Radiological findings in developmental delay

Radiological Findings in Developmental Delay G. Bradley Schaefer and John B. Bodensteiner This article reviews the neuroimaging findings in patients with nonsyndromic mental retardation and global developmental delays. The frequency and type of abnormal neuroimaging findings in this patient population are discussed. Specifically addressed are the issues of which patients should have neuroimaging studies in light of (in the vernacular) "cost-benefit" analysis. The extension of these studies to "milder" developmental delays, and other neurodevelopmental disorders are also discussed. Copyright 9 1998 b y W.B. Saunders Company

HE EVALUATION OF the child with developmental delays is a frequent problem for any practitioner providing care for young persons. Many times, for the pediatrician and the family practitioner, the unifying diagnosis is readily apparent as with a recognizable syndrome such as Down syndrome. Sometimes, a referral to a specialist in the area of neurodevelopmental disabilities (clinical geneticist, pediatric neurologist, or developmental pediatrician) is required. After careful investigation by the consultant, the diagnosis may be identified. However, all too frequently, patients with neurodevelopmental delays continue to represent a diagnostic challenge. The focus of this article is to discuss the radiological findings in this group of patients, specifically the "nonsyndromic" patients with mental retardation/development delays. The epidemiology of idiopathic mental retardation has been well described in the past. 1,2Approximately 3% Of the United States population is mentally retarded. If this group is divided into severe (IQ less than 50) and mild (IQ between 50 and 70), several important facts are noted. As far as incidence is concerned, the milder group is 10 times more frequent than the severe group. However, the patients with severe mental retardation have a much higher chance of having an identifiable etiology. It has been estimated that, in the severe category, diagnosis is possible 7Q% to 80% of the time, whereas perhaps only 20%,to 30% of the time is this possible in the milder group. The even milder neurodevelopmental conditions (ie, learning disabilities, speech and language deficits) represent a group that is even more common (10% to 15% of the school-aged population), and even more difficult in which to define an underlying cause. In fact, in the best of hands, this group probably has an identifiable cause in only 5% to 10% of the cases. Taken as a whole, then, patients with" idiopathic mental retardation or developmental delays" probably represent 2% to 3% of the entire living population in this country.

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Seminars in Pediatric Neurology, Vol 5, No 1 (March), 1998: pp 33-38

The diagnostic approach to defining the etiology for these conditions is outlined in other articles in this issue. The focus here is, specifically, the role of diagnostic neuroimaging in the clinical management of these patients. Various neuropathological studies have shown anywhere from 40% to 90% of all patients with mental retardation have abnormal findings when studied microscopically. Early on, with techniques such as pneumoencephalography, the premortem diagnosis came nowhere close to identifying neuroanatomic correlates in this group. However, with the progression from pneumoencephai0graphy to computed tomography (CT) to high-resolution CT and magnetic resonance imaging (MRI), the premortem diagnosis of brain changes in idiopathic mental retardation has greatly improved. Currently, the technology of MRI is readily available in most hospitals of significant size. Beyond the realm of MRI, newer techniques for the study of neuroanatomy and neurophysiology with specific applications have been developed. In particular, quantitative image analysis of MRI scans has proven to be a very useful tool in identifying subtle changes not readily apparent by visual inspection. 3 The use of quantitative image analysis in MRIs, however, does require the following: 1. Rigorous establishment of normative data (to determine the range of normal biologic variance). 2. Knowledge of the prevalence and incidence of specific findings in an unselected population. From the Department of Pediatrics, Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE; and the Departments of Neurology and Pediatrics, West Virginia University Health Science Center, Morgantown, WV. Address reprint requests to G. Bradley Schaefer, MD, Department of Pediatrics, Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, 600 S. 42 "d St, Omaha, NE 68198-5430. Copyright o 1998 by W.B. Saunders Company 1071-9091/98/0501-000658.00/0 33

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SCHAEFER AND BODENSTEINER

3. The absolute necessity to use appropriately selected controls. In addition to quantitative image analysis of MRIs, positron emission tomography (PET), and MRI spectroscopy are also providing additional information into the neuroanatomy, neurophysiology, and cerebral metabolism of patients with neurodevelopmental disabilities. 4 WHO TO IMAGE?

