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United States Navy Marine Mammal Program, San Diego, CA
Abstract
A 2 and a half-year-old male California sea lion (Zalophus californianus) presented with a history of intermittent generalized seizures. Magnetic resonance imaging revealed a large focal mass occupying the right cerebral hemisphere with moderate dilatation of the contralateral lateral ventricle. At necropsy, the right cerebral hemispheric white matter was expanded by numerous irregularly shaped, pale pink nodules up to 10 mm in diameter. The overlying cortex was characterized by increased numbers of small, poorly developed gyri with shallow, often indistinct, sulci (polymicrogyria). Microscopically, nodules were composed of neurons, oligodendroglia, microglia, and supporting neuropil and were well delineated from the surrounding white matter. The gross, histological, and immunohistochemical features of this lesion are consistent with a neuronal migration defect resulting in unilateral subcortical heterotopia.
Key words: California sea lions; central nervous system; malformation; neuronal migration defect; nodular heterotopia; subcortical heterotopia; Zalophus californianus.
In humans, cortical dysplasia is relatively common in patients with epilepsy and mental retardation. Disruption of neuronal migration due to a fundamental fault in the migratory process or an early insult to neuronal progenitor cells during development of the cerebral cortex has been suggested for many of these conditions.11,15 The formation of neuronal heterotopias within cerebral white matter is one such manifestation. Traditionally, heterotopias due to disruption of migration were classified as nodular or laminar. Clinically, it was found more useful to divide heterotopias into 3 categories: 1) subependymal, 2) subcortical, and 3) band heterotopia.3 Subcortical heterotopias are defined as "irregularly lobulated masses of gray matter that are located primarily in the subcortical white matter of the cerebral hemispheres."2
Reports of developmental lesions or malformations resulting in cortical dysplasia are not uncommon in the veterinary literature. Although often idiopathic, frequently reported etiologies include in utero infections, maternal toxin exposure, and those with a genetic basis.8,17 Well-characterized examples with distinctive lesions include ovine orbiviral hydranencephaly, holoencephaly in lambs caused by maternal ingestion of Veratrum californicum, and lissencephaly in Lhasa Apso dogs. 8,17 Sporadically, hamartomatous lesions are also described.7,13 To our knowledge, there are no reports in the veterinary literature of subcortical heterotopia as a result of a neuronal migration defect.
At 1 year of age, a captive-born male California sea lion had a single, self-limiting, generalized seizure. The subsequent physical exam, neurological exam, complete blood cell count, and clinical chemistry were unremarkable. For approximately 1 year, no additional seizures were observed and the animal progressed in training and development along with his peers. At 2 years of age, another self-limiting, generalized seizure was observed. Again the physical exam, neurological exam, complete blood cell count, and clinical chemistry were unremarkable. Protozoal and morbilliviral serology and domoic acid assays were negative. To explore a possible anatomical basis for the seizures, a magnetic resonance imaging (MRI) study was performed. The T2-weighted MRI study done without contrast revealed a large focal mass occupying or replacing much of the right cerebral hemisphere. The overlying cortex was thin and irregular, and there was moderate dilatation of the left lateral ventricle (Fig. 1). Within weeks, multiple generalized seizures were observed, and the animal was placed on appropriate anticonvulsant therapy. Over the following months, the animal was observed as becoming progressively more ataxic during land-based training sessions and had brief periodic episodes of altered behavior and apparent awareness interpreted as petit mal seizures. A second MRI was ordered to better establish the limits and anatomical relationship of the lesion. However, the animal expired during this procedure.
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Microscopically, nodules were well delineated from the surrounding white matter and composed of numerous irregularly arranged neurons, oligodendroglia, and microglia along with supporting neuropil (Fig. 4). There was strong NSE immunoreactivity for the numerous neurons within the nodules (Fig. 5). No cells within nodules exhibited GFAP immunoreactivity (Fig. 6), and there was only scattered immunoreactivity for MBP (Fig. 7). The lack of GFAP staining within nodules not only demonstrates an absence of mature astrocytes but also suggests an absence of radial glial cells. Within the surrounding white matter, there was strong multifocal immunoreactivity for GFAP-positive astrocytes (Fig. 6) and strong diffuse immunoreactivity for MBP (Fig. 7). Rare NSE–positive neurons were also observed within the white matter (Fig. 5). The overlying cerebral cortex was hypocellular and of variable thickness. Cortical neurons were irregularly arranged and lacked any apparent lamination or organization.
