CSWS-related autistic regression versus autistic

regression without CSWSRoberto Tuchman

Miami Children’s Hospital, Miami Children’s Hospital Dan Marino Center, Miami, Florida, U.S.A

SUMMARY

Continuous spike-waves during slow-wave sleep

(CSWS) and Landau-Kleffner syndrome (LKS)

are two clinical epileptic syndromes that are

associated with the electroencephalography

(EEG) pattern of electrical status epilepticus dur-

ing slow wave sleep (ESES). Autistic regression

occurs in approximately 30% of children with aut-

ism and is associated with an epileptiform EEG in

approximately 20%. The behavioral phenotypes

of CSWS, LKS, and autistic regression overlap.

However, the differences in age of regression,

degree and type of regression, and frequency of

epilepsy and EEG abnormalities suggest that

these are distinct phenotypes. CSWS with autis-

tic regression is rare, as is autistic regression

associated with ESES. The pathophysiology and

as such the treatment implications for children

with CSWS and autistic regression are distinct

from those with autistic regression without

CSWS.

KEY WORDS: Autism, Regression, CSWS, ESES,

LKS.

Continuous spike-waves during slow-wave sleep(CSWS) is one of two clinical epileptic syndromes that areassociated with the electroencephalography (EEG) patternof electrical status epilepticus during slow wave sleep(ESES), the other being Landau-Kleffner syndrome(LKS) (1989). ESES describes an electroencephalo-graphic pattern in which the epileptiform dischargesincrease during sleep (Patry et al., 1971). CSWS and LKSare considered distinct epileptic encephalopathies withcommon clinical features including seizures, regression,and epileptiform abnormalities that are activated by sleep(Nickels & Wirrell, 2008). In CSWS there is a regressionin global skills, whereas in LKS the primary clinical mani-festation is a regression of language, and both can have abehavioral phenotype that overlaps with autism (Nickels& Wirrell, 2008). In the epileptic encephalopathies suchas CSWS, the hypothesis is that the seizures or the interic-tal epileptiform activity are responsible for the cognitive,language, and behavioral deterioration (Nabbout & Dulac,2003). The implications are that the EEG abnormalitieslead to the language, behavioral, and cognitive regression

and that the treatment of these epileptic encephalopathiesrequires reversal of the ESES pattern on the EEG.

Autism is a behavioral phenotype characterized byqualitative deficits in social interaction and in language, inassociation with repetitive behaviors (Tuchman, 2003).Epilepsy is present in 30% of children with autism and isusually associated with cognitive dysfunction, with thehighest rate of epilepsy in those with the greatest impair-ment in intellectual capabilities (Tuchman & Rapin,2002). Reports on the prevalence of epileptiform abnor-malities in individuals with autism and no clinical historyof seizures are varied with studies reporting rates of6.1–31% (Kagan-Kushnir et al., 2005). Approximatelyone-third of parents report a regression of language,usually 3–5 words between 18 and 24 months, togetherwith the appearance of autistic behaviors (Goldberg et al.,2003; Lord et al., 2004; Luyster et al., 2005; Werner &Dawson, 2005). This regression has been termed autisticregression and can be superimposed on prior abnormaldevelopment. There has been considerable controversyregarding the role of epilepsy and EEG abnormalities inautistic regression (Deonna & Roulet, 2006; Tuchman,2006). Some studies have reported higher rates of epilepsyin children with autism and regression (Kobayashi &Murata, 1998; Hrdlicka et al., 2004) and others have notfound any relationship among autism, epilepsy, andregression (Tuchman et al., 1991; Baird et al., 2008).

Address correspondence to Roberto Tuchman, MD, Director, AutismProgram Miami Children’s Hospital, Miami Children’s Hospital DanMarino Center, 2900 South Commerce Parkway Weston, Florida U.S.A.E-mail: tuchman@att.net

