A STUDY OF BRAIN MRI FINDINGS IN A SERIES OF 99 PROFOUNDLY RETARDED ADULTS WITH VARIOUS NEUROLOGICAL SIGNS AND SYMPTOMS: RELATIONSHIP OF VENTICULAR SIZE TO ABNORMAL BEHAVIOR AND SPONTANEOUS DYSKINESIA.

Philip B. May, Jr. MD Clinical Associate Professor of Medicine and Pediatrics UMDNJ/Robert Wood Johnson Medical School, New Brunswick, NJ Attending Physician, UMDNJ/Robert wood Johnson Medical School, Department of Medicine, Developmental Medicine Clinic. Physician Specialist, Hunterdon Developmental Center, Clinton, NJ

Kevin DeMarco, MD Medical Director, Laurie Imaging Center, New Brunswick, NJ Associate Professor of Radiology, UMDNJ/Robert Wood Johnson Medical School

Eric B. London, MD Medical Director, Advanced Psychological Associates, Freehold, NJ Clinical Assistant Professor of Psychiatry,UMDNJ/Robert Wood Johnson Med. School

Robert Thompson, MA Staff Psychologist,Hunterdon Developmental Center

Terri L. Mento, BA Administration, Hunterdon Developmental Center

Leonard Buscemi, MA Staff Psychologist, Hunterdon Developmental Center

Ronald Cody, EdD Associate Professor of Environmental and Community Medicine UMDNJ/Robert wood Johnson Medical School, Piscataway, NJ

Communications regarding this manuscript should be sent to: Philip May MD Hunterdon Developmental Center PO Box 4003 Clinton, NJ 08809 Phone: (908) 735-4031, Fax: (908) 730-1322, e-mail: pmay@interactive.net

Introduction: Individuals who sustain brain injury during the “developmental” period demonstrate, in adulthood, a wide variety of general medical as well as neurological signs and symptoms (1). Neurological manifestations include cognitive impairment (mental retardation), epilepsy, neuromotor dysfunction ( paralysis or plegia,“cerebral palsy”, spontaneous dyskinesias), and, pehaps most significantly, severe abnormal destructive behaviors. Of the 350,000 mentally retarded individuals who receive services from the state and federal government, approximately 160,000 demonstrate these severe destructive behaviors at a cost to society of 3 billion dollars per year (2). The etiology of behaviors, which include impulsive assaultiveness, property destruction, and self-injury, is rarely clear. Health-care professionals are called upon to evaluate and treat, but because of diagnostic uncertainties, ineffective or inappropriate medications are often administered. Misuse of medication has at times led to costly litigation, especially when related to "tardive dyskinesia" secondary to neuroleptic drugs (3). Furthermore, since history-taking is unreliable in a non-verbal mentally retarded individual, it is virtually impossible to determine a diagnosis of "psychosis" in a person with profound mental retardation by the usual clinical evaluation methodologies (4). There is therefore a need for better understanding of the mechanisms of those bizarre destructive behaviors encountered in profoundly retarded individuals.

Previous studies have demonstrated that "ventricular enlargement" is a non-specific MRI abnormality frequently found in a variety of neuropsychiatric conditions associated with abnormalities of cognition and/or abnormal behavior (5-10). Since numerous brain MRI's had been obtained at our facility since 1993, we decided to review them in order to determine whether, as with other neuropsychiatric conditions, there might be an association of ventricular size with dysfunctional behavior problems or other neurological manifestations of neuro-developmental disability. We reasoned that if such a correlation could be demonstrated this might suggest prognostic or diagnostic possibilities for brain MRI determination as well as insight regarding the mechanism of the behavioral disorder.