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Proper neuronal migration requires the successful interaction between cell ligands, cell adhesion molecules, and extracellular matrix molecules and the coordinated movements of cytoskeletal proteins.5,15 In humans, studies of neuronal migration defects with a familial basis, identification of their associated genes, and observations of their characteristic phenotypes have led to an understanding of the mechanisms underlying neuronal migration. As a result, 4 key steps have been identified: 1) onset of neuronal migration, 2) ongoing neuronal movement, 3) neuronal migration into the preplate, and 4) neuronal migration completion.9 Conditions best illustrating these 4 key steps include periventricular heterotopia, classical lissencephaly and double cortex, lissencephaly with cerebellar hypoplasia, and cobblestone lissencephaly, respectively.5,9,15 Filamin 1 (FLN1) was identified as the gene underlying periventricular heterotopia. Filamin 1 protein, an actin-binding/cross-linking protein, plays a critical role in the onset of neuronal migration. Mutation results in neuronal nodules lining the lateral ventricle.5,9,10 Classical lissencephaly and double cortex are the result of defects in ongoing neuronal migration associated with mutations in lissencephaly 1 (LIS1) and doublecortin (DCX). LIS1 and DCX are microtubule-binding proteins key in the microtubule stability and reorganization necessary for proper migration. Mutations result in collections of neurons within subcortical white matter.5 Lissencephaly with cerebellar hypoplasia is the result of a reelin (RELN) gene mutation identified in some families and the Reeler strain of mouse. The reelin protein appears to be responsible for the entry of migrating neurons into the preplate and their proper positioning.14,15 In the absence of the reelin protein, migrating neurons populate the cortex in an inverted "outer to inner" fashion.14,15 Cobblestone lissencephaly appears to be a defect in the signal responsible for halting neuronal migration. Mutations in the fukutin gene result in the loss of the fukutin protein, a protein expressed by layer 1 neurons, where it is believed to produce a stop signal. Without the appropriate stop signal, migrating neurons pass the cortical plate, penetrate the pia, and present as follicular heterotopias.9,15
PMG is defined as excessive cortical infoldings. Grossly, gyri are small and separated by shallow or indistinct sulci.4,6 The defect can be focal or widespread. Histologically, PMG has been described as layered, characterized by a cell-sparse zone in layer 5, or unlayered where there is disorganization of cortical layers and nearly random orientation of neurons.4 The pathogenesis of PMG in humans is less well understood than neuronal migration defects. Most authors suggest ischemia as a major cause, but genetic, viral, and maternal toxicities have also been reported.4,18 PMG is also associated with seizure activity and mental retardation and often accompanies other malformations, including nodular heterotopias, enlarged lateral ventricles, and schizencephaly.1,6,18 Schizencephaly, a condition defined as a full-thickness defect of the cortical mantle lined by gray matter, is thought to have etiologies similar to PMG. Although not observed in this case, schizencephaly is commonly observed concurrently with PMG in humans.12,19
In addition to germline mutations, other identified causes of heterotopia in humans include injury, ischemia, and infection in the late first trimester or early second trimester.2 The unilateral distribution of the lesion observed in this young sea lion, as well as the apparent absence of this condition in any siblings, suggest a sporadic insult as the cause rather than a genetic or germline mutation. The nature of the lesion and the accompanying cranial deformity suggest the lesion's presence since before parturition, the likely pathogenesis being an early insult to the ventricular zone. Possibilities in this case include an in utero infection, maternal exposure to a toxin, and an ischemic event. In humans, the age of seizure onset is variable (usually during the first or second decades of life), and the seizure severity is often progressive in nature.3,9 Patients with large bilateral heterotopias were more likely to have severe developmental delays or motor dysfunction, whereas those with focal or even extensive unilateral heterotopias were more likely to have less severe (if any) mental retardation with variable motor function. 2,3 Our case was similar to human reports in that the seizure onset was delayed and the seizure activity was progressive in frequency and severity. In humans with neuronal migration defects or PMG, mental retardation is usually present, although the degree is variable.3,9 Interesting in this case was the degree, or lack thereof, of any perceived reduction in the animal's learning or motor abilities, especially for an animal in an intensive and active training program.
Acknowledgements
We thank Dr. Joseph Gleeson for his critical review of this manuscript; Drs. James Barkovich, Lawrence Hansen, and Henry Powell for assistance with microscopic interpretation; Drs. Dale Dunn, Judy St. Leger, and Mark Xitco for their invaluable input; and Steve Van Adestine for photographic assistance.
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