degree of these major behavioral trou-bles; and (c) mild (+) when minor social disorders andabnormal adaptive problems such as aggressiveness, hy-peractivity, or major inhibition were present.

RESULTS

Main clinical data are reported in Table 1. Twenty-nineof the 32 patients showed a dramatic activation of parox-ysmal activities during sleep, shaping a pattern of CSWSin 12 cases; only three were the patients with thalamicinjury and without paroxysmal activation during sleep.The follow-up mean after the first seizure was 4 years 9months (range, 7 months to 13 years 10 months). Mostof the cases had a hemiplegia; nine cases had a doublehemiplegia (cases 9, 11, 15. 20, 23, 25, 27, 28, and 30),and only one patient (case 7) had a spastic diplegia. Cases14 and 22 were neurologically normal. All the patients

Epilepsia, Vol. 46, No. 6, 2005

EARLY THALAMIC INJURY AND CSWS 891

FIG. 1. Case 2. a: Awake EEG: focal right centrotemporal spikes and synchronous bilateral frontocentrotemporal SW discharges. b:Diffuse continuous SW during slow sleep with typical SW morphology (synchronous, rhythmic, and symmetrical). c: Well evident at400-mV sensitivity.

but two (cases 31 and 32) had epilepsy; 12 of them wereseizure free for at least the last year of the follow-up.

At the onset of sleep EEG disorders, we avoided us-ing antiepileptic drugs (AEDs) possibly supporting them,

FIG. 2. Case 4. a: Awake EEG: multifocal spikes. b: Continuous irregular, asynchronous spikes and SW during slow sleep. c: Moreevident at 200-mV sensitivity.

such as carbamazepine (CBZ), phenytoin (PHT), and phe-nobarbital (PB). CSWS was treated with usual specificdrugs [valproate (VPA), ethosuximide (ESM), benzodi-azepines (BZDs), and steroids]; two patients (cases 1

Epilepsia, Vol. 46, No. 6, 2005

892 F. GUZZETTA ET AL.

FIG. 3. Case 13. a: Awake EEG: strongly asymmetrical background activity with left parietooccipitotemporal spikes. b, c: Subcontinuousspikes and sharp waves on the left hemisphere and polyspikes discharges predominant on the left regions.

and 17) were given neurosurgical treatment: extensive cor-ticectomy around a large porencephaly at 7 years and ahemispherectomy at 4 years, respectively.

Neuroimaging dataThe results of MRI examination are shown in Table 2.

Various cortical/subcortical injuries, consistent with dif-ferent etiologies, were observed in all cases. The mostcommon causes were ischemic or hemorrhagic in ori-gin, with unilateral, or predominantly unilateral, locations.Vascular causes were common in 13 patients: with peri-natal ischemic infarction in nine term newborns and withhemorrhagic venous infarction in four preterms. In other15 patients, a more diffuse ischemic mechanism can beevoked, such as neonatal hypoxic–ischemic encephalopa-thy, periventricular leukomalacia, or posthemorrhagic hy-drocephalus; the only case with a developmental disor-der of the CNS (myelomeningocele) showed ischemicinjury also, presumably linked to a vascular mechanisminvolving the posterior thalamic perforating arteries orig-inating from the precommunicating portion of posteriorcerebral artery (PCA). The remaining three patients hadpostmeningitic hydrocephalus.

Characteristically, thalamic lesions were unilateral orpredominantly unilateral, always ipsilateral to vascular in-farction (Figs. 4 and 5). In eight of nine cases with bilat-eral thalamic injury, one side was predominantly involved(Fig. 6). Among thalamic nuclei, the lateral part of thala-mus, including nRT, and the ventral mass were commonlyinjured; the other nuclei were differently affected accord-ing to the kind of injury. In one patient (case 15), the leftthalamus was completely destroyed. (The percentage of

the involvement for each considered part of thalamus isreported in Fig. 7.)