Methods: During the period 1993-1996, brain MRI scans were obtained in 106 adult residents of Hunterdon Developmental Center, a 650 bed ICF/MR facility in Clinton NJ. All patients fell within the severe/profound range of mental retardation (less than 40) as determined by the Slossen Intelligence Test. The etiologies of mental retardation included prematurity, birth injury, phenylketonuria, tuberous sclerosis, neurofibromatosis, and Down Syndrome, but the vast majority were of unknown etiology. A 1.5 T MRI Scanner was used in all cases. Scanning was performed in one of two imaging centers located in the region. Intravenous sedation was required in most cases. MRI's were obtained for a variety of reasons, but usually to establish an etiologic diagnosis or to rule out a space occupying lesion as a cause of motor dysfunction, seizures, or bizarre behavior.

There was one group of seven non-retarded individuals who were evaluated at the Robert Wood Johnson Medical School, Neurology Clinic for a variety of complaints (usually headache) and who had normal brain MRI's (see group 1, Table 1).

Click here for Table 1

For purposes of comparison, MRI's obtained from mentally retarded patients were divided into five clinical groups:

(1) Severe/Profound Mental Retardation only (IQ less than 40),

(2) Seizures,

(3) Spontaneous Dyskinesia (abnormal involuntary movements unrelated to medication),

(4) Plegia (paralysis),

(5) Severe Behavior

(see groups 2-6, Table 1).

Group 2 patients (Mental Retardation only) had profound cognitive deficits, but no seizures, abnormal involuntary movements, significant abnormal destructive behavior, or skeletal muscle dysfunction (cerebral palsy). Group 3 patients (Seizures) were also profoundly cognitively impaired, but were also receiving medication (usually Tegretol and/or Depakote) for seizures. Some had cerebral palsy as well but most were ambulatory. None had abnormal involuntary movements or were receiving medication for significant destructive behaviors. Group 4 patients (Dyskinesia) had a variety of abnormal involuntary movements, including myoclonus, choreoathetosis, dystonia, and tremor. All had cerebral palsy and most had seizures as well, but none of these group 4 patients received medication for abnormal destructive behaviors. Group 5 patients (plegia) had skeletal muscle dysfunction (cerebral palsy) but no seizures, dyskinesia, or behavior problems which required medication. Group 6 patients (Behavior) were all receiving neuroleptic medication (usually Mellaril) for what was felt to be uncontrollable destructive behavior (self-injurious, assaultive, destructive of property). Almost all were ambulatory and a few had seizures. What distinguished group 6 patients was the fact that neuroleptic medication was being prescribed at the time of MRI determination.

Ventricular size was evaluated in all six groups (1 non-retarded control, 5 mentally retarded patient groups) in the following manner: A ventriculo-cerebral ratio (VCR) was determined by dividing the width of the ventricle by the width of the cerebrum in coronal view, at the level of the anterior commissure at a point on the septum pellucidum one-third the distance below the corpus callosum (see Figures 1A and 1B below).

Figure 1A: Normal VCR. R= right, L= left, AMY= amygdala. Patient with profound mental retardation and seizures, but no behavior problems (group number 3).

Figure 1B: Increased VCR in patient with severe destructive behavior responsive only to neuroleptics (group 6)

For convenience, the ratio was multipled by 1000. Three patients were excluded from the study because of absense of the corpus callosum and septum pellucidum. In addition, four patients were excluded because of a known diagnosis of hydrocephalus. Thus 99 patients were available for analysis.

Results: Intraobserver reliability was measured by having the first observer measure the VCR on two separate occasions one month apart. The observer was blinded to the results of the first set of results while repeating the measurements. The correlation between the two measurements was extremely strong with the r = 0.99 (p<0.0001). The means of the two measurements were 185.2 versus 183.1. This demonstrates excellent reproducibility of these measurements by a single observer. Next, the interobserver reliability was analyzed by having a second observer also measure the data. This observer had no previous experience with measuring VCR and used a different computer system and display program. The correlation between the first measurement of observer A to observer B was 0.98 (p<0.001). This represents an extremely strong correlation between the two observers. There was an observed shift in the VCR with observer B having a mean VCR of 171.3 compared to 185.2 for observer A. A similar shift was seen when mean VCR for both observers was calculated for each patient category.