Almost from the inception of neuroimaging techniques, there has been a discussion as to which patients should or should not undergo such studies as part of their diagnostic workup. 5 Debate has been longstanding, and to date there has really been no consensus reached in this arena. 6,7 In addition, as newer (and not necessarily more expensive) techniques become available, this debate shows no signs of resolution in the near future. Perpetual changes in health care financing continue to press the issue of "cost effectiveness." The question of cost effectiveness in diagnostic testing for complex conditions, such as neurodevelopmental delays, is indeed an extremely convoluted issue with several variables, many of which are very difficult, if not impossible, to quantify. When one looks at the issue of cost effectiveness, there are two important considerations, namely risks versus benefits. The analysis of benefits in the area of neuroimaging for patients with developmental delays is based on the diagnostic yield (how often the tests will be positive) and the clinical efficacy (what can be done with the results if they are indeed positive). T h e "risk" of these procedures primarily equates to a pricing issue. Other than the issues related to the costs of the tests (and potentially the accessibility

for some of the newer technologies) the biological medical risks are mir/imal--modest amounts of radiation for CT and oral sedation with MRI in a subgroup of patients imaged.

Diagnostic Yield In analyzing the cost effectiveness of neuroimaging findings in idiopathic retardation and developmental disabilities, the denominator must first be determined. In particular, the frequency of positive neuroimaging findings should be known? Table 1 summarizes many of the pertinent articles that have looked at this question. Review of Table 1 notes varying results from study to study. The significant variations in the results of these studies are mainly due to the following: 1. Differences in techniques (CT versus highresolution CT versus MRI; use/nonuse of quantitative techniques). 2. Sample size. 3. Selection criteria used for the study population (abnormal head size or shape, presence or absence of seizures, presence or absence of neurological findings) versus an unselected population. 4. The expertise in interpretation. 5. The severity of the delays in the population surveyed. The variances of these studies are also due to some practical (possibly insurmountable) limitations in these types of studies. Ideally, a prospective, longitudinal series of neuroimaging studies should be done in unselected individuals with and without neurodevelopmental disabilities. The neuroimaging findings would then be correlated with objective psychometric testing. However, many factors,

Table 1. Reported Incidences of Abnormal Neuroimaging Findings in Patients With Mental, Retardation Study Moeschler (1981) 8 Lingham et al (1982) 9 Lingham & Kendall (1983) 1~ Sugimoto et al (1993) 11 Curryet al (1996) 12 Curry et al (1996) 12 Majnemer & Shevell (1995) 13 Root & Carey (1996) 14 Root & Carey (1996) TM Kjos et al (1990) 15 Schaefer (1995) le

Scan Type CT CT CT CT CT/MRI CT/MRI CT/MRI CT/MRI CT/MRI MRI MRI

N

Selection Type

23 Normocephaly 76 NSMR 29 NSMR + infantile spasms 55 Microcephaly 31 Microcephaly 46 Normocephaly 60 Unselected significadt DD 40 Profound MR 53 Clinical gentics referral 76 DD unknown cause 681 All referrals for MR/DD

% Abnormal 9 28 75 80 68 39 27 80 26 28 60

Comments

Less frequent with other seizure types

63% of all patients had definable etiology

Higher yield if microcephaly, seizures

Abbreviations: MR, mental retardation; NSMR, nonspecific MR; DD, developmental delay. Adapted and reprinted with permission. 2

RADIOLOGY IN DEVELOPMENTAL DISABILITIES

such as the cost of ascertaining enough patients, make this type of study practically impossible. Until such studies can and are performed, there are still many meaningful conclusions that can be derived from existing data. A summary of the results presented in Table 1 provides several pertinent insights. With the newer techniques (highresolution CT and MRI), positive findings are found on neuroimaging studies in 30% to 60% of unselected patients with mental retardation and "significant" developmental delays. This yield is significantly increased if selection criteria are used for factors, such as abnormalities of head size, presence of'absence of seizures, or the presence or absence of abnormal findings on neurological examination. The diagnostic yield is also increased with the application of quantitative techniques to the neuroimaging studies. Additionally, of all of the patients with mental retardation and developmental delays who do have a definable etiology for their mental retardation, almost one third to one half of these may be due to isolated cerebral dysgenesis/ cerebral injury. For these patients, then, neuroimaging would be the only method of accurate, premortem diagnosis.

Clinical Efficacy As shown previously, there is no doubt that neuroimaging in a population of persons with mental retardation and developmental delays has a sufficiently high yield, with or without the use of any other selection criteria, to justify its use. The next obvious question is "So what?" Specifically, what will be done with the information obtained from a positive neuroimaging study? As we 1 and others 13 have noted before, the identification of abnormal findings in neuroimaging studies provide the clinician and the family with invaluable information and insight into the patient's medical condition. The types of information provided to the family include information about possible pathogenesis. This would include information regarding injury versus dysgenesis. In addition, such studies are often helpful in determining the timing of the event, whether injury or dysgenesis. This remains a critical issue to consider when discussing "cost effectiveness," especially considering the large number of medical litigations involved in suspected "perinatal injury," and the extremely high awards sought in such cases. 17 Additionally, the identification of such changes may provide informa-

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tion regarding prognosis--a progressive versus static encephalopathy. Depending on the findings, recurrence risks may be available for the family. This can range from extremely low recurrence risk in cases of isolated cerebral dysgenesis 1 up to the 50% recurrence risk of an autosomal dominant condition, such as a cerebral dysgenesis associated with the sonic hedgehog mutation in holoprosencephaly and its variants. 18 Finally, specific medical interventions may be suggested by particular imaging findings.

