An expert team conducted a ten-year survey of eight children with Landau-Kleffner
syndrome (LKS) identified among children referred to Polyclinic »SUVAG« in Zagreb
because of hearing disturbances. Although LKS is a rare disorder it is extremely important
to detect it because early diagnosis and prompt medicinal treatment may improve
the prognosis, whereas neglect and late diagnosis result in language disability. Standard
diagnostic criteria must be established to enable timely treatment

A. Vrca

H. Škobić

J. Ivičević-Desnica

N. Šikić

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Coll. Antropol. 25 (2001) 2: 529–534UDC 616.853-036:612.821.5Original scientific paperImportance of Early DrugTreatment in Prognosis ofthe Landau-Kleffner SyndromeN. [iki}1, J. Ivi~evi}-Desnica1, A. Vrca2 and H. [kobi}31 Hearing and Speech Rehabilitation Center, Polyclinic »SUVAG«, Zagreb, Croatia2 Department of Neurology, Clinical Hospital »Dubrava«, Zagreb, Croatia3 Department of Neurology, Clinical Hospital, Mostar, Bosnia and HerzegovinaA B S T R A C TAn expert team conducted a ten-year survey of eight children with Landau-Kleffnersyndrome (LKS) identified among children referred to Polyclinic »SUVAG« in Zagrebbecause of hearing disturbances. Although LKS is a rare disorder it is extremely impor-tant to detect it because early diagnosis and prompt medicinal treatment may improvethe prognosis, whereas neglect and late diagnosis result in language disability. Stan-dard diagnostic criteria must be established to enable timely treatment.IntroductionSymptomatologyLandau-Kleffner syndrome (LKS) is arare childhood neurological disorder. Itusually occurs in children between theages of 3 and 9. It is manifested as a formof aphasia, with epileptiform activityshown up in EEG tests (multifocal spikesand spike wave complexes, which are notstable buts tending to progress). Othersymptoms observed include epileptic sei-zures (in 67% of examinees) as well asdisturbances in behavior and psychomo-tor development (in 71% of examinees,according to literature published interna-tionally). From neuropathological point ofview, verbal-auditory agnosia is observedwith rapid reduction of spontaneous ver-bal expression. In affected individualswho have seizures, these seizures are ty-pically infrequent, and occur either asgeneralized convulsions or partial seizu-res. The seizures disappear and epilepti-form electroencephalogram usually set-tles down by the age of 15. However, theprognosis of receptive and expressive lan-guage ability varies and is much impro-ved when treatment including medica-tions and speech therapy is started early.Since 1957, when original paper ofLandau and Kleffner was published,about two hundred new cases have been529Received for publication March 7, 2001.reported in literature. Pathogenesis ofthis syndrome has remained hypotheti-cal. What is clinically observable is thedisrupture in the chain: hearing – verbalintegration – verbal expression. The ex-act location of pathological process hasnot been identified with certainty. Hy-potheses included either a disruption ofsubcortical links responsible for activa-tion of temporal lobe1 or disturbed matu-ration of functional structures of inter-hemispheric paths, notably corpus callo-sum2. Some authors fined symmetricalthalamic nuclei despite significant corti-cal asymmetries, they suggest that cor-ticothalamic neurons do not participatein the generation of spike-and-wave dis-charges or that they are inhibited by thepathological mechanisms. They have hy-pothesized that the acquired deteriora-tion of cognitive function is caused byalteration of the maturation of one or sev-eral associative cortices, primarily in-volving local interneurons and cortico-cortical associative neurons3. Korkman(1998)4 suggests that the primary deficitof the receptive aphasia is an impairmentof auditory phonological discriminationrather than a generalized auditory agno-sia. Paetau (1991, 1994)5,6 find the epilep-tiform activity of LKS patients producedby sound-responsive neurons in the non-primary auditory cortex within the mid-dle and posterior sylvian fissures. Hesuggests that unilateral discharges at ornear the auditory cortex disrupt auditorydiscrimination in the affected hemi-sphere, and lead the suppression of audi-tory information from the opposite hemi-sphere is the two main criteria of LKS.Because the disorder does not affectlife expectancy, the reported cases havenever included pathohistological analy-sis.ObjectivesAn expert team at our institution, Po-lyclinic »SUVAG« in Zagreb, was involvedin a ten-year survey of children withLKS. In our experience the prognosis offurther speech development varied con-siderably. Out of eight children involvedin treatment during that period, fourchildren recovered, whereas four childrendeveloped severe language disability.Although LKS is a rare disorder, it isextremely important to suspect it becau-se early diagnosis and prompt treatmentmay improve the prognosis, whereas ne-glect and late diagnosis leave permanentand irreparable consequences. Thereforestandard diagnostic criteria must be es-tablished to enable that treatment is pro-vided on time to all children affected withthe disorder.Materials and MethodsFrom 1989 to 1999 in Polyclinic »SU-VAG« in Zagreb eight children with LKSwere diagnosed and treated. The totalnumber of children with speech disorderexamined in that period is about 13,000or 1,296 per year on the average. In 1,586children with speech disorders there wasone case diagnosed as LKS. The rateseems rather high compared to the lowrate of cases reported in literature. How-ever, one should bear in mind that our in-stitution is specialized in hearing andspeech disorders, therefore the childrenreferred to it had already been detectedas having auditory problems.The age of children at the time of LKSdiagnosis was between 4 and 7 years.There were four boys and four girls (Table1).At the first examination carried out bya speech pathologist at Polyclinic SU-VAG, children were suspected of havingaphasia. Because the disorder was ac-quired (the children affected had alreadyacquired language abilities before the on-set of the disorder), the speech patholo-gist referred the children to other special-ists in the team.530N. [iki} et al.: Landau-Kleffner Syndrome, Coll. Antropol. 25 (2001) 2: 529–534First of all, hearing tests were con-ducted, including objective audiometry.For all examinees tone audiogram indi-cated either a normal hearing status, or alight hearing disorder of conductive typethat could not have affected the develop-ment of speech because it enabled normalsocial contacts. In brainstem auditoryevoked potentials tests, conducted withall examinees, absence of upper corticalresponses (auditory evoked potentials ofslow latencies) either bilaterally or onlyon the left was detected. In literature,these findings are related to dysphasicdisorders in speech development7.In psychological assessment all exa-minees demonstrated normal nonverbalintelligence. Verbal diagnostic methods,if applicable, indicated deviation (bymore than two standard deviations) of re-ceptive language development in compar-ison to expressive language development.Other tests included Reynell Develop-mental Language Scales, Leiter Nonver-bal Performance Scale R, and Develop-mental Test ^utiri} (psychomotor deve-lopment scales), BL, BS and WISC.Psychiatric assessment was neededbecause behavioral disturbances were ap-parent in all examinees. Psychiatrist ob-servation, continuous monitoring and fa-mily history did not give any indication ofa primary psychotic disorder in develop-ment of the children. The presence of be-havioral disturbances was associatedwith inability to understand speech oreven gestures.Neurological examination did not con-firm existence of any neurological defectsin the are of enervation of cranial nerves,lateralization, dynamostatics or sensibil-ity. Primary problem was emotional dis-turbance.EEG test performed with all childrenin wakefulness detected one or more foci,manifested as spikes or spike wave com-plexes 3–4 Hz, multiple spike elementsand slow waves. Because of clearly identi-fied signs of EEG abnormality, abnormal-ities in behavior, detected epileptic sei-zures of the GM type or complex psycho-motor crises in wakefulness and in sleep,further neuro-radiological examinationwas requested8.Computerized Axial Tomography wasperformed with all eight cases and thefindings were normal. The findings ofMagnetic Resonance Imaging scan of thebrain (with contract dye) were also nor-mal.531N. [iki} et al.: Landau-Kleffner Syndrome, Coll. Antropol. 