Electrophysiologic resultsEEG data are presented in Table 3. In all patients, focal

and/or multifocal EEG abnormalities were observed, gen-erally consistent with the location of cortical injuries. Inall the 30 epilepsy patients but one (case 30), a strong acti-vation of paroxysmal abnormalities was seen during slowsleep. Twelve patients had CSWS; three of these showedthe typical form (patients 1–3), and nine, the atypical one(patients 4–12). The remaining 17 (patients 13–29) hadonly a “sleep overactivation.” Among them, two had fea-tures that were similar to Lennox–Gastaut syndrome, inparticular, rapid recruiting rhythms and low frequency ofSW (patients 16,17). Cases 31 and 32 had neither sleepoveractivation nor epilepsy. The EEG, at awake and sleep,of patient 32 was normal in the first 3 years. Successively,the EEG showed rare right frontal spikes and rare gen-eralized SWs during sleep. At 4 years, a worsening wasobserved, with the appearance of frequent spikes and SWsin the awake EEG in the right hemisphere, mildly activatedby sleep.

For six children (patients 1, 2, 6, 7, 16, and 17), it wasdifficult to determine the very onset of sleep activationbecause they were referred to our center at a later date. Atfollow-up, we confirmed that the CSWS disappeared inonly three patients, at 15 years for case 1, 12 years for case2, and 5.6 years for case 7. In two patients, CSWS outcomewas still unstable, and transitory recovery was depen-dent on the response to treatment (ESM, corticosteroids).

Epilepsia, Vol. 46, No. 6, 2005

EARLY THALAMIC INJURY AND CSWS 893

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Epilepsia, Vol. 46, No. 6, 2005

894 F. GUZZETTA ET AL.

TABLE 2. Neuroimaging

Thalamic lesions Cortical/subcortical injury location

No. Side Involved nuclei Location Origin

1 R nRT-V-P-DM Right F-T-P Stroke (MCA)2 R nRT-V Right periventricular PHI/PHH3 L nRT-V-P-DM Left F-P-T-O Stroke (MCA)4 BIL (L+) DM-P Bil periventric PVL + IVH/PHH5 L nRT-V-DM Left periventricular PVL + IVH/PHH6 R nRT-V-P-DM Right F-T-P Stroke (MCA)7 BIL (L+) nRT-V-P-DM Left subcortical, right T-O Post. ischemia, MMC8 R nRT-V-P Periventricular WM PVL + IVH/PHH9 R nRT-V-P Posterior WM Infectious/PMH

10 L nRT-DM Left P-T-O WM HIE11 L nRT-V Left F-O-T, right P-T-O WM Infectious/PMH12 R nRT-V-P Bil F-P-T-O, basal ganglia HIE13 L nRT-V-P-DM Left F-T-P Stroke (MCA)14 BIL (R+) Right V Periventricular WM HIE

Left nRT-V15 BIL (L+) nRT-V-P-DM Periventricular WM PHI/PHH16 L nRT-V Left F-T-Pt Stroke (MCA)17 L nRT-V-P-DM Left periventricular (F-P-O) PHI/PHH18 L nRT-V-P-DM Bil Periventricular PHI/PHH19 R nRT-V-DM F-T-P-O right Stroke (PCA)20 BIL (L+) nRT-V-P Left T-O WM PHH21 L nRT-V-P Left T-P-O Stroke (MCA)22 L V-P Diffuse WM IVH/PHH23 R nRT-V-P Right F-P-T-O Infectious/PMH24 BIL (R+) nRT-V-P Left P-O PVL + IVH/PHH25 BIL nRT-V Bilateral WM HIE26 L nRT-V L subcortical, basal ganglia Stroke (MCA)27 R nRT-P Right F, diffuse WM PVL + IVH/PHH28 BIL (L+) nRT-V-P Bilateral WM PVL + IVH/ PHH29 R P Diffuse WM Cerebellar hemorrh, PHH30 R nRT-V-P Posteriorly diffuse PVL + IVH/PHH31 L nRT-V Left P Stroke (MCA)32 BIL (L+) nRT-V Left periventricular WM HIE