Risk The primary "risk" issue that has been raised in the question of whom to image or whom not to image revolves around the cost of said procedures. Currently, an average high-resolution CT scan may cost on the order of $400 to $600, and a full MR! series may cost anywhere from $800 to $1,000. Although at first blush, this may seem a relatively large amount of money; in the context of the habilimtion costs, both within and without the school system, the costs of the neuroimaging procedures are dwarfed. In addition, it is impossible to quantify the benefit of such knowledge provided to the family, specifically dealing with lifelong issues of the child/adult with mental retardation and their ongoing care. Other than cost, and potentially accessibility of these studies, there are relatively few other risks associated with diagnostic neuroimaging. There is a modest amount of radiation associated with a CT scan of the head, but again, from the standpoint of etiological investigation, these are not studies that need to be repeated on an ongoing basis. The only identifiable problem with MRI is that of the minimal risk associated with oral sedation, which is required for some patients. In summary, then, we continue to recommend neuroimaging studies for all patients with idiopathic mental retardation or significant developmental delays. The test of choice remains the MRI scan. If there are limitations in accessibility or cost issues involved in MRI, a high-resolution CT scan presents an acceptable second choice. TYPES OF FINDINGS IN DIAGNOSTIC NEUROIMAGING IN PATIENTS WITH MENTAL RETARDATION

After having discussed the diagnostic yield of such studies, the next issue to be addressed is, when

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there is a positive finding, specifically what does one find? When diagnostic neuroimaging is performed in patients with idiopathic mental retardation or global developmental delays, the findings can be categorized into three major groups, namely cerebral injury, overt cerebral malformations, and subtle markers of cerebral dysgenesis. Although the clinical correlates of cerebral injury are most often seen in the context of the clinical picture of cerebral palsy, this is not always the case. (Conversely, many children with cerebral palsy have MRI findings that are unmistakably that of cerebral dysgenesis, x9) As an aside, then, we believe that all children with cerebral palsy should have diagnostic neuroimaging as part of their complex evaluation. When findings of cerebral injury are seen in patients with idiopathic mental retardation, one commonly may see findings of hypoxic ischemic encephalopathy (HIE) or those of congenital infections. In the HIE group, findings include periventricular leukomalacia (mainly seen in premature infants), and a spectrum of other problems related to hemorrhage, encephaloclastic processes, and ex vacuo conditions (ventriculomegaly or enlargement of the extra cerebral fluidfilled spaces). The findings of congenital infection are those of cerebral injury, with or without the added findings typically of intracranial calcifications. Many patients with idiopathic mental retardation will have readily identifiable overt cerebral malformations noted on "standard" neuroimaging studies. A comprehensive discussion of the entire spectrum of cerebral malformations is beyond the scope of this review. However, the reader is referred to a recent review of this topic? ~ In general, however, one can summarize that the overt cerebral malformations most often seen in patients with idiopathic neurodevelopmental delays fit into categories of disorders of ventral induction (such as holoprosencephaly, agenesis of the corpus callosum, and septo-optic dysplasia), migrational abnormalities (lissencephaly, schizencephaly, pachygyria, and polymicrogyria), and aberrant white matter development (demyelinating/dismyelinating syndromes). With the application of high-resolution neuroimaging studies coupled with quantitative techniques, many patients who were previously believed to have no identifiable cause for their developmental abnormalities have subsequently been shown to

