CNS Spectr. 2010;15(9):574-578
Dr. Katz is research associate, Ms. Burket is research assistant, and Dr. Deutsch is Ann Robinson endowed chair of psychiatry in the Department of Psychiatry and Behavioral Sciences at Eastern Virginia Medical School in Norfolk. Ms. Rosse is research assistant at the Mental Health Service Line in the Deparment of Veterans Affairs Medical Center in Washington, DC. Dr. Rosse is Chief of Psychiatry at the Department of Veterans Affairs Medical Center and professor of psychiatry in the Department of Psychiatry at Georgetown University School of Medicine in Washington, DC. Dr. Schwartz is research psychologist at the Department of Veterans Affairs Medical Center and associate professor of psychiatry at Georgetown University School of Medicine.
Faculty Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Submitted for publication: August 18, 2008; Accepted for publication: January 7, 2010.
Please direct all correspondence to: Stephen I. Deutsch, MD, PhD, Ann Robinson Endowed Chair in Psychiatry, Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Ave, Ste 710, Norfolk, Virginia 23507. Tel: 757-446-5888; E-mail: DeutscSI@evms.edu
A 60-year-old patient with a clinical diagnosis of schizophrenia underwent a magnetic resonance imaging (MRI) scan related to the evaluation of isolated seizures that emerged while medicated with clozapine. Unexpectedly, the MRI scan revealed evidence of asymmetric and enlarged cerebral ventricles that were interpreted as congenital in origin. The presence of both congenital lateral ventricular asymmetry and ventriculomegaly may interact to increase risk of schizophrenia. The history and clinical features, including cognitive testing, of the illustrative patient are presented.
• Sonography of the fetal brain may emerge as an indicated procedure for all pregnant women with schizophrenia.
• Sonographic evidence of brain abnormalities in fetuses of parents with schizophrenia may emerge as anatomic intermediate phenotypes of increased susceptibility to a spectrum of neurodevelopmental disorders.
• Mild ventricular enlargement of the fetal brain as an “isolated” finding may be associated with normal neurodevelopmental outcomes.
Increasingly, antepartum ultrasonographic examination of the fetal neural axis occurs routinely during pregnancy.1-3 Mild cerebral ventriculomegaly is usually defined operationally as the measured transverse diameter of the atria of the lateral ventricles in the fetus that is >10 mm and <15 mm; the mean width is 7.6 mm+0.6 and remains stable from week 14–38 of gestation.4,5 The incidence of congenital cerebral ventriculomegaly in general that is frequently associated with other intracranial anomalies (eg, hypoplasia and agenesis of the corpus callosum, trisomy 21, neural tube defects, and microcephaly) and extracranial anomalies may be as high as 2.5 per 1,000 births.5,6 However, the incidence of mild cerebral ventriculomegaly as an isolated finding is not known.2,3 In two different series collected over a 6-year period of women undergoing ultrasonography, the frequency of occurrence of mild cerebral ventriculomegaly in the fetus was 0.2% (ie, 94 cases out of 41,575 sonograms) and 0.7% (ie, 82 cases out of 11,864)2,3; these frequencies included fetuses with associated anomalies.
In one of the series,22 infants <2 years of age with sonographic evidence of mild isolated cerebral ventriculomegaly were contrasted with 22 matched control infants on the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales.2 The ventriculomegaly group scored significantly lower than the controls on the Bayley mental and psychomotor development indices, whereas the groups did not differ on the Vineland Scales. Importantly, a significantly higher percentage of the infants with mild isolated ventriculomegaly had scores on the Bayley mental development index <85 indicating delay (36.4% versus 4.5%; P=.021). One infant with a mental development index <70 manifested progressive ventriculomegaly that required placement of a ventriculoperitoneal shunt. Among the infants with mild isolated ventriculomegaly, a significant inverse correlation emerged between the size of the index measurement of the lateral ventricular atrium and the mental development index score. Thus, mild isolated cerebral ventriculomegaly in the fetus may be associated with evidence of developmental delay in the infant that may not be reflected in parental observations of the infant’s adaptive functioning at age 2.2
The atrial size appears to be larger when associated anomalies are present3; for example, in one series, the atrial sizes of 19 of 34 cases associated with anomalies were 12.0–14.9 mm, whereas only 3 of 48 isolated cases of mild cerebral ventriculomegaly were in this range. The types of associated anomalies in this series included aqueductal stenosis, neural tube defect, agenesis of the corpus callosum, arachnoid cysts, Dandy-Walker anomaly, choroid plexus cysts, renal dysplasia, bilateral clubfoot, heart defects, cerebellar hypoplasia, lissencephaly, and karyotypic abnormalities such as trisomy 21, trisomy 13, an unbalanced autosomal translocation and triploidy. Trisomy 21 was detected and attributed as the cause of progression of ventricular size in two of four of the isolated 48 cases of mild cerebral ventriculomegaly.3 Progression in one of the four cases was due to partial stenosis of the aqueductas of Sylvius that required shunting at age 1 year. However, in the majority of the 48 cases of isolated mild cerebral ventriculomegaly, the enlargement remained stable (58%) or resolved in utero (33%). Moreover, motor and neurological development in the majority of the isolated cases at median follow-up age of 30 months was described as normal. Thus, the consequences of isolated mild cerebral ventriculomegaly may be clinically unapparent or insignificant for a majority of infants.3