nRT, reticular nucleus; V, ventral mass; P, posterior mass; DM, dorsomedial nucleus; F, frontal; P, parietal; T, temporal; O, occipital; WM, whitematter; PHI, periventricular hemorrhagic infarction; PHH, posthemorrhagic hydrocephalus; PVL, periventricular leukomalacia; IVH, intraventricu-lar hemorrhage; PMH, postmeningitic hydrocephalus; HIE, hypoxic–ischemic encephalopathy; MCA, medial cerebral artery; MMC, myelomeningocele.

These were qualified as “variable.” In the remaining cases,CSWS or “overactivation” was still ongoing.

Cognitive and behavioral disordersData in relation to sleep abnormalities (29 cases) are

shown in Table 4. We performed cognitive tests ≥3 daysafter the last seizure. However, in cases 4, 5, 9, 16, 19, and28, several seizures per day occurred; in these cases (threewith borderline or mildly delayed IQ and three with severemental retardation), it was not possible to exclude a role ofthe seizures in a worsening of the test performances. Weshould also consider that each patient, with the exclusionof the three without epilepsy, was administered ≥1 AED.

In the 20 epilepsy patients, where reliable informationbefore the onset of sleep abnormalities was available, cog-nitive development was normal or borderline in 11 cases;the remaining nine cases had mild retardation in one,and severe, in the other eight. After the onset of sleepabnormalities, a definite deterioration of the cognitiveskills was observed in nine of 19 patients. The remaining10 patients also generally showed signs of mental retarda-tion, but these were severe in eight patients and borderline

in one; in one case, development was normal before andremained normal after the onset of the sleep disorder.

Only in one case (patient 2) of three with recoveryfrom CSWS, was an improvement in cognitive compe-tence seen. In all but one of the patients with longitu-dinal assessment, the comparison between DQ was reli-able because the successively performed scales were thesame. Behavioral disorders were present before the onsetof sleep abnormalities in one patient with severe men-tal retardation; he belonged to the group of patients thatwould thereafter have CSWS. During the period of sleepabnormalities, six patients of 12 with typical or atypicalCSWS and only three of 17 cases with a sleep overac-tivation of paroxysms, had behavioral disorders. All thethree patients followed up after CSWS recovery showedan improvement of behavior.

DISCUSSION

CSWS is a specific pattern of electrical status “epilep-ticus” during slow sleep originally described by Tassinariet al. (15). In the latest scheme proposed by the

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FIG. 4. Case 3. a: Axial fluid-attenuated inversion recovery image (FLAIR; TR, 8,800 ms; TI, 2,200 ms; TE, 140 ms). b: Axial turbospin-echo T2-weighted image (TR, 2,750 ms; TE, 100 ms). The images show an extensive area of parenchymal loss involving the lefttemporooccipital lobes, with consequential dilation of the homolateral ventricle. Along the medial margins of the lesion, a mildly hyperintensesignal on T2-weighted and FLAIR images is evident (arrow), involving the lateral aspect of the left thalamus, the reticular nucleus, andinternal capsula, related to parenchymal gliotic changes.

FIG. 5. Case 5. a: Axial unenhanced computed tomography (CT) scan image. b: Axial spin-echo T1-weighted image (TR, 650 ms; TE, 15ms). A focal hyperdense area (arrow), related to acute hemorrhage, is evident along the lateral aspect of the left thalamus, also involving thereticular nucleus. Coexistent hydrocephalic dilation of both ventricles, particularly evident on the left side. The MR examination, obtainedafter the ventriculoperitoneal cerebrospinal fluid shunt, confirms the parenchymal hemorrhagic injury (arrow) with perilesional edema.The inner white matter of the both cerebral hemispheres is reduced in thickness and mildly hyperintense on T2-weighted images withasymmetrical dilation of both ventricles (left>right), related to a previous diffuse parenchymal injury.

