Magnetic resonance imaging (MRI) scanning of the brain, soft neurologic signs, and personality and neuropsychologic assessment were used in a pair of monozygotic twins aged 25, discordant for schizophrenia. Brain MRI showed diffuse cortical atrophy of frontal, parietal and temporal brain lobes in both twins. Coronal plane MRI revealed decreased amygdala and hippocampus, and enlarged third and fourth lateral ventricles in the affected twin.Snimanje mozga magnetskom rezonancom (MR), nedefinirani (soft) neurološki znaci, neuropsihologijsko i psihologijsko testiranje osobnosti primijenjeni su na jednom paru jednojajčanih blizanaca starih 25 godina, od kojih jedan boluje od shizofrenije. MR mozga je u oba blizanca pokazao difuznu kortikalnu atrofiju frontalnih, parijetalnih i temporalnih režnjeva. MR u koronalnom presjeku pokazao je smanjene amigdale i hipokampus u bolesnog blizanca. U bolesnog je blizanca nađeno i proširenje trećega i lateralnih ventrikla

Dalibor Karlović

Miljenko Kalousek

Vlasta Solter

English

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Karloviæ D. et al. MRI in schizophreniaActa Clin Croat, Vol. 42, No. 4, 2003 333MAGNETIC RESONANCE IMAGING OF BRAINAND NEUROPSYCHOLOGICAL TESTING IN MONOZYGOTICTWINS DISCORDANT FOR SCHIZOPHRENIADalibor Karloviæ1, Vlasta Solter1 and Miljenko Kalousek21University Department of Psychiatry, 2University Department of Radiology, Sestre milosrdnice University Hospital, Zagreb,CroatiaSUMMARY  Magnetic resonance imaging (MRI) scanning of the brain, soft neurologic signs, and person-ality and neuropsychologic assessment were used in a pair of monozygotic twins aged 25, discordant forschizophrenia. Brain MRI showed diffuse cortical atrophy of frontal, parietal and temporal brain lobes inboth twins. Coronal plane MRI revealed decreased amygdala and hippocampus, and enlarged third andfourth lateral ventricles in the affected twin.Key words: Brain abnormalities; Schizophrenia, pathology; Schizophrenia, genetics; Magnetic resonance imaging, diagno-sis; Twins, monozygoticActa Clin Croat 2003; 42:333-336 Profes ional PaperCorrespondence to: Dalibor Karloviæ, M.D., M.S., University Departmentof Psychiatry, Sestre milosrdnice University Hospital, Vinogradska c. 29,HR-10000 Zagreb, CroatiaE-mail: dalibor.karlovic@zg.htnet.hrReceived May 26, 2003, accepted September 15, 2003IntroductionSchizophrenia is a relatively common disorder with life-time prevalence in the general population of 1%1. Theonset of schizophrenia symptoms typically occurs in earlyadulthood, with a recurrent course and continued disabil-ity refractory to treatment in most patients2. The diseasecurrently referred to as schizophrenia was first more thor-oughly described in the late 19th century under the termdementia praecox in the scientific works of Emil Krae-pelin1. He separated it from the manic-depressive illnessand senile dementias. Later, in 1911, Eugen Bleuler re-named Kraepelins dementia praecox into schizophrenia,to highlight the fact that the disorder produced severefragmentation of the personality and cognition. The symp-toms and signs of schizophrenia are complex, and the di-agnostic process was burdened with poor reliability andvalidity of the diagnosis until modern classification systemssuch as International Classification of Diseases (ICD) andDiagnostic and Statistical Manual of Mental Disorders(DSM) have been designed1,2. For convenience, the symp-toms and signs of schizophrenia can be divided into pos-itive and negative ones. Negative symptoms and signsinclude aphasia, affective blunting, anhedonia and listless-ness, whereas positive symptoms and signs are hallucina-tions, delusions, disorganized speech, and disorganized/bizarre motor behavior. The etiology of the disorder ismultifunctional, implying biochemical and neuroendocri-nologic factors as well as brain morphology. The more so,genetic studies have offered several explanations of thiscomplex, perhaps multiple rather than single disease pro-cess2. Genetic predisposition is the most important knownrisk factor. Some studies have shown the relative risk torise 40 times in patients with one or more first degree rel-atives affected, however, no strongly linked genes havebeen identified.Studies using early computed tomography (CT) brainimaging revealed enlarged areas of lateral and third ven-tricles in schizophrenic patients3,4. With the developmentof nuclear magnetic resonance imaging (NMRI), generalreduction in the brain volume and mesial temporal lobestructures (i.e. amygdala and hippocampus) has been dem-onstrated4-10. These findings support the neurodevelop-Karloviæ D. et al. MRI in schizophrenia334 Acta Clin Croat, Vol. 42, No. 4, 2003mental hypothesis of schizophrenia2. According to thishypothesis, schizophrenia is a sequel of abnormal neuronalmigration and/or myelinization, along with excessive apo-ptosis during the intrauterine development.In this report, we present findings of psychologicalexamination and MRI brain scanning in monozygotic twinsdiscordant for schizophrenia.Case ReportA pair of 