Whereas ventriculomegaly in utero is often a sensitive indicator of anomalous fetal development of the brain and spinal cord, asymmetry of the lateral ventricles, particularly when it is unaccompanied by unilateral or bilateral ventriculomegaly (ie, atrial width <10 mm) and does not progress during gestation, may be a normal anatomic variant.7 In one series that used a strict definitional criterion of lateral ventricular asymmetry in utero to examine 7,200 singleton fetuses of low-risk pregnant women scanned between 18 and 24 weeks of gestation, only 21 cases were found.7 The occurrence rate of 0.3% in this series is dramatically lower than previous subjectively and less-rigorously determined rates that ranged between 21% and 44%. Asymmetry was defined operationally as a difference between the two sides that was >2.4 mm, which is two standard deviations from the established mean atrial ventricular diameter; cases with atrial widths >10 mm were excluded. In the majority of cases, the index sonogram showed that the left lateral ventricle was larger than the right one in 15 of the 21 cases. Serial sonograms performed on 20 of the cases showed resolution of asymmetry in four cases, progression in one case, and persistence in the remainder. The case showing progression reached 12 mm and fulfilled the criterion for ventriculomegaly (>10 mm), which led to amniocentesis, karyotyping, and the fetal diagnosis of trisomy 21. Possible etiologies of the ventricular asymmetry were found in only two other cases, which were subclinical cytomegalovirus ventriculitis and insidious periventricular hemorrhage.7 Unfortunately, one of the pregnancies was terminated because of the parental anxiety over the ventricular asymmetry. However, 17 cases followed-up at 6 months of age were reported to be developing normally; thus, the authors concluded that significant ventricular asymmetry in the absence of ventriculomegaly may be a normal anatomic variant.7 Importantly, in a small series of cases, sonographic evidence of mildly enlarged and asymmetric lateral ventricles showed persistence in magnetic resonance imaging (MRI) scans performed as late as 6 years later and, in general, mild ventriculomegaly was associated with a spectrum of childhood developmental disorders, including attention-deficit/hyperactivity disorder, learning disorders, motor and language delays, and autism.8 The mild neurodevelopmental abnormalities associated with isolated mild ventriculomegaly detected in utero (eg, motor and language delays, lower educational test scores, and social maladjustment) are similar to those reported in childhood histories of patients with schizophrenia and observed in children at high-risk for the disorder.8 However, isolated asymmetric and enlarged fetal ventricles that do not show signs of progression may not be associated with neurological abnormalities during infancy; clearly, prospectively designed, long-term follow-up studies are required.9
JOV is a 60-year-old, African-American male, continuously employed for the past 38 years by the United States Postal Service, working the “midnight” shift as an “expediter.” He was recently widowed after 30 years of marriage. JOV has a history of two psychiatric hospitalizations; the first one occurred at age 19 years while attending high school because of command auditory hallucinations telling him to kill himself. JOV is unaware of any problems during his mother’s pregnancy with him, labor and delivery and, to the best of his knowledge, there were no concerns about delays or deviances with respect to achieving his developmental milestones prior to entering school. Although never formally diagnosed, JOV reported that he “didn’t pay attention...daydreamed a lot” while in elementary school and repeated fifth grade because “my grades were bad I guess, I don’t know.” He also reported that he did not have friends in school and did not participate in extracurricular activities, saying that he “slept mostly,” stayed in the apartment, and had “just one boring life.” He reported that he started hearing “voices” at age 16 and was fearful of people in the neighborhood. In spite of his psychiatric hospitalization, JOV graduated high school at age 19, enlisted in the US Marine Corps, and served a 13-month deployment in active combat in Vietnam. JOV reported that his father was hospitalized because of “voices” and had a personal history of alcohol dependence. JOV presented to our hospital with the diagnoses of schizophrenia with persistence of command auditory hallucinations, posttraumatic stress disorder, and alcohol abuse, the latter has remained in remission for more than three decades. The examination of the mental status was significant for a flattened and occasionally inappropriate affect, poorly articulated and monotonic speech, command auditory hallucinations “at least 3 times a week” telling him to kill himself (although he did not endorse active intent or plan), concretization of thought, and difficulty with long-term memory and calculations. Recent cognitive assessment using a standardized battery called the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)10 indicated generalized cognitive impairment in attention, visual scanning, and verbal and visual memory (Table).