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FIG. 6. Case 10. a: Axial fluid-attenuated inversion recovery (FLAIR) image (TR, 8,800 ms; TI, 2,200 ms; TE, 140 ms). b: Axial turbospin-echo T2-weighted image (TR, 2,750 ms; TE, 100 ms). A focal area of mildly hyperintense signal on T2-weighted and FLAIR imagesis evident, involving the ventral aspect of the right thalamus (arrow) related to parenchymal gliotic changes. Along the lateral aspectof the ventral left thalamus, a small area with similar features is evident (small arrow), also involving the reticular nucleus. Some smallparenchymal foci with similar features also are evident in the inner white matter of both cerebral hemispheres.

FIG. 7. Oblique dorsolateral view and medial coronal section of the thalamus, with the percentage of injury involvement of each areaconsidered in the study.

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TABLE 3. EEG features

Slow sleep abnormalitiesDetection age Detection age

No. Awake EEG abnormalities Morphology Symmetry Synchrony Index Spindles of sleep abnormalities of sleep recovery

1 Sharp W, S, SW S, SS, SW Yes Yes ≥85% No ND 15 yr2 SW S, SW Yes Yes ≥85% No ND 12 yr3 SW parietooccipital SW Yes Yes ≥85% No 7 yr Ongoing4 S, SW, SSW bilat S, SW, SS No Yes/No ≥85% No 4 yr 5 mo Variable5 S, slow W SW SW, SSW No No ≥85% Unilateral (R) 3 yr Ongoing6 S, SS, SSW S, SW No Yes ≥85% Bilateral (R+) ND Variable7 Sharp W, SW, SSW S, slow W No No ≥85% No ND 5 yr 6 mo

multifocal8 S, SW multifocal S, SS, SW No No ≥85% Unilateral (L) 4 yr 3 mo Ongoing9 S, SW multifocal, diffuse S, SW No Yes ≥85% Bilateral 4 yr 5 mo Ongoing

10 S, SW multifocal S, SW Yes No ≥85% Bilateral 6 yr 1 mo Ongoing11 S, SW multifocal S, SW Yes Yes ≥85% Bilateral 4 yr Ongoing12 S, SW (R+) SW, S, OL No No ≥85% Unilateral (L) 6 yr 6 mo Ongoing13 Slow W, S, SW S No No ≥50% ≤ 80% Unilateral (L) 3 yr Ongoing14 Slow W, sharp W, S, SW SW No No/Yes ≥50% ≤ 80% Unilateral (L) 4 yr 5 mo Ongoing15 S, SW multifocal S, SW,OL No No ≥50% ≤ 80% Unilateral (L) 4 yr 6 mo Ongoing16 SW S,SS,SW,SSW Yes Yes ≥50% ≤ 80% Bilateral (R+) ND Ongoing17 S, slow SW, SS S,SW,SS No Yes ≥50% ≤ 80% Unilateral (L) ND Ongoing18 S, SW S,SW No No ≥50% ≤ 80% Bilateral 3 yr 6 mo Ongoing19 S, SW S,SW No No ≥50% ≤ 80% Bilateral (L+) 3 yr Ongoing20 S, SW S,SW No No ≥50% ≤ 80% No 2 yr 8 mo Ongoing21 S, SW S, SW No Yes ≥50% ≤ 80% Bilateral 5 yr Ongoing22 S, SW S, SW No Yes ≥50% ≤ 80% Bilateral 3 yr 4 mo Ongoing23 S, SS, SW S, SS, SW No Yes ≥50% ≤ 80% No 1 yr 7 mo Ongoing24 S, slow W S, slowW, SW No Yes ≥50% ≤ 80% Bilateral 6 yr 2 mo Ongoing25 S, SW, multifocal S, SW No No ≥50% ≤ 80% No 1 yr 8 mo Ongoing26 S, SW S, SW No No ≥50% ≤ 80% Bilateral 8 yr 5 mo Ongoing27 S S No No ≥50% ≤ 80% Bilateral 3 yr Ongoing28 Hypsarrhythmia S, SS, SW No No ≥50% ≤ 80% No 4 yr Ongoing29 S S, SS, SW No No ≥50% ≤ 80% Bilateral 5 yr 8 mo Ongoing30 S, SW, left frontotemporal − − − − Bilateral31 S, SW − − − − Bilateral32 S,SW − − – − Bilateral

SW, spike–wave; S, spike; SS, polyspikes; SSW, polyspikes–waves; slow W, slow waves; sharp W, sharp waves; ND, not determined.

