Fetal Alcohol Syndrome and Secondary Schizophrenia: A Unique Neuropathologic Study

Abstract

We report the unique neuropathologic study of an adult brain of a patient with fetal alcohol syndrome (FAS) who developed the well-recognized complication of schizophrenia in adolescence. The major finding was asymmetric formation of the lateral temporal lobes, with marked enlargement of the right superior temporal gyrus, suggesting that alcohol is preferentially toxic to temporal lobe patterning during gestation. Critical maturational changes unique to adolescence may unmask psychotic symptomatology mediated by temporal lobe pathology that has been clinically dormant since birth. Elucidating the neuropathologic basis of the secondary psychiatric disorders in FAS may help provide insight into their putative developmental origins.

Introduction

Fetal alcohol syndrome (FAS) represents the severe end of the spectrum of disorders related to prenatal alcohol exposure, affecting 0.5–2/1000 live births in the United States alone, with higher rats among vulnerable populations such as the American Indians.¹ It is characterized by: 1) craniofacial dysmorphology; 2) underweight and/or structurally abnormal brain with clinical cognitive deficits; and 3) somatic growth retardation.² Of note, the definition of FAS requires a history of prenatal alcohol exposure, but no specific documentation.² Secondary features may develop in FAS with increasing age; they include delinquency, job failure, abnormal sexual behaviors, and psychiatric illness.^3–6 Psychotic entities develop beyond childhood in up to 40% of individuals with fetal alcohol spectrum disorders (FASD).³ The question arises, does the neuropathology of FAS in adults include “secondary” abnormalities that develop over time, and potentially account for the clinical features that develop beyond childhood? Little insight into the answer is available, mainly because there have been no reports of the neuropathology of adult FAS, including in patients with secondary psychiatric manifestations that develop and/or are diagnosed and often these psychiatric conditions are diagnosed in adolescence or early adulthood. Thus, the natural history of prenatal alcohol exposure upon the human brain in adults is unknown.

Below, we report the neuropathologic study of an adult brain of a 34-year-old woman with FAS who developed schizophrenia in adolescence, and who had anomalous development of the temporal lobes at autopsy, of particular interest because of the known role of the temporal lobes in schizophrenia.^7–9 A major hypothesis in schizophrenia research today is that this disorder has its origins during brain development in early life, with clinical expression arising later in adolescence,⁸ an intriguing possibility for pediatric neuropathologists in search of neuropathologic evidence for it. Indeed, the study of adult brains with developmental disorders originating during gestation is rare, as brain malformations are more commonly associated with lethality in early life. The case reported here provided the unique opportunity to study the brain of an adult with FAS who developed schizophrenia in adolescence, with the potential to help elucidate the natural history of FAS and the developmental substrate of schizophrenia.

Case Report

The patient was a 34-year-old, American Indian woman with a diagnosis of FAS since early childhood that was based upon facial dysmorphology, global cognitive disabilities, short stature, and a reported history of maternal drinking during pregnancy. Due to adoption, the details of the amount, pattern, and/or timing of the prenatal alcohol exposure were unknown. The characteristic facial pattern of FAS included short palpebral fissures, thin upper lip, smooth philtrum, and flat midface, as confirmed upon review of childhood and adolescent photographs by us. Behavioral problems necessitated group home placement at age 15 years. In adolescence, the patient developed schizophrenia with auditory hallucinations, and comorbid depression with multiple suicide attempts. As an adult, she still required moderate supervision and continued to live in a group home; she maintained, however, steady jobs of low complexity. There was no history of cognitive decline; handedness was unknown. Psychiatric medications were: aripiprazole for schizophrenia; buproprion, mirtazapine, and trazodone for depression; dexmethylphenidate for attention deficit disorder; and lorazepam for anxiety. Other medical problems included obesity and a four-pack year history of cigarette smoking. On the day of her death, the patient collapsed at a local store; vigorous resuscitative efforts were unsuccessful. The general (standard) autopsy revealed massive pulmonary embolus, attributed to obesity, oral contraceptive use, and cigarette smoking. There were no systemic malformations.

Results

The brain weighed 1150 grams (normal for age and gender: 1233 grams; range: 1038–1440 grams). The cerebrum had an overall globular shape due to disproportionately enlarged right lateral temporal lobe, giving the frontal lobe a foreshortened appearance (Fig. 1). On the right, there was a markedly enlarged superior temporal gyrus (STG), abnormally deep superior temporal sulcus (4 cm in length), disproportionately small middle and inferior temporal gyri and facial fusiform gyrus (FFG), relatively flat planum temporale, and short insula (Figs. 1 and 2). On the left, the anterior opercula was slightly open, and the middle and inferior temporal gyri and FFG varied in size and shape through the anterio-posterior plane, with a thin STG and inferior temporal gyrus, thick middle temporal gyrus, and blunted FFG at the midthalamic level. Representative tissue blocks of the cerebral and cerebellar hemispheres and brainstem were examined with standard light microscopy with cell and myelin (Luxol-fast-blue) stains.

Figure 1.

A. The right cerebral hemisphere is notable for a disproportionately enlarged lateral temporal lobe (dotted lines), giving the brain an overall globular appearance with a foreshortened frontal pole. The superior temporal sulcus (asterisk) that divides the superior temporal and middle temporal gyri is deep, open, and cleft-like. Straight, diagonal artifacts (Artifact) related to brain removal at autopsy are present. B. The medial surface of the right hemisphere is intact. The corpus callosum (CC) was without total or partial agenesis. The cerebellum is without atrophy of the vermis and/or lateral hemisphere (not shown). Abbreviations; CG, cingulate gyrus; CS, calcarine sulcus; FX, fornix; MTT, Mammillothalamic tract; OC, optic chiasm; POS, parieto-occipital sulcus; RO, rostrum of the corpus callosum; SP, splenium of the corpus callosum.