JOV was treated initially with clozapine, which had to be discontinued because of episodes of seizures, and was switched to maintenance pharmacotherapy with risperidone. An MRI scan performed because of his clozapine-associated seizures reported “abnormally shaped large lateral third and fourth ventricles,” a “markedly hypoplastic” corpus callosum, and “no transependymal fluid migration present to suggest decompensated hydrocephalus.” The probable etiology was reported “likely representing a congenital or developmental anomaly (Figure).”
Although isolated mild cerebral ventriculomegaly without associated anomalies or macrocephaly may be a “normal” anatomic variant, it may also reflect diverse and unrelated pathological processes, including increased intraventricular pressure due to impaired cerebrospinal fluid flow or absorption, neuronal cell loss, neonatal white matter damage, and delayed myelination.3,11 Relative to the more commonly occurring intraventricular hemorrhages and viral infections during pregnancy, genetic etiologies of fetal hydrocephalus are rare.12 Causes of post-hemorrhagic hydrocephalus include maternal hypertension, trauma in pregnancy, and coagulation disorders. However, the true incidence of coagulation disorders appears to be low. Also, twin pregnancies are associated with an increased incidence of fetal hydrocephalus.12 Many viral candidates have an ependymal tropism that can lead to aqueductal atresia and, possibly, hydrocephalus due to viral-related involvement of the choroid plexuses and arachnoid villi.12 Although genetic factors may not be prominent in terms of etiology, a higher than expected percentage of malformations was reported in first-degree relatives of children with congenital hydrocephalus. Toxic, drug-induced and metabolic etiologies (eg, alcohol, lysergic acid, barbiturates, warfarin, zinc deficiency, and vitamin B12 or folic acid deficiencies) have been associated with congenital aqueductal stenosis, which may be a cause or epiphenomenon of hydrocephalus.12
Ventricular enlargement and “pathological” asymmetry in fetal life may be among the earliest imaging correlates of various neurodevelopmental processes that could result in, or contribute to, schizophrenia and other neurodevelopmental disorders. The most consistent neuroimaging abnormality of patients presenting with a first-episode diagnosis of schizophrenia is enlargement of the lateral ventricles; moreover, this enlargement may reflect abnormalities originating in fetal life.13 The ventricular enlargement precedes onset of psychotic symptoms, may be associated with cognitive dysfunction, and may not progress in a majority of first-episode patients. Thus, the suggestion has been made that at least some premorbid childhood abnormalities of patients with schizophrenia such as delayed developmental milestones, lags in educational achievement, poorer performance in sports and handicrafts, and tendencies for solitary and anxious play may reflect neurodevelopmental, as opposed to neurodegenerative, pathological processes.13 A study of 33 patients with early-onset schizophrenia (mean age at onset=15.7 years+1.4[SD]) revealed a relationship between earlier age of onset and larger proportion of ventricular volume to total brain volume on MRI scans.14 Thus, larger ventricular volumes may reflect neurodevelopmental processes that predispose to earlier onset of schizophrenia.
The case report highlights the possibility that congenitally-enlarged and asymmetric ventricles may contribute to and reflect pathological mechanisms of schizophrenia. The performance of routine fetal ultrasonography and repeated studies when operationally-defined enlargement and/or asymmetry are present, should trigger careful follow-up during childhood and adolescence and, perhaps, interventions designed to prevent or mitigate emergence of neurodevelopmental disorders, including schizophrenia. The case report also emphasizes that neuroimaging studies, including quantitative computed tomography and MRI, may be indicated in the index evaluation of many patients with psychiatric disorder, especially when positive and deficit symptoms are persistent15; the enlarged and asymmetric ventricles in this patient may have increased susceptibility to seizures with clozapine administration. CNS
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