International League Against Epilepsy (ILAE), CSWS,associated with various seizure types and a prominentneuropsychological disorder, has been considered to bea unique epileptic encephalopathy in children, called “en-cephalopathy with electrical status epilepticus during slowsleep (ESES), or ESES syndrome” (16). It is an age-related and self-limited disorder generally occurring be-tween ages 4 and 12 years and has typical EEG fea-tures during slow sleep, consisting in almost continuous(>85%) bilateral and diffuse slow SWs. However, afterseveral hundred patients, we should consider many vari-ants of the typical slow-sleep features (focal to diffuseparoxysmal activities, various percentages of SWs <85,morphology of the SWs), and realize that the typical char-acters of slow-sleep abnormalities are only the “tip of aniceberg” (1).

An intriguing point has been raised by a recent studycarried out by Monteiro et al. (2) that reports a case inwhich primary neonatal thalamic hemorrhage was associ-ated with a strong activation of focal paroxysmal activitiesin the left parietotemporal region; they also pointed out asimilar case previously reported in the literature (3). To

explain this association, the authors drew inspiration fromthe experimental work of the Steriade school concerningthe role of the thalamus in generating physiologic sleeposcillations and their possible changes into SW seizures(17). In particular, they built on experimental studies car-ried out by Steriade and Contreras (18) that described“long sequences of continuous spike–wave activity of 2–4Hz, with a spectacular synchronization across all corticalleads” in unilateral athalamic cats. Afterward, some spo-radic cases of early thalamic lesions associated with slowsleep paroxysmal activation were reported (4–8). Further-more, if the possible role of corticothalamic injuries as acofactor predisposing to CSWS (4–6) must be considered;the cases of CSWS described by Veggiotti et al. (19) inearly shunted hydrocephalic children could be explainedby the involvement of thalamocortical circuitries deter-mined by the ventricular dilatation.

Our series comprises 32 patients with early thalamic in-jury, 29 of which had epilepsy with CSWS or paroxysmaloveractivation during sleep.

The peculiarity of our sample, consisting of early clas-tic encephalopathies, could explain the high frequency of

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TABLE 4. Cognitive/behavioral disorders in relation to sleep abnormalities

Before sleep abnormalities During After

Cognitive Behavioral Cognitive Behavioral Cognitive BehavioralCase development disorders development disorders development disorders

1 ? ? S.M.R. (IQ 19) +++ S.M.R + − −2 ? ? Mi.M.R. (IQ 69) ++ − B.M.D. (IQ 77) − − −3 N.M.D. (IQ 95) − − − B.M.D. (IQ 76) − − − − −4 S.M.R. (IQ 30) ++ − S.M.R. (IQ 30) +++ − −5 B.M.D. (IQ 78) − − − Mi.M.R. (IQ 60) + − − − −6 ? ? Mi.M.R. (IQ 56) + − − − −7 ? ? Mo.M.R. (IQ 29) +++ Mo.M.R. (IQ 30) ++ −8 B.M.D. (IQ 72) − − − B.M.D (IQ 71) − − − − −9 S.M.R. (IQ 25) − − − S.M.R. (IQ 27) − − − − −