25-year-old male monozygotic twins discor-dant for schizophrenia, with university degree of specialeducators, were examined. They are unemployed, singleand live with their parents in a small town near Zagreb.History data revealed normal pregnancy, delivery and ear-ly psychomotor development in both twins. During theirearly childhood, they had all infectious children diseases,received all vaccines, and suffered no medical or psycho-logical problem or disorder. They described their familydynamics as free from any specificities. They were goodstudents and completed their military service. Their med-ical history contained no data on any substance or alcoholabuse or addiction.At the age of 21 years, the affected twin manifestedinitial symptoms of schizophrenia, such as auditory impera-tive hallucinations, disorganized speech and motor actions,blunted affect, he began to interpret some routine eventsas special signs, and developed insomnia. According to ICD10, he met the criteria for schizophrenia, the paranoid-hallucinatory type.On that occasion, he was hospitalized for the first time.Initially, he was treated as inpatient with a typical antip-sychotic agent haloperidol, however, a switch to clozapineas pharmacotherapy was dictated by the poor response ofblunted affect, and extrapyramidal side effects with clin-ical features of akathisia. The initial dose of clozapine was300 mg, which was subsequently tapered to 100 mg per day.Since his first hospitalization, the patient and his twinbrother have been continuously attending family psycho-therapy once a week, during which period of time he wastreated as inpatient on two more occasions, mostly forpsychopharmacotherapy titration.During the last patients hospital stay, we explained tothe twins the study design and medical procedures andtesting involved. The twins gave their informed consentfor the study.Hematology, coagulation, biochemistry and urine anal-yses produced normal findings in both twins. The levelsof hypothalamus hormones (vasopressin and oxytocin) andpituitary gland hormones corticotropin (ACTH), prolac-Fig. 1.Magnetic resonance imaging, coronal plane, at the level of hippocampus in the monozygotic twin with (A) and without (B) schizo-phrenia. Arrows show enlargement of the lateral and third ventricles, smaller hippocampus, and more pronounced parietal and temporalcortical atrophy in the affected twin as compared with the unaffected twin.A BÚÚÚ ÚÚÚKarloviæ D. et al. MRI in schizophreniaActa Clin Croat, Vol. 42, No. 4, 2003 335tin (PRL), thyrotropin hormone (TSH), luteinizing hor-mone (LH) and follicle-stimulating hormone (FSH), werewithin the normal range. Thyroid hormones triiodothyro-nine (T3), thyroxine (T4), free triiodothyronine (FT3)and free thyroxine (FT4); adrenal gland hormones corti-sol, plasma renin activity and aldosterone; and gonadalhormones testosterone, estrogens and progesterone werenormal.An experienced psychiatrist applied several psychiat-ric rating scales, i.e. Positive and Negative Symptom Scalefor Schizophrenia (PANSS), Hamilton Depression Scale,and Hamilton Anxiety Scale. On the PANSS scale, theschizophrenic twin achieved a total score of 25 versus 3scored by the healthy twin. Psychological assessment wasbased on the administration of two different questionnairesets. One set included personality tests such as Minneso-ta Multiphasic Personality Inventory-201 (MMPI-201),Emotions Profile Index (EPI) and Eysenck PersonalityQuestionnaire (EPQ). The other set included neuropsy-chological tests such as Bender Gestalt test (BG), BentonVisual Retention test, and Complex Figure Rey Test(CFRT). Personality tests showed increased scores on theparanoid, anxiety and depression MMPI-201 subscales inthe schizophrenic twin, whereas in the healthy twin all testvariables were normal. The affected twin also showed anincreased level of aggression and affect disturbance, alongwith a decreased level of social functioning. Both twins hadhigh IQ (around 120). On neuropsychological testing, bothtwins showed visuospatial difficulties, poor attention andvigilance. A neuropsychiatrist also applied a set of tests toassess the soft neurologic signs.Both twins are right-handed, being clumsy on right-and left-sided motor sequencing tests and fine motormovements. On reproduction drawings, they showed milddistortion or rotation.Brain MRI (Fig. 1) showed diffuse cortical atrophy ofthe frontal, parietal and temporal lobes in both twins. Thiscortical atrophy was more pronounced in the affected twin.MRI in coronal plane showed smaller amygdala and hip-pocampus, and enlarged lateral third and fourth ventriclein the affected twin as compared with the healthy one. Thestructures such as medulla oblongata, pons, cerebellum andoccipital lobe were of normal morphology in both twins.DiscussionTo the best of our knowledge, only a few reports de-scribing brain morphology in monozygotic twins discordantfor schizophrenia based on MRI studies have appeared inthe literature to date. These studies pointed to lateral andthird ventricular enlargement, frontal