25 (2001) 2: 529–534TABLE 1TIME FROM THE FIRST EPILEPTIC SEIZURE TO THE IMPLEMENTATION OF AET (TES-AET),IQ MEASURED BY VERBAL AND NON-VERBAL SCALE AT THE TIME OF ARRIVAL (T0) ANDAFTER 10 YEARS PERIOD (T10)Patients Sex TES-AET(months)IQ by verbalscale at T0*IQ by non-verbal scaleat T0IQ by verbalscale at T10*IQ by non-verbal scaleat T10Case 1 M 0 76 140 – 85Case 2 M 24 67 94 75 80Case 3 M 12 – 95 95 105Case 4 M 3 83 118 100 120Case 5 F 6 62 95 100 100Case 6 F 0 60 110 – 110Case 7 F 18 – 80 85 90Case 8 F 6 65 92 90 95* In cases denoted by »–« verbal IQ-test was not applicablePolysomnogram was conducted in theSleep Disorders Center at Clinical Hospi-tal »Vrap~e«. In the test, carried out dur-ing the night, EEG epileptic status wasdetected, having duration of 3–5 hours.The findings were considered pathogno-monic.Routine biochemical blood tests wereperformed (CBC, ESR, liver enzymes,blood sugar levels, amino-acids, alkalinephosphatase, ammonium in blood, ceru-loplasmin, urea, creatinine, urine) and allvalues were normal. An ophthalmologicexam (fundus) was requested. All eightexaminees had normal findings.ResultsOne boy and one girl in the group wereincluded only in speech therapy becausethe parents had not consented to anymedication. Both children developed thesyndrome of verbal agnosia. Seizureswere not observed in the ten-year period(the period in which the older girl was in-cluded in speech therapy). Behavioraldisturbances were reduced. EEG pat-terns settled into normal values. Todaythe two children attend the regular ele-mentary or secondary school with specialprogram. They communicate by gesturesand lip-reading although they both havenormal tone audiogram values.One boy was referred to our institu-tion for diagnosis and therapy only threeyears after the onset of the disorder. Inthat period he had been diagnosed as andtreated with monovalent antiepileptics.When he was admitted at our institutionthe seizures settled down, and EEG pat-terns did not indicate the need for achange in medications. Today, at the ageof 18, the patient has verbal agnosia. Themost recent audiograms indicated theprogressive loss of hearing (isolated to-nes) and progressive development of cen-tral auditory dysfunction. The boy com-pleted the special vocational educationfor an assistant cook, but since the lastyear the loss of intellectual abilities hasbeen observed. Epileptic manifestationshave not been observed. In spite of nor-mal hearing functions identified in audio-grams, the sounds he utters are as if hewas a deaf child. He is not able to lip-readand he uses gestures to communicate.One boy was prescribed cortico-ste-roids two years after the onset of firstsymptoms. In that period he had beentaking AED carbamazepine because hisparents rejected any additional therapy.At present he attends elementary schoolwith special program at our institution.His behavior is normal but he still hassignificant difficulties in communicationbecause of reduced ability to comprehendspeech (dysphasic disturbances). He isable to hear and speak at a lower develop-mental level.Four children took combined anti-epi-leptic therapy (mainly valproic acid, car-bamazepine and clonazepame) and cor-ticosteroids (dexamethason). Three yearsafter discontinuation of drug therapy, thethree children attend the regular elemen-tary school with normal program. Theyhave normal behavior, normal hearingand speech, normal EEG patterns andnormal sleep cycles.DiscussionPathophysiology of the syndrome isstill unknown. Some suggested causes in-cluded a very slow viral infection as inslowly progressive local encephalitis, butthis was not confirmed in neuropatho-logical studies. Other authors suggestedthe existence of vascular anomaly or se-quel of cysticercosis9,10.Authors from USA report a treatmentwith subpial intracortical transection insome patients with LKS, success dependson selection of cases having severe epi-leptogenic abnormality than can be dem-onstrated to be unilateral in origin de-532N. [iki} et al.: Landau-Kleffner Syndrome, Coll. Antropol. 25 (2001) 2: 529–534spite a bilateral electrographic manifes-tation11.Aphasia is a consequence of verbalagnosia caused by cortical or subcorticaldysfunction of auditory system. Loss ofspeech with paroxysmal EEG patternsindicates that the two features are corre-lated. It has been observed that symp-toms improve when EEG patterns set-tle12–14.Many authors agree that the periodfrom the onset of the first LKS symptomsto the time when anti-epileptic therapy isintroduced is critical15,16. The corticoste-roids should be given in high doses assoon as the diagnosis is firmly establi-shed and should be continued in mainte-nance dose for several months or years toavoid escape.It is considered that LKS is not an uni-form but a complex syndrome in whichthree forms can be distinguished: 1)aphasia of transitory character; 2) apha-sia of persistent character; 3) aphasia ofatypical character.Prognosis is difficult to make. In a pa-per that included a series