10 ? ? B.M.D. (IQ 82) − − − − −11 S.M.R. (IQ 32) − − − S.M.R. (IQ 30) − − − − −12 ? ? B.M.D. (IQ 84) − − − − −13 N.M.D. (IQ 102) − − − B.M.D. (IQ 83) − − − − −14 N.M.D. (IQ 90) − − − N.M.D. (IQ 88) − − − − −15 S.M.R. (IQ 27) − − − S.M.R. (IQ 28) − − − − −16 ? ? Mi.M.R. (IQ 55) + + − − −17 ? ? Mi to Mo MR + + − − −

(IQ 73->47->44)18 Mi.M.R. (IQ 51) − − − Mo.M.R. (IQ 40) − − − − −19 B.M.D (IQ 81) − − − Mi.M.R. (IQ 48) − − − − −20 S.M.R. (Bayley MD <50) − − − S.M.R. (IQ 26) − − − − −21 N.M.D. (IQ 101) − − − ? − − − − −22 N.M.D. (IQ 110) − − − N.M.D. (IQ 89) − − − − −23 S.M.R. (IQ 18) − − − S.M.R. (IQ 19) − − − − −24 N.M.D. (IQ 92) − − − B.M.D. (IQ 78) − − − − −25 S.M.R. (IQ 28) − − − S.M.R. (IQ 28) − − − − −26 N.M.D. (IQ 91) − − − B.M.D. (IQ 75) + − − − −27 ? ? N.M.D. (IQ 86) − − − − −28 S.M.R. (IQ 25) − − − S.M.R. (IQ 24) − − − − −29 B.M.D. (IQ 81) − − − Mi.M.R. (IQ 71) − − − − −

N.M.D., normal mental development; B.M.D., borderline mental development; Mi.M.R., mild mental retardation; Mo.M.R., moderate mentalretardation; S.M.R., severe mental retardation.

For symbol explanations, see text (Methods).

the epileptic disorder associated with thalamic injuries.Conversely, several were cases in whom thalamic lesionswere detected since birth or occasionally in routine diag-nostic procedures. Thus even though without epidemio-logic value, given the selected origin of the sample, it isnoteworthy that only in three of 32 cases, thalamic lesionswere not associated with sleep paroxysmal activation. Thefact that sometimes in our series we detected thalamic in-juries after the diagnosis of sleep activation may suggestthat these lesions could be not always accurately lookedfor and therefore were underestimated in children withCSWS.

Apparently no significant difference of clinical and neu-roimaging features exists in the three patients withoutparoxysmal EEG activation during slow sleep. Other coex-isting mechanisms may play a role, as the lack of epilepsyin two of them may suggest. We should point out the rel-atively young age of the three patients, between 6 and 7years, and thus liable to a possible subsequent onset of thedisorder.

Thalamic lesions in our series were unilateral in mostcases; in other cases, an evident predominance of later-

alization was noted. The involvement of the reticular nu-cleus and of the ventral nuclear mass was almost con-stant, and consistent with the following types of injurymechanisms: ischemic infarction of the medial cerebralartery territory in nine cases, periventricular hemorrhagicinfarction in four, and an underlying ischemic pathogen-esis in all the remaining patients but four, including thosepatients with postinfectious hydrocephalus or with a pri-mary malformation (myelomeningocele). The pathogenicvascular mechanism in our series frequently involves theanterior choroidal artery for patients with ischemic in-farction in the middle cerebral artery (MCA) or thalam-ostriate vein area that confluences with the terminal veinfor patients with venous infarction; it may account forthe generally predominant injury of the lateral aspect ofthe thalamus, including the reticular nucleus and the ven-tral nuclei. In only three patients was a different under-lying (infectious) pathogenesis found: however, becauseof the association with hydrocephalus, we cannot excludean ischemic mechanism in determining thalamic injuries.The analysis of electrophysiologic data showed an ar-ray of “iceberg” manifestations concerning the slow sleep