Wiley Periodicals, Inc.ª 2009 International League Against Epilepsy

Epilepsia, 50(Suppl. 7): 18–20, 2009doi: 10.1111/j.1528-1167.2009.02212.x

FIFTY YEARS OF LANDAU-KLEFFNER SYNDROME

18

The mean age of onset in CSWS is between 4 and8 years of age and the peak age of onset in LKS is4–5 years (Nickels & Wirrell, 2008). Autistic regression,as discussed in the preceding text, usually occurs before24 months of age. There are children with late-onset autis-tic regression who have been given the diagnostic label ofdisintegrative disorder (DD) (Whitehouse, 1990). Regres-sion in DD includes motor regression and loss of boweland bladder use, and usually occurs after age 3 years(Burd et al., 1989; Volkmar, 1992; Rapin, 1995;Mouridsen et al., 1999; Rogers, 2004). EEG abnormalitiesare significantly more common in the histories of thosewith DD than those with infantile autism (Kurita et al.,1992), and the prevalence of epilepsy in DD has beenreported to be as high as 77% (Mouridsen et al., 2000).There are rare reports of children with an acquired frontalsyndrome with CSWS with a phenotype similar to that ofDD (Roulet Perez et al., 1993). DD is a rare disorder witha prevalence of 1.1–6.4 per 100,000 (Fombone, 2002).The regression that occurs in DD is more global than autis-tic regression and these children usually have a worse out-come than those with autistic regression (Rapin, 1995;Burd et al., 1998; Dawson, 2000). Although children withDD are more likely to be associated with an epileptiformEEG than those with autistic regression, it is not knownhow often ESES occurs in this group of children.

There is adifference between thosechildren who developautism andregress prior toage 2 years and those that regressafter age 3 years when language skills are clearly estab-lished. For example, seizures in autistic regression are morelikely to occur in children who regress in language after age3 (Klein et al., 2000; Shinnar et al., 2001; Wilson et al.,2003). This finding is different from data on children withLKS, as only 12–14% of these children regress before age3 years (Bishop, 1985) and the peak age of onset of symp-toms is between 5 and 7 years (Bureau, 1995). McVicaret al. (2005) found that children with isolated languageregression have a higher frequency of epileptiform dis-charges and seizures than children with both language andautistic (i.e., social and behavioral) regression.

CSWS with autistic regression is a rare occurrence. Onestudy reported on 102 children with ESES identified from aretrospective review of 1,497 records over a 5-year interval,and stated that of the 90 children with clinical information20% met criteria for LKS (Van Hirtum-Das et al., 2006). Itis unclear how many met criteria for CSWS with autisticregression. In this latter study in those that did not meet cri-teria for LKS, a spike-wave index of >50% was more likelyto be associated with global developmental impairmentthan in those children with a spike-wave index of £50%.There are differences in the frequency and severity of epi-lepsy between patients with CSWS and LKS, with childrenwith CSWS having more severe and frequent and difficult-to-treat seizures than those with LKS (Jayakar & Seshia,1991; Smith & Hoeppner, 2003). Although both CSWS and

LKS are sleep-activated epileptic encephalopathies, thereis great variability in the EEG findings, and ESES may notbe present in every EEG or there may be significant fluctua-tions in the ESES between EEGs done at differenttime-points (Nickels & Wirrell, 2008). Furthermore, thedefinition of ESES has varied among studies, making itdifficult to accurately determine the prevalence of ESES(McVicar & Shinnar, 2004; Van Hirtum-Das et al., 2006).

In most studies that have reported EEG findings inchildren with autistic regression, the pattern of ESES isnot found (Tuchman & Rapin, 1997; Shinnar et al., 2001;Baird et al., 2006). In a retrospective chart review of chil-dren with language regression and overnight video-EEGmonitoring, 9 of 149 children included in the study metcriteria for LKS and had the EEG pattern of ESES(McVicar et al., 2005). The investigators of the latter studyreported that two of the children met criteria for LKS, butwere not included in the LKS group as they had a previousdiagnosis of autism, and one of these two children hadESES. This study suggest that ESES is rare in autisticregression, as in a >12-year period, during a time when itwas the practice of that institution to admit all childrenwith language regression for overnight EEG monitoring,only 10 children with ESES were identified. In fact, ofthose 10 children with ESES, only one had a history ofautism, suggesting that although epileptiform EEG abnor-malities occurred in 28% of children with autism andlanguage regression, ESES is a rare occurrence in associa-tion with autistic regression (McVicar et al., 2005).

Approximately 20% of children with autistic regressionwithout epilepsy have an abnormal EEG, the majoritywith spikes or spike-and-wave discharges (epileptiform)(Tuchman & Rapin, 1997). This abnormal EEG is foundusually after the regression, and there is no evidence of acausal relationship between the epileptiform abnormali-ties and the regression (Canitano et al., 2005). A recentstudy (Giannotti et al., 2008) investigated the role of sleepin autistic regression and found that disrupted sleep pat-terns were common among those with autistic regression,as was epilepsy. In addition, they found that epileptiformactivity did not differ among those with and without regres-sion, except that those with autistic regression were morelikely than those without regression to have more ‘‘frequentepileptiform EEGs.’’ The investigators of this latterstudy defined ‘‘frequent epileptiform abnormalities’’ as >2spikes per minute or 5–10 s/bursts of spikes (Giannottiet al., 2008). They did not comment on how many of thechildren with autistic regression met criteria for ESES.