SCHAEFER AND BODENSTEINER

have less obvious findings of cerebral dysgenesis. We have chosen to call these findings "subtle markers" of cerebral dysgenesis, as clearly each of these findings represents the "tip of the iceberg" in regard to overall impact on central nervous system development. Many of these subtle markers are not visualized or not visualized optimally by CT scan. MRI is clearly a much better study for identifying these markers, but again, as mentioned previously, sometimes even this requires the application of quantitative techniques. Positron emission-computed tomography scanning and single photon emission-computed tomography scanning also provide insights into some patients who, by CT scan and MRI scan, still have no identifiable abnormality. However, these studies are even less readily available than MRI scan and are potentially more expensive. Not surprisingly, with advances in neuroimaging techniques, the list of subtle markers of cerebral dysgenesis continues to grow (Table 2). This has been particularly so in the case of "milder" neuronal migration defects. With continued increases in the resolution of the neuroimaging studies, not only can subtle disorders of cerebral dysgenesis be identified, but focal/partial3~ defects in cerebral formation can also be identified. However, it is important to exercise caution when interpreting specific findings as being true markers of cerebral dysgenesis. Other less specific findings, such as ventriculomegaly32 and enlargement of the subarachnoid spaces, 33 have been reported to occur as isolated findings at an increased incidence in populations with developmental disabilities. Whether or not these are true events of cerebral dysgenesis as characterized above remains to be seen. Many of the subtle markers of cerebral dysgenTable 2. Reported Subtle Markers of Cerebral Dysgenesis Wide cavum septum pellucidum 20 Persistence of the cavum septum pellucidum 2~ Hypoplasia of the corpus callosum 2~ Macro cisterna magna 20 Open operculum 21 Macro cerebellum ~2 Colpocephaly2~ Focal cortical dysplasia 24 Double cortex (band heterotopia) 25 Bilateral perisylvian syndrome 26 Hemimegalencephaly27 Cerebral hemiatrophy 28 Abnormal myelin maturation 29

RADIOLOGY IN DEVELOPMENTAL DISABILITIES

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esis have no specific neurological "syndrome" associated with them, most often demonstrating generalized findings, such as mental retardation, developmental delays, hypotonia, or epilepsy. However, some of these findings provide specific information with important clinical implications for patients with those findings. For example, in our patients with the Macro cerebellum, most have oculo-motor apraxia. 22 Patients with the bilateral perisylvian syndrome 26 are noted consistently to have pseudobulbar palsies, and in patients with focal cortical abnormalities, infantile spasms, and bitemporal glucose hypometabolism, 34 cortical resection has been shown to be of poor efficacy. NEUROIMAGING FINDINGS IN MILDER NEURODEVELOPMENTAL SYNDROMES

So far, the discussion has addressed patients with mental retardation and "significant" developmental delays. However, a body of literature has been accumulating over the last 10 years regarding the neuroimaging findings in the less severe neurodevelopmental syndromes. This topic is too broad to cover in any great detail, but several examples will serve to highlight the importance of neuroimaging studies in even the milder conditions. Bergstr6m et aP 5 evaluated 109 patients with "minor" developmental delays (specifically not mental retardation or cerebral palsy). In this patient population, 25% of CT scans were noted to be abnormal. Major findings included anomalies, such as arachnoid cysts, and absence of the septum pellucidum. Patients with learning disabilities have been evaluated in a variety of studies, looking at cerebral morphometry. A repeatedly reported finding in this group of patients has been the reversal of normal cerebral asymmetry particularly in those patients with learning disabilities and verbal delays. 36 Similar findings were noted in the early 1980s in patients with specific reading disabilities. 37 More recently, MRI studies in dyslexia have noted reproducible findings of bilateral hypoplasia of the insular region, smaller left plannm temporale, aberrant cerebral asymmetry, and atypical asymmetry in the perisylvian region. %

Patients with infantile autism have been the subject of extreme scrutiny regarding neuroimaging findings. Early suggestions of selected hypoplasin of cerebellar vermal lobules VI and VII in autistics, have recently been shown to be a nonspecific finding for patients with this condition. 39 However, more recently, findings of an increased size of the cranium, 4~ and overall brain size, 41 have been noted in patients with autism. Specifically, they have been noted to have an increase in the total brain volume, total amount of central nervous system tissue, and in the size of the lateral ventricles. Even patients with normal mentation, but with psychiatric disturbances, have been reported to have a frequent occurrence of abnormalities of neuroimaging studies. In one study, 42 37 patients with a variety of psychiatric and/or behavioral problems underwent neuroimaging. In this study, 13 (30%) had abnormal findings on their MRI scans:The findings were most common in patients with schizophrenia and autism/pervasive developmental disorders. However, there were no consistent findings noted for any one diagnostic group. Taken as a whole, these studies suggest that even patients with less striking neurodevelopmental abnormalities have a significant incidence of abnormal findings on neuroimaging studies. CONCLUSION The significance of neuroimaging studies in patients with idiopathic mental retardation and developmental disabilities have been reviewed. Data have been described that suggest that neuroimaging is an important tool in the diagnostic regimen of these patients. With increasing accessibility of MRI for standard clinical use, these studies should be readily available for most patients. Positive findings on these studies provide important information at minimal risk, and these studies are recommended to be prescribed liberally for the benefit of the patients, their families, and their health care providers.

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