Figure 2.

The temporal lobe of our FAS case (B) is compared to that of an adult control (A) (bar = 15 centimeters). In the FAS case, the superior temporal gyrus (STG) is abnormally enlarged with a smooth planum temporale and deep, cleft-like superior temporal sulcus separating the STG from the underlying middle temporal gyrus. The hippocampus (HIPP) and parahippocampal gyrus (BA 28) in the medial temporal lobe are grossly comparable in formation between the FAS case (B) and control (A). The thalamus, basal ganglia, hippocampus, parahippocampus gyrus, amygdala (not shown), and hypothalamus (not shown) are intact at the gross and microscopic (not shown) levels. In the STG of the patient (C), there are fetal-like, vertical columns compared to the normal STG (D). At higher power, the neuropil is cell-sparse and abnormally widened in the FAS case (E) compared to the control (F). Hematoxylin-and-eosin, scale bars in place.

Microscopically, the lamination pattern and neuronal differentiation of the cerebral cortex was generally appropriate. In the right and left STG and insula and left inferior temporal gyrus, however, there was persistence of a fetal-like cortex, with vertical columns of ≥8 neurons (putative range for a developmental anomaly),¹⁰ separated by large spaces of acellular neuropil (Fig. 2). There was no gliosis, obvious neuronal loss, or infarction in any cortical region; senile plaques or neurofibrillary tangles were not observed with β-amyloid immunostaining.

There were no macro- or microscopic abnormalities of the thalamus, hypothalamus, basal ganglia, amygdala, hippocampus, or cerebellum (Fig. 2). The cerebral arteries and Circle of Willis were without atherosclerosis. The degree of myelination appeared appropriate, including in temporal lobe pathways, e.g., superior medullary lamina of the subiculum and presubiculum, which has been reported to be delayed in schizophrenic brains.¹¹ Scattered axonal spheroids were noted in the fasciculus gracile of the caudal medulla bilaterally, consistent with acquired nutritional deficiency. There were no other abnormalities in the brainstem. The spinal cord was not available for microscopic examination.

Discussion

We report the unique study of the brain of an adult woman with FAS in which the major finding was maldevelopment of the lateral temporal lobes with unilateral (right) overgrowth. Asymmetric growth disturbances in the temporal lobes in FASD are supported by the report of preferential increases in the gray matter density and volume of perisylvean regions and middle and posterior STG in adolescents exposed to heavy levels of prenatal alcohol, as demonstrated by neuroimaging.¹² In our case, the cytoarchitecture of the STG was also immature (fetal-like), implicating a long-lasting effect of prenatal alcohol toxicity upon the intrinsic organization of the temporal cortex. Although the precise nature of the global intellectual deficits from childhood in our adult patient was unknown, this case suggests that anomalous temporal lobes may account, at least in part, for early onset cognitive impairments, given that the these structures play roles in memory,¹³ language,⁷ and auditory and thought processing^7–9 that are known to be affected in FASD.^2,14

The abnormal size and shape of the temporal lobe in our case raises the possibility that prenatal alcohol exposure targets the patterning center(s) of the embryonic forebrain that contains a protomap of the future temporal lobes. The cortical area map is established in proliferating ventricular cells by gradients in transcription factors which in turn are modulated by diffusible morphogens and signaling factors from specific patterning centers in the embryonic brain.^15,16 Genetic mutations in the fiber growth factor receptor 3 (FGFR3) gene, for example, results in excessive activation of the Fgfr3 receptor and enlarged and abnormally folded temporal lobes in thanatophoric dysplasia.¹⁶ We speculate that prenatal exposure to the environmental toxin alcohol can also disrupt the temporal lobe protomap through perturbations of the relevant signaling center(s), transcription factor gradients, and/or morphogens. The human superior temporal sulcus that demarcates the STG from the middle temporal gyrus normally first appears around 23 gestational weeks.¹⁷ Thus, prenatal alcohol exposure in our case likely occurred at least at this time, if not earlier, and extended into the second half of gestation when further sulcation of the temporal lobe is dramatic.¹⁶

Our case further suggests that anomalous formation of the lateral temporal lobes may underline the patient’s schizophrenia, as abnormalities in this key site have variously correlated with the formal thought disorder, auditory hallucinations, and verbal memory problems in schizophrenic patients.^7,9 In our patient, the right STG was markedly enlarged, with of note as this structure is involved in auditory and thought processing, as well as auditory hallucinations.^7,8 While reduced STG volume, unilaterally or bilaterally, is among the most robust findings in schizophrenia,⁷ our case suggests that overgrowth of this structure can also be detrimental.

The neurobiologic basis of the emergence of mental illness as a secondary feature of FAS in adolescence is puzzling since the malformative neuropathology is considered “fixed” at birth. Yet, it is possible that prenatal alcohol exposure sets in motion an unknown pathologic process that takes years to develop. The analysis of our single case, however, does not indicate any slowly evolving disease process in complicating the primary malformation, as there is no evidence of neuronal loss or glial reactions. An alternative explanation is that the maldeveloped pathways arising during gestation are immature early in life, and therefore dormant, until abnormal function is unmasked by critical developmental changes occurring in adolescence. Maturational changes in myelination and connectivity, for example, are postulated to account for the enhanced cognitive and emotional processing of adolescence compared to childhood.^11,18 Indeed, our case supports the hypothesis that schizophrenia originates during gestation and late developmental changes account for its emergence in adolescence.⁷ It also supports the speculation that schizophrenia is some cases is associated with prenatal alcohol toxicity.¹⁹ Elucidating the neuropathologic basis of the secondary psychiatric manifestations in FAS may help provide urgently needed insight into their early developmental origins.