CSWS with autistic regression is rare. In children withautistic regression the EEG pattern of ESES is rare. At thepresent time the evidence does not support a causal rela-tionship between epilepsy or epileptiform abnormalitiesin autistic regression (Deonna & Roulet, 2006). It is likelythat genetic and molecular biology explanations willemerge and clarify the overlap between the epileptic

19

CSWS-Related Autistic Regression vs. Autistic Regression without CSWS

Epilepsia, 50(Suppl. 7):18–20, 2009doi: 10.1111/j.1528-1167.2009.02212.x

encephalopathies such as LKS and CSWS and behavioralphenotypes such as autism and autistic regression withan epileptiform EEG (Abrahams & Geschwind, 2008;Coutelier et al., 2008).

Acknowledgment

Disclosure: The author has no conflicts of interest to disclose.

References

Abrahams BS, Geschwind DH. (2008) Advances in autism genetics: onthe threshold of a new neurobiology. Nat Rev Genet 9:341–355.

Baird G, Robinson RO, Boyd S, Charman T. (2006) Sleep electroenceph-alograms in young children with autism with and without regression.Dev Med Child Neurol 48:604–608.

Baird G, Charman T, Pickles A, Chandler S, Loucas T, Meldrum D,Carcani-Rathwell I, Serkana D, Simonoff E. (2008) Regression,developmental trajectory and associated problems in disorders in theautism spectrum: the SNAP study. J Autism Dev Disord 38:1827–1836.

Bishop DV. (1985) Age of onset and outcome in ‘acquired aphasia withconvulsive disorder’ (Landau–Kleffner syndrome). Dev Med ChildNeurol 27:705–712.

Burd L, Fisher W, Kerbeshian J. (1989) Pervasive disintegrative disorder:are Rett syndrome and Heller dementia infantilis subtypes? Dev MedChild Neurol 31:609–616.

Burd L, Ivey M, Barth A, Kerbeshian J. (1998) Two males with child-hood disintegrative disorder: a prospective 14-year outcome study.Dev Med Child Neurol 40:702–707.

Bureau M. (1995) Outstanding cases of CSWS and LKS: analysis of datasheets provided by the participants. In Beaumanoir A, Bureau M,Deonna T, Mira L, Tassinari CA (Eds) Continuous Spikes and WavesDuring Slow Sleep, Electrical Status Epilepticus During Slow Sleep,Acquired Epileptic Aphasia and Related Conditions. John Libbey,London, pp. 213–216.

Canitano R, Luchetti A, Zappella M. (2005) Epilepsy, electroencephalo-graphic abnormalities, and regression in children with autism. J ChildNeurol 20:27–31.

Coutelier M, Andries S, Ghariani S, Dan B, Duyckaerts C, van Rijckevor-sel K, Raftopoulos C, Deconinck N, Sonderegger P, Scaravilli F,Vikkula M, Godfraind C. (2008) Neuroserpin mutation causes electri-cal status epilepticus of slow-wave sleep. Neurology 71:64–66.

Dawson G. (2000) What is Childhood Disintegrative Disorder, how is itdifferent from autism, and what is believed to be its cause? J AutismDev Disord 30:177.

Deonna T, Roulet E. (2006) Autistic spectrum disorder: evaluating apossible contributing or causal role of epilepsy. Epilepsia 47(Suppl.2):79–82.

Fombone E. (2002) Prevalence of childhood disintegrative disorder.Autism 6:149–157.

Giannotti F, Cortesi F, Cerquiglini A, Miraglia D, Vagnoni C, SebastianiT, Bernabei P. (2008) An investigation of sleep characteristics, EEGabnormalities and epilepsy in developmentally regressed and non-regressed children with autism. J Autism Dev Disord 38:1888–1897.

Goldberg WA, Osann K, Filipek PA, Laulhere T, Jarvis K, Modahl C,Flodman P, Spence MA. (2003) Language and other regression:assessment and timing. J Autism Dev Disord 33:607–616.

Hrdlicka M, Komarek V, Propper L, Kulisek R, Zumrova A, Faladova L,Havlovicova M, Sedlacek Z, Blatny M, Urbanek T. (2004) NotEEG abnormalities but epilepsy is associated with autistic regressionand mental functioning in childhood autism. Eur Child AdolescPsychiatry 13:209–213.

Jayakar PB, Seshia SS. (1991) Electrical status epilepticus during slow-wave sleep: a review. J Clin Neurophysiol 8:299–311.

Kagan-Kushnir T, Roberts SW, Snead OC 3rd. (2005) Screeningelectroencephalograms in autism spectrum disorders: evidence-basedguideline. J Child Neurol 20:197–206.

Klein SK, Tuchman RF, Rapin I. (2000) The influence of premorbidlanguage skills and behavior on language recovery in children withverbal auditory agnosia. J Child Neurol 15:36–43.

Kobayashi R, Murata T. (1998) Setback phenomenon in autism and long-term prognosis. Acta Psychiatr Scand 98:296–303.

