Special focus on veterinary neuropathology

Far from being a “vast pink wasteland,” the world of neuropathology is a rich and rewarding specialty area in veterinary pathology. Disease entities and presentations are incredibly variable across species, with novel diseases being characterized routinely. Over the last several decades, significant inroads have been made in better characterizing central and peripheral nervous system neoplasia, novel or re-emerging infectious diseases, and species-specific conditions. In this special issue of Veterinary Pathology, we provide a series of original and review articles that highlight important novel conditions in veterinary species or clarify pre-existing conditions that benefit from further exploration. With advancements in ancillary testing, including transcriptomics and in situ hybridization, veterinary neuropathology sits at the edge of a molecular revolution, with many diseases clamoring for characterization beyond histology.

The special issue starts with a timely editorial discussing the career trajectory of a pre-eminent veterinary neuropathologist, Dr Brian A. Summers, which highlights the critical role that intimate knowledge of clinical neurology and neuroanatomy has in refining one’s ability as a neuropathologist. ¹⁶ The reader is encouraged to internalize the lessons offered in this editorial and remember that no case can be understood in a vacuum. A broad understanding of the nervous system is needed to correctly interpret neuropathology. This is not a lesson limited to the nervous system and should be an important lifelong learning objective for all pathologists, regardless of their role.

Tumor diagnoses and terminology remain a fraught area of neuropathology. Two of the more commonly misconstrued terms are palisades and perinecrotic palisades, and a richly illustrated review of these 2 terms and their use in veterinary pathology is included. ¹³ Similarly challenging and equally misunderstood are rosettes and pseudorosettes, which are found in many different neoplasms, including those of the nervous system. This equally well-illustrated review should serve as a guide for how and when to utilize these terms in the pathology lexicon. ¹² Also included in this special issue is an in-depth review of the paraganglionic system and its associated neoplasms, paragangliomas. Paragangliomas encompass many different individual tumors, including pheochromocytoma and chemodectoma, and this article utilizes standardized histologic, histochemical, and immunohistochemistry to provide a systematic and comprehensive methodology to diagnose these tumors accurately. ² The authors describe results from the application of a novel immunohistochemical marker, insulinoma-associated protein 1 (INSM1), which furthers another recent study published in Veterinary Pathology on this same marker.^2,17 Oligodendroglioma is the most common glioma in the dog and is increasingly studied from a molecular standpoint, with known overexpression of many different proteins, including platelet-derived growth factor receptor alpha (PDGFRA). A new study that delves into the mutations associated with PDGFRA overexpression in canine high-grade oligodendroglioma indicates a role for chromosome 13 polysomy. ¹⁸

The Lagotto Romagnolo dog breed is susceptible to several different neurologic diseases, including a juvenile form of epilepsy. Further study of this dog breed revealed that regardless of neurologic status, they commonly have inclusion bodies in cells of the nervous system. A detailed study of these inclusions, their potential origin, and their role is presented in this special issue and should serve as an excellent basis to study similar inclusions noted in the central nervous system (CNS) of other, unrelated, dog breeds. ¹¹ Equine spinal neurodegenerative conditions are a frequent cause of morbidity and eventual mortality in the horse. A detailed study of spatial transcriptomics of the normal dorsal root ganglia as a proof-of-concept study offers a novel way to study disease development related to neuron- and glia-associated changes. ⁷ Also included in this special issue is a review article detailing neurotropic enteric viruses in animals. Many of these viruses are novel or recently emerging, and this review provides diagnostic criteria and additional tests that will clarify the diagnosis including in situ hybridization tests that allow for localization of the virus in tissue sections. ³

Neurologic disease investigations of captive and wild animal species often suffer from poor accessibility to tissues, thereby limiting the depth of their pathologic, especially neuropathologic, studies. However, this special issue contains several important studies that describe novel conditions or provide the first description of diseases known to the species but not well characterized. Polyglucosan bodies are seen sporadically in a number of different species; however, they appear to be a common finding in the CNS of the Montserrat orioles (Icterus oberi), a critically endangered passerine bird native to the island of Montserrat. The authors conclude that while abundant in the CNS of this species, it is unlikely to be a limiting factor for conservation as it is not directly associated with neurologic disease. ¹⁵ Gibbons are endangered nonhuman primates that have a species survival plan that involves many network zoologic institutions in the United States. It has long been recognized that gibbons suffer from an unusual neurologic disease; however, it has remained poorly characterized. Here, they describe the first detailed study of gibbon infarctive encephalopathy, which suggests that small vessel disease in the CNS is the primary culprit for the infarcts. ¹⁴ The cause of this small vessel disease remains to be elucidated. The European hedgehog remains a species of special concern in the United Kingdom, and an article included in this special issue details the role that hedgehog arterivirus has in neurologic disease in this species. This report is richly illustrated by in situ hybridization studies that reveal virus distribution and pathologic patterns of the infection. ⁸ A retrospective study of neurologic disease in captive lions in Germany highlights the different disease presentations that afflicted this population. This includes identification of the recently described Rustrela virus (RusV) as a previously undetected cause of encephalomyelitis in this population. ⁴

Novel case reports and small case series continue to have a critical role in sharing novel disease presentations and opening a window to future studies. An in-depth study of 3 Dorset-cross sheep with lissencephaly revealed mutations in the reelin gene, which is associated with similar diseases in other species, including humans. ¹⁰ This article offers classic gross and histologic findings coupled with in-depth genomic studies that we hope will become the mainstay for disease investigations in our animal species. A case report of a piscichuvirus in a free-ranging American alligator highlights the potential for disease transmission across different orders and utilizes a novel in situ hybridization probe to characterize the virus distribution. ¹ A report of an atypical intraventricular neoplasm in a cat highlights diagnostic challenges related to tumor diagnosis and overlap between histologic, immunohistochemical, and electron microscopic findings in different neoplasms. ⁵

Hereditary neurologic malformations in a herd of Tabapuã cattle are also described in detail within the special issue. Cattle seem to offer a plethora of interesting congenital neurologic defects, and this article uses detailed anatomic studies to define them in the herd. ⁶ This article serves as a timely reminder to the importance of neuroanatomy and embryology. Finally, germane to those working with animal models of disease and drug discovery comes an article detailing the occurrence of ring hemorrhages in the CNS of cynomolgus macaques with severe anemia. This is a finding that can be misinterpreted, and this article provides a thorough investigation that will help investigators better understand the relevance of this lesion. ⁹

Although advanced diagnostics continue to move disease investigation forward, well-developed descriptive studies of gross and/or histologic features remain a cornerstone of neuropathology. This special issue contains a neuropathology image challenge that continues the tradition of excellent photography paired with thought-provoking questions.

Publication of the works in this special issue would not have been possible without the dedicated editorial and administrative staff at Veterinary Pathology. We hope that the reader enjoys this collection of articles and is able to use them in their neuropathology studies. All of us are eager to see the field of veterinary neuropathology continue to expand and look forward to the integration of more advanced molecular studies into our field.