Overall no significant differences in VCR as a function of gender were noted (p =0.59). The mean VCR for females was 179 versus males at 188. No significant correlation between age and VCR was seen with a Pearson correlation coefficient of 0.11 (p=0.29). Analysis of variance comparing the mean age among the various categories of patients found no significant differences in mean age as well. The mean age was 36.3 years with an interquartile range of 13 ( 30 to 43).

A one way analysis of variance was used to compare the relationship of VCR to the six clinical diagnostic categories ( 1 normal, 5 mentally retarded), see Table 1. The dependent variable was the VCR and the independent variable was the diagnostic category. The ANOVA was highly significant (p < 0.0001). A Duncan multiple range test (p = 0.05) was performed. This demonstrated that the behavior (group 6) and dyskinesia (group 4) patients had a significantly larger VCR than any of the other patient groups. The VCRs in the remaining four groups (seizures, plegia, mental retardation alone, and normal) were not statistically significantly different from each other.

Discussion: Mental retardation alone or associated with seizures or paralysis was not associated with ventricular enlargement as we define it. On the other hand ventricular enlargement of the frontal area was associated with a history of destructive behavior requiring neuroleptic medication (group 6) and in addition, the presence of abnormal involuntary movements (group 4). While the pathophysiological significance of these findings has not been determined by the present study, one might speculate that ventricular enlargement may reflect damage to frontal cortical-subcortical circuits needed for normal impulse control (11,12). If this is true then one might expect abnormal involuntary behavioral and motor responses to a variety of internal and/or external stimuli such as appeared to be the case in our Groups 4 and 6. While our data demonstrate that ventricular enlargement is present in some but not all groups with severe/profound mental retardation (i.e. those with behavioral and movement disorders) the etiology of ventricular enlargement in Groups 4 and 6 remains unknown. Since all members of the "behavior" group had received long term neuroleptic medication, one might speculate that neuroleptic medication itself had caused subcortical atrophy which led to ventricular enlargement. If drug toxicity were the mechanism for ventricular enlargement, it does not explain the fact that the movement disorder group (group 4) also had ventricular enlargement, but no history of neuroleptic use. Also we had several patients who were withdrawn from neuroleptics years previously and demonstrated no behavior problems. MRI's in these patients did not show ventricular enlargement. Others have reported that imaging studies of "first episode" schizophrenics, who had never received neuroleptics, also have ventricular enlargement, compared to non-schizophrenic controls (13,14). Morphometric studies of schizophrenic brains taken before the era of neuroleptics show "degenerative" changes (15). Clearly ventricular enlargement can occur by mechanisms other than drug toxicity. There is abundant evidence that a variety of intrauterine insults can damage prospective cortical neurons which are generated near the cerebral ventricles (16-22) and it has been known for years that these insults can be associated with an increased frequency of neuro-behavioral problems in childhood (23) It is apparent that these same insults can cause profound cognitive impairment as well. In the setting of profound cognitive impairment, the psychiatric diagnosis of “psychosis” becomes more difficult. One might speculate that severe behavioral problems, when encountered in patients with profound mental retardation who also demonstrate ventriculomegaly on MRI, might represent a form of “psychosis”.

Studies are currently in progress to compare the “neuroleptic response” of patients with severe/profound mental retardation who possess uncontrollable behavior and ventricular enlargement to the “neuroleptic response” of a similar group of mentally retarded individuals who demonstrate severe behaviors but have normal ventricles. If, as has been suggested by previous reports in non-retarded individuals (24-26), behavior-problem mentally retarded patients with enlarged ventricles respond differently to neuroleptic medications, then brain MRI determination might become an important prognostic and/or diagnostic tool in non-verbal profoundly retarded adults who display severe destructive behaviors.

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