Kurita H, Kita M, Miyake Y. (1992) A comparative study of developmentand symptoms among disintegrative psychosis and infantile autismwith and without speech loss. J Autism Dev Disord 22:175–188.

Lord C, Shulman C, DiLavore P. (2004) Regression and word loss inautistic spectrum disorders. J Child Psychol Psychiatry 45:936–955.

Luyster R, Richler J, Risi S, Hsu WL, Dawson G, Bernier R, Dunn M,Hepburn S, Hyman SL, McMahon WM, Goudie-Nice J, Minshew N,Rogers S, Sigman M, Spence MA, Goldberg WA, Tager-Flusberg H,Volkmar FR, Lord C. (2005) Early regression in social communica-tion in autism spectrum disorders: a CPEA Study. Dev Neuropsychol27:311–336.

McVicar KA, Shinnar S. (2004) Landau–Kleffner syndrome, electricalstatus epilepticus in slow wave sleep, and language regression in chil-dren. Ment Retard Dev Disabil Res Rev 10:144–149.

McVicar KA, Ballaban-Gil K, Rapin I, Moshe SL, Shinnar S. (2005)Epileptiform EEG abnormalities in children with language regres-sion. Neurology 65:129–131.

Mouridsen SE, Rich B, Isager T. (1999) Epilepsy in disintegrativepsychosis and infantile autism: a long-term validation study. DevMed Child Neurol 41:110–114.

Mouridsen SE, Rich B, Isager T. (2000) A comparative study of geneticand neurobiological findings in disintegrative psychosis and infantileautism. Psychiatry Clin Neurosci 54:441–446.

Nabbout R, Dulac O. (2003) Epileptic encephalopathies: a briefoverview. J Clin Neurophysiol 20:393–397.

Nickels K, Wirrell E. (2008) Electrical status epilepticus in sleep. SeminPediatr Neurol 15:50–60.

Patry G, Lyagoubi S, Tassinari CA. (1971) Subclinical ‘‘electrical statusepilepticus’’ induced by sleep in children. A clinical and electroen-cephalographic study of six cases. Arch Neurol 24:242–252.

Rapin I. (1995) Autistic regression and disintegrative disorder: howimportant the role of epilepsy? Semin Pediatr Neurol 2:278–285.

Rogers SJ. (2004) Developmental regression in autism spectrum disor-ders. Ment Retard Dev Disabil Res Rev 10:139–143.

Roulet Perez E, Davidoff V, Despland PA, Deonna T. (1993) Mental andbehavioural deterioration of children with epilepsy and CSWS: acquiredepileptic frontal syndrome. Dev Med Child Neurol 35:661–674.

Shinnar S, Rapin I, Arnold S, Tuchman RF, Shulman L, Ballaban-Gil K,Maw M, Deuel RK, Volkmar FR. (2001) Language regression inchildhood. Pediatr Neurol 24:183–189.

Smith MC, Hoeppner TJ. (2003) Epileptic encephalopathy of late child-hood: Landau–Kleffner syndrome and the syndrome of continuousspikes and waves during slow-wave sleep. J Clin Neurophysiol20:462–472.

Tuchman RF, Rapin I, Shinnar S. (1991) Autistic and dysphasic children.II: Epilepsy. Pediatrics 88:1219–1225.

Tuchman RF, Rapin I. (1997) Regression in pervasive developmentaldisorders: seizures and epileptiform electroencephalogram correlates.Pediatrics 99:560–566.

Tuchman R, Rapin I. (2002) Epilepsy in autism. Lancet Neurol 1:352–358.

Tuchman R. (2003) Autism. Neurol Clin 21:915–932, viii.Tuchman R. (2006) Autism and epilepsy: what has regression got to do

with it? Epilepsy Curr 6:107–111.Van Hirtum-Das M, Licht EA, Koh S, Wu JY, Shields WD, Sankar R.

(2006) Children with ESES: variability in the syndrome. EpilepsyRes 70(Suppl. 1):S248–S258.

Volkmar FR. (1992) Childhood disintegrative disorder: issues forDSM-IV. J Autism Dev Disord 22:625–642.

Werner E, Dawson G. (2005) Validation of the phenomenon of autisticregression using home videotapes. Arch Gen Psychiatry 62:889–895.

Whitehouse W. (1990) Pervasive disintegrative disorder? Dev Med ChildNeurol 32:556.

Wilson S, Djukic A, Shinnar S, Dharmani C, Rapin I. (2003) Clinicalcharacteristics of language regression in children. Dev Med ChildNeurol 45:508–514.

20

R. Tuchman

Epilepsia, 50(Suppl. 7):18–20, 2009doi: 10.1111/j.1528-1167.2009.02212.x