Early Intervention Strategies for Necrotizing Meningoencephalitis in Pugs – Are Stem Cells the Future?
November 12, 2024
Necrotizing meningoencephalitis (NME), also known as Pug Dog Encephalitis, is a fatal neuroinflammatory condition that primarily affects Pugs. It is a progressive disease characterized by the destruction (necrosis) of brain tissue, leading to clinical signs including seizures, obtundation, circling, and visual deficits. While the condition has historically been difficult to treat with a grave prognosis, recent advancements suggest a more prolonged disease course. Early intervention may be the key to preventing disease progression and providing a cure for this devastating disease.
Pathogenesis and Clinical Presentation of NME
NME shares many similarities to Multiple Sclerosis (MS). Both diseases are immune-mediated with similar risk factors, the strongest of which is genetic risk. In Pugs, NME has been associated with genetic alterations within the dog leukocyte antigen (DLA) class II complex; similar at-risk mutations have been identified within the human leukocyte antigen (DLA) class II complex, many of which determine immune response.
The classic presentation of NME in Pugs is one of rapid onset and progression of clinical signs including seizures, behavioral changes, and visual deficits. The disease is diagnosed through a combination of clinical signs, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. MRI typically reveals lesions in the brain’s gray and white matter, particularly in the parietal and occipital lobes. The pathognomonic findings in NME are areas consistent with necrosis.
An ongoing Ethos Discovery clinical trial screening young Pugs for signs of early NME, called the Signs of Early Encephalitis in Pugs (SEEP) trial, has identified what may be an early form of NME. In this early phase of disease, subtle neurological signs including spinal hyperesthesia, proprioceptive deficits, and visual impairments have been identified on screening exams in Pugs that otherwise appear normal. These early signs mimic the clinical signs seen in the earliest stages of MS in humans, offering a potential window for therapeutic intervention before the disease progresses to its more severe form. Approximately half of dogs with early NME had a seizure in the weeks preceding presentation, raising the importance of screening a Pug for early NME even after a single seizure.
Traditional Treatments and Their Limitations
Historically, treatment for NME has focused on aggressive immunosuppressive therapy using high dose corticosteroids and other immunosuppressants (i.e. cytarabine arabinoside, cyclosporine). The effectiveness of these therapies has been limited for the classic form of NME where the disease is well advanced by the time of diagnosis. Median survival times with traditional treatments range from 6-7 months.
Stem Cell Therapy as a New Approach
An ongoing Ethos Discovery clinical trial titled Stem Cell Therapy for Early Encephalitis in Pugs (STEEP) trial has explored the use of mesenchymal stem cells (MSCs) as a potential treatment for NME. Stem cells have been shown to possess immunomodulatory and regenerative properties, making them a promising option for treating neuroinflammatory diseases like NME.
Stem cells have the ability to home to areas of inflammation and damage, releasing factors that can modulate the immune response, promote tissue repair, and reduce fibrosis. In NME, the goal of stem cell therapy is to reset the overactive immune response to be more anti-inflammatory, thereby preventing further damage to the brain and promoting the regeneration of damaged tissue. This therapeutic approach is particularly promising for dogs in the early stages of NME, where stem cells may have a greater ability to halt disease progression and potentially reverse early damage.
Early results of the STEEP trial are promising. Most dogs showed improvement in neurological symptoms within 24 hours of receiving their first dose of stem cells, and follow-up examinations over 1-3 years revealed sustained improvements in most cases. MRI and CSF analyses after treatment also showed improvement in the MRI lesions for many dogs.
While these results are promising, more extensive follow-up time is necessary to determine whether stem cell therapy can provide a lasting cure or simply delay disease progression.
Future Directions
The parallels between NME in Pugs and MS in humans suggest that NME may serve as a potential natural animal model to study MS therapies. Early neurological exam screening and genetic risk assessment in young Pugs may allow for the identification and treatment of dogs before they show severe symptoms, offering new hope for dogs affected by this devastating condition.