Uncovering the source of a “silent” syndrome

Learning to speak is an important developmental milestone for children. Speech allows them to express themselves and connect with the world. But for some children who undergo surgery to remove brain tumors, such as medulloblastoma — the most common malignant brain tumor in children — their ability to speak can be disrupted.  

Posterior fossa syndrome (PFS) can be a devastating outcome following surgery in the posterior fossa, a compartment that holds the cerebellum — a structure of the brain vital for various aspects of movement and balance. Also called cerebellar mutism syndrome due to the associated loss of speech, PFS is notably understudied. 

The apparent transient nature of the syndrome – patients usually recover speech and motor functions within a few weeks – masks its potential harm. Relatively little is understood about the root causes of PFS. In recent years, St. Jude has positioned itself as a central hub for research and treatment of PFS. Stu McAfee, PhD, St. Jude Department of Diagnostic Imaging, is working to demystify the syndrome. 

A survival instinct gone haywire 

“A lot of times, when we communicate about mutism, it's said to be transient mutism. That's true; patients usually have some improvement,” McAfee said, “But if they go through a period of mutism then they're going to have a worse long-term outcome than the patients that didn't. It’s very difficult to understand why because PFS is relatively rare.”  

Compounding the relative scarcity of cases is the delayed onset of symptoms, which also include emotional changes and loss of motor skills and cognition. Patients may wake up with some fogginess but with full ability to speak and move, only to fall into a locked-in state over the following days. The locked-in appearance of individuals with PFS may relate to the survival instinct of being extremely still and quiet to evade predation. “It's thought that this is a powerful master switch when a small mammal senses danger. The current hypothesis is that this circuit is going haywire and shutting down these patients' ability to speak and move.”  

Researchers at St. Jude, including McAfee, are well-positioned to address the gaps in knowledge around PFS. “At St. Jude, we see enough of these patients that it is possible to gather data to arrive at some reasonable conclusions.”  

Understanding its origin is key to unlocking the syndrome 

The importance of understanding the origin of PFS lies in the guidelines it offers the surgeons who must navigate the complexity of removing a medulloblastoma tumor. Hence, the first study that McAfee and his collaborators put together, published in 2022 in Neuro-Oncology, was to systematically identify which areas of the brain were injured in the patients who experienced mutism versus ones that did not.  

“We did some spatial mapping, and with that we identified a specific nucleus and portion of the cerebellum that was injured in patients with mutism but not in those without,” said McAfee, referring to a connection between a region of the cerebellum known as the fastigial nuclei, and an area of the midbrain called the periaqueductal gray area. “It's great to have something concrete that we can communicate back to neurosurgeons.” 

The physical location only tells one side of the story. PFS can be regarded as a syndrome of disconnection. The interconnectivity of the brain implies not just a localized effect in PFS-causing injuries, but a chain of effect based on the synaptic connections those areas make. 

McAfee and colleagues used functional magnetic resonance imaging (fMRI) to tease out the networks affected by injury in a 2023 Brain publication to help predict changes in function and secondary locations of effect in PFS. “There has generally been a belief that injuries to the connections between the cerebellum and cerebral areas involved in speech were the cause of mutism,” said McAfee, “We wanted to test the hypothesis that the specific area we identified in the previous paper was the main culprit for the dysfunction that led to the speech impairment.”  

A more complete syndrome 

As McAfee points out, these findings add to the accumulating evidence of a specific connection between the cerebellum and the midbrain that drives the loss of speech and inhibition of volitional movement. “The patients, when they have that transient state where they're basically locked in, these findings explain those symptoms in both the motor and the speech domain,” he said. 

Most recently, in a 2024 publication in Neuro-Oncology, McAfee and colleagues presented a more comprehensive view of these findings to better understand PFS as a more complete syndrome. “We identified a lot of evidence for dysfunction that accumulates in other parts of the brain,” McAfee said. “This manifests in areas that are related to emotional regulation and motor planning and things that these patients struggle with in the long term.” 

Society meeting fuels conversation  

Recently, St. Jude hosted the second annual Posterior Fossa Society meeting in collaboration with the Pediatric Biomedical Imaging Initiative. As part of this gathering, neuroradiologists, imaging scientists, neurosurgeons, neuro-oncologists, psychologists, speech therapists, rehabilitation specialists and families affected by PFS all met to discuss the advancements made and hurdles related to the syndrome. 

As more is uncovered about the origins of the syndrome, McAfee and the Posterior Fossa Society continue to gain ground toward the prevention and treatment of PFS. “There's an opportunity to start using models to study specific features of the disease and test interventions,” McAfee said. “This was the first meeting where somebody proposed an animal model and showed some evidence that it replicated certain features of the disorder.”  

While McAfee looks ahead to the next society meeting, the entire PFS community can remain hopeful that the “silent” disorder is finally being heard.