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activation of interictal EEG abnormalities. They extendfrom a simple strong activation of paroxysmal activities(with <85% and often with a focal predominance or mor-phologic atypical aspects) to an activation that was >85%shaping a true CSWS. Matching neuropathologic and elec-trophysiologic data, we first remark that all patients hadcorticosubcortical lesions, in two of them associated withbasal ganglia injuries. Furthermore, we observed that allpatients with bilateral thalamic injury (eight patients) hadless typical forms of the epileptic sleep disorder. This sug-gests that the lack of at least one intact thalamus seems in-compatible with typical CSWS. Finally, in cases with onlya “sleep EEG overactivation,” the paroxysmal anomalieswere generally asymmetrical (excepted case 16). We canthus distinguish the series in two different groups; the firstincluded typical and almost all atypical CSWS with >85%of SWs, possibly symmetrical, and often with no spindlesat all; the second one presented a usual asymmetry of SWsand an absence or reduction of spindles, plus other atypicalfeatures concerning the synchronism and morphology ofSWs. This distribution, in at least two distinct groups withcoherent characteristics, casts some doubt on the continu-ity of the “iceberg” and may suggest in our series differentpathogenic mechanisms.

As regards cognitive features, we frequently observedcognitive deterioration or behavioral disorders or bothat the onset of the sleep EEG activation in our series,and this is consistent with general findings in cases ofCSWS (20,21). Furthermore, we note that behavioral dis-orders were significantly more present in patients with trueCSWS. Only in one case of the three patients in whomCSWS disappeared was a definite improvement of cogni-tive competence noted, whereas behavior improved in allthree patients. We were not able to draw any informationfrom our series about the possible role of injury, epilep-tic disorder, or EEG focal location on the behavioral orcognitive profile of the disorder.

A possible explanation of the mechanism underlyingthe EEG activation in our series could be an imbalancebetween GABAB- and GABAA-mediated receptors due tothalamic injury, especially of the GABAergic reticular nu-cleus. Evidence exists that physiologic oscillations duringsleep, such as spindles, and paroxysmal epileptic disor-ders, like absence seizures, are related phenomena (22,23)whose cellular mechanisms are based on the cyclical in-teraction between excitatory thalamocortical cells and in-hibitory GABAergic nRT cells (24,25). In CSWS, epilep-tic discharges during slow sleep seem related to spindle-inducing mechanisms (25). The switch from physiologicoscillation frequency at 6–10 Hz to a slow paroxysmal(SW) oscillation frequency of 3–4 Hz could be related tothe passage from GABAA receptor–mediated inhibitorypostsynaptic potentials (IPSPs), setting the network os-cillation frequency at 6–10 Hz, to GABAB receptor–mediated IPSPs changing the spindle-wave frequency to

3–4 Hz (26,27). The switch mechanism can possiblybe linked to the increased firing of the cortex, leadingto increased firing in the GABA cells of the thalamus.The release of higher amounts of GABA into thalamicsynapses activates GABAB receptors and changes the nor-mal GABAA receptor–mediated oscillation setting (28).An imbalance of GABAB- versus GABAA-mediated re-ceptors, such as determined by GABAA-antagonist block-ade of fast IPSPs, produces three to four large oscillationsindependent of the kind of cortical firing (29).

In some way similar, an ill-balanced condition due tothalamic injury, in particular of nRT, could be a predis-posing cofactor of CSWS. In conclusion, our series is aselected cohort of children with thalamic early injury as-sociated with symptomatic CSWS or sleep SW overacti-vation. A comparative study of clinical features betweenCSWS epileptic children with and without early thalamicinjuries could better highlight the role played by thalamiclesions in predisposing to the sleep electrical disorder andthe consequent clinical picture. If our data are confirmed,early thalamic injury may be considered a cofactor pre-disposing to CSWS, and its detection in infancy or earlychildhood could be considered a warning sign of the on-set of CSWS. It should indicate an accurate EEG sleepmonitoring for an early treatment, to prevent the cognitivedeterioration and the behavioral disorders that are usuallyassociated with the sleep EEG disorder.

Acknowledgment: We warmly thank Professor C.A. Tassi-nari and Professor R. Guerrini for reading the paper and givingprecious comments and suggestions.

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