lobe atrophy, andsmaller hippocampus and amygdala in schizophrenictwins3-8. Unaffected twins often have bigger hippocampusand amygdala, and smaller ventricular system in compari-son with affected twins3-8. Results of these studies are inline with our case report. In contrast to other reports, wefound temporal and parietal cortical atrophy in both theschizophrenic and healthy monozygotic twins.Although our and other studies in monozygotic twinsdiscordant for schizophrenia found affected twins to havesmaller hippocampus and amygdala, larger ventricular sys-tem and frontal atrophy, the studies comparing brain MRIof unaffected twins or relatives at a high risk of develop-ing schizophrenia showed their MRI findings to bear great-er similarity with those of their affected relatives in com-parison with normal population9,10. These studies haveindicated that these morphological changes are associat-ed with familial predisposition to schizophrenia. Thesechanges have also found explanation in the neurodevelop-mental model of schizophrenia2,9,10. According to this neu-rodevelopmental model of schizophrenia, the symptomsof schizophrenia are postulated to be a manifestation ofdisturbed brain development. However, the question re-mains whether these brain abnormalities are geneticallymediated.Our study also included psychological personality as-sessment, neuropsychological evaluation and assessmentof soft neurologic signs. Personality assessment showedexpected changes in the schizophrenic twin and no suchchanges in the healthy twin, however, neuropsychologicalevaluation and soft neurologic signs were pathologic inboth twins.It should be noted that the present study suffered froma number of limitations, as it is just a case report, which isalso characteristic of other MRI studies in monozygotictwins discordant for schizophrenia, and is thus inadequatefor statistical comparison. Additional comparisons at themolecular level, such as serotoninergic or dopaminergictransporter genes, morphological studies, and larger studysamples are needed to validate the findings recorded so far.References1. ANDREASEN NC. Symptoms, signs, and diagnosis of schizophre-nia. Lancet 1995;346:477-81.2. CARLSSON M, CARLSSON A. Schizophrenia: a subcortical neu-rotransmitter imbalance syndrome? Schizophr Bull 1990;16:425-32.3. BAREE WF, OEL van CJ, HULSHOFF HE, SCHNACK HG,DURSTON S, SITSKOORN MM, KAHN RS. Volumes of brainKarloviæ D. et al. MRI in schizophrenia336 Acta Clin Croat, Vol. 42, No. 4, 2003structures in twins discordant for schizophrenia. Arch Gen Psychi-atry 2001;58:33-40.4. McNEIL TF, CANTOR-GRAAE E, WEINBERGER DR. Relation-ship of obstetric complications and differences in size of brain struc-tures in monozygotic twin pairs discordant for schizophrenia. Am JPsychiatry 2000;157:203-12.5. GOLDBERG TE, TORREY EF, BERMAN KF, WEINBERGERDR. Relations between neuropsychological performance and brainmorphological and physiological measures in monozygotic twinsdiscordant for schizophrenia. Psychiatry Res 1994;55:51-61.6. STABENAU JR, POLLIN W. Heredity and environment in schizo-phrenia, revisited. The contribution of twin and high-risk studies.J Nerv Ment Dis 1993;181:290-7.7. WEINBERGER DR, BERMAN KF, SUDDATH R, TORREY EF.Evidence of a prefrontal-limbic network in schizophrenia: a mag-SaetakSNIMANJE MOZGA MAGNETSKOM REZONANCOM I NEUROPSIHOLOGIJSKO TESTIRANJE UJEDNOJAJÈANIH BLIZANACA NESUKLADNIH NA SHIZOFRENIJUD. Karloviæ, V. Solter i M. KalousekSnimanje mozga magnetskom rezonancom (MR), nedefinirani (soft) neuroloki znaci, neuropsihologijsko i psihologijskotestiranje osobnosti primijenjeni su na jednom paru jednojajèanih blizanaca starih 25 godina, od kojih jedan boluje od shizofrenije.MR mozga je u oba blizanca pokazao difuznu kortikalnu atrofiju frontalnih, parijetalnih i temporalnih renjeva. MR u koronalnompresjeku pokazao je smanjene amigdale i hipokampus u bolesnog blizanca. U bolesnog je blizanca naðeno i proirenje treæega ilateralnih ventrikla.Kljuène rijeèi: Nenormalnosti mozga; Shizofrenija, patologija; Shizofrenija, genetika; Snimanje magnetskom rezonancom, dijagnostika;Blizanci, jednojajèaninetic resonance imaging and regional cerebral blood flow study ofdiscordant monozygotic twins. Am J Psychiatry 1992;149:890-7.  8. SUDDATH RL, CHRISTISON GW, TORREY EF, CASANOVAMF, WEINBERGER DR. Anatomical abnormalities in the brains ofmonozygotic twins discordant for schizophrenia. N Engl J Med1990;322:789-94.  9. LAWRIE SM, WHALLAY H, KESTELMAN JN, ABUKMEL SS,BYRNE M, HODGES A, RIMMINGTON JE, BEST JK, OWENSCG, JOHNSTONE EC. Magnetic resonance imaging of brain inpeople at high risk of developing schizophrenia. Lancet 1999;353:30-3.10. McDONALD C, GRECH A, TOULOPOULOU T, SCHULZE K,CHAPPLE B, SHAM PC. Brain volumes in familial and non-famil-ial schizophrenic probands and their unaffected relatives. Am J MedGenet Neuropsychiatr Gen 2002;114:616-25.

Snimanje mozga magnetskom rezonancom i neuropsihologijsko testiranje u jednojajčanih blizanaca nesukladnih na shizofreniju

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