of 45 cases, theappearance of first symptoms was asses-sed as critical because at the age of 5–6there exists a plasticity of language rep-resentation in cortex and a damage in thedominant hemisphere results in creatinglanguage structures in other hemisphere.All authors agree that behavioral distur-bances develop because of the syndromeand the frustrating inability to communi-cate typical for aphasia17,18.In the series of eight cases diagnosedwith LKS, treated and included in speechtherapy at Polyclinic SUVAG, the progno-sis was directly related to the time elap-sed from the onset of the disorder to thebeginning of treatment. The four childrenthat were diagnosed in less than a yearafter the first appearance of symptoms(seizures) and promptly treated (anti-epi-leptics for one-two years, corticosteroidstwo months) had a good recovery. Todaythey have normal EEG patterns and noclinical symptoms.ConclusionThe following guidelines must be fol-lowed to identify LKS syndrome:• speech pathologist examination to de-tect aphasia• detailed audiological tests (includingauditory evoked potentials) to excludeperipheral hearing impairment• psychological tests, non verbal meth-ods, to assess intellectual ability• psychiatric observation to exclude pri-mary psychotic developmental distur-bances and psychotherapy to treat be-havioral disturbances• neurological examination includingEEG tests (in wakefulness and insleep), and neuro-radiological examina-tion (CAT and MRI scan) to exclude ex-istence of any other neurological disor-dersMultidisciplinary approach must beused to arrive at diagnosis. Because ofcomplexity of symptoms, medicinal treat-ment and speech therapy must be contin-ually followed up by a team of specialistsat an institution specialized in diagnosisand therapy of language disorders.R E F E R E N C E S1. KELERMAN, K., Eur. J. Pediatr., 128 (1978)207. — 2. NJIOKIKTJEN, CH., Neuropediatrics, 14(1983) 123. — 3. MAQUET, P., E. HIRSCH, M. N.METZ-LUTZ, J. MOTTE, D. DIVE, C. MARES-CAUX, G. FRANCK, Brain, 118 (1995) 1497. — 4.KORKMAN, M., M. L. GRANSTROM, K. APPEL-QUIST, E. LIUKKONEN, J. Int. Neuropsychol. Soc.,4 (1998) 566. — 5. PAETAU, R., M. KAJOLA, M.533N. [iki} et al.: Landau-Kleffner Syndrome, Coll. Antropol. 25 (2001) 2: 529–534KORKMAN, M. HAMALAINEN, M. L. GRAN-STROM, R. HARI, Neuroreport, 2 (1991) 201. — 6.PAETAU, R., J. Clin. Neurophysiol., 11 (1994) 231. —7. MARN, B.: Ocjena funkcionalne sposobnosti afe-rentnih slu{nih puteva u djece s dislalijom. In Croat.M.Sc. Thesis. (University of Zagreb, Zagreb, 1992). —8. [IKI], N., Arhiv ZMD, 30 (1988) 69. — 9.NAKANO, S., T. OKUNO, H. MIKAWA, Brain Dev.,11 (1989) 43. — 10. HOLMES, G. L., M. MCKEEVER,Z. SAUNDERS, Epilepsia, 22 (1981) 631. — 11. MOR-RELL, F., W. W. WHISLER, M. C. SMITH, T. J.HOEPPNER, L. DE TOLEDO-MORRELL, S. J. PI-ERRE-LUIS, A. M. KANNER, J. M. BUELOW, R.RISTANOVI], D. BERGEN, Brain, 118 (1995) 1529.— 12. THARPE, A. M., G. D. JOHNSON, M. E.GLASSCOCK, Am. J. Oto., 12 (1991) 3. — 13. LAN-DAU, W. M., Arch. Neurol., 49 (1992) 353. — 14.LANDAU, W. M., F. R. KLEFFNER, Neurology, 7(1957) 523. — 15. LERMAN, P., T. LERMAN-SAGIE,S. KIVITY, Dev. Med. Child Neurol., 3 (1991) 257. —16. MARESCAUX, C., E. HIRSCH, S. FINCK, P. MA-QUET, E. SCHLUMBERGER, F. SELLAL, M. N.METZ-LUTZ, Y. ALEMBIK, E. SALMON, G.FRANCK, Epilepsia, 31 (1990) 768. — 17. RAPIN, I.,S. MATHIS, A. J. ROWAN, G. G. GOLDEN, Dev.Med. Child Neurol., 19 (1977) 192. — 18. METZ-LUIS, M. N., P. MAQUET, A. DE SAINT MARTIN, G.RUDOLF, N. WIOLAND, E. HIRSCH, C. MARES-CAUX, Int. Rev. Neurobiol., 45 (2001) 505.N. [iki}Hearing and Speech Rehabilitation Centre, Polyclinic »SUVAG«, Lj. Posavskog 10,10000 Zagreb, CroatiaZNA^AJ RANOG MEDIKAMENTOZNOG LIJE^ENJA U PROGNOZILANDAU-KLEFFNEROVOG SINDROMAS A @ E T A KEkspertni tim proveo je 10-godi{nje pra}enje osmero djece s Landau-Kleffnerovimsindromom. Ova djeca identificirana su me|u djecom koja su primljena u Polikliniku»SUVAG« u Zagrebu, zbog poreme}aja u slu{anju. Premda je LKS rijedak poreme}aj,iznimno je va`no da se on prepozna jer rana dijagnoze i pravovremeno medicinsko lije-~enje mogu pobolj{ati njegovu prognozu, dok zapu{teni i kasno dijagnosticirani slu~a-jevi rezultiraju s te{ko}ama govora. Autori zaklju~uju kako se standardni dijagnosti~kikriteriji moraju ustanoviti kako bi se omogu}ilo pravovremeno lije~enje.534N. [iki} et al.: Landau-Kleffner Syndrome, Coll. Antropol. 25 (2001) 2: 529–534

Importance of Early Drug Treatment in Prognosis of the Landau-Kleffner Syndrome

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