Brooke Black awoke early as usual one Friday morning in April 2023. It would be the last moment of “usual” she and husband Lance would experience for the next month.

She turned to him in bed and asked what he thought of the comedy show they had gone to last night – what with her having been up onstage and funny enough to win a “joke of the year” award, even.

Lance hadn’t thought much of it at all, seeing as they had never been to a comedy show together, not last night, not ever. He figured Brooke, then 37, had had a vivid dream. He got up, got dressed, and took the dog out to the backyard. His phone rang. Brooke was calling from inside, panicked.

“Lance, there’s a guy outside the window, telling me to let him in,” she hollered.

He hustled around to the front to find… no one.

Back inside, he called Brooke’s mom, Jan Richardson. He had never seen Brooke, a longtime Starbucks barista and trainer, act like this. Had Brooke done such things in the past?

She had not, Richardson said. They agreed that Lance should get Brooke to UCHealth Greeley Hospital, nearly 40 miles southeast of their home in Briggsdale. The had traveled most of the way when Brooke looked over at Lance from the passenger seat, giggled, and started convulsing in seizure.

Lance fumbled with his phone to try and dial 9-1-1, then decided instead to use his free hand to hold Brooke’s head up so she didn’t choke herself. Over much of the last few miles, he learned that his Ford Explorer could go about 130 mph.

A diagnosis of encephalitis and the role ovarian cysts play

So began a series of events that led to a 28-day hospital stay, one that would end only after a diagnosis that perhaps one in 100,000 people will receive in their lifetimes: autoimmune encephalitis.

During that time, Brooke would look out the window to watch people who weren’t there; confuse a heart rate monitor for a remote control that changed channels on a phantom television; speak in her normally energetic way but make no sense; and require restraint to control violent outbursts completely out of character with an otherwise kind, funny, gentle human being. Lance took a month off from his job in oil & gas to be with her throughout.

“Those 28 days are something I never want to relive, ever again,” he says.

Brooke’s symptoms, scans, and labs led to a diagnosis of encephalitis – brain inflammation. But her spinal fluid showed no hint of infection – the most common cause of encephalitis. So, what could the cause be?

A neurologist on rotation mused whether it might be autoimmune encephalitis – that is, Brooke’s own immune system attacking brain cells and causing the inflammation. Richardson, her mom, homed in on the idea. One of the key clues: Brooke had been dealing with ovarian cysts, and roughly half of anti-NMDA receptor encephalitis cases, those of the most common adult-onset autoimmune encephalitis, were triggered by ovarian cysts called teratomas.

Understanding anti-NMDA receptor encephalitis

Richardson told the UCHealth Greeley Hospital neurology team about Brooke’s ovarian cysts. Given that other attempted therapies weren’t working, the team put Brooke on intravenous immunoglobulin (IVIG, which consists of purified antibodies from healthy donors). Within three days, Richardson said, “she was like the old Brooke.” But given the ovarian cysts and the complexity of the case, the care team reached out to the UCHealth DocLine to connect with neurology subspecialists at UCHealth University of Colorado Hospital on the Anschutz Medical Campus.

Dr. Amanda Piquet happened to be in room when her colleague received the call. Piquet is a University of Colorado School of Medicine neurologist specializing in autoimmune neurology. Piquet suggested transferring her to UCHealth University of Colorado Hospital.

Once there, Piquet met Brooke and family. She noted that, although Brooke was conversant, “there were short-term memory problems, and it was clear she wasn’t understanding what the conversation was.” Testing confirmed anti-NMDA receptor encephalitis, but Piquet and the care team’s focus was on the ovarian cysts. They turned out to be teratomas. Understanding why that mattered – and, by extension, why the IVIG worked for Brooke – requires a brief lesson in autoimmune neurology.

The trigger for Brooke’s anti-NMDA receptor encephalitis were antigens sloughed off by the teratoma cells in her ovaries. Antigens are proteins that alert the immune system to the presence of invaders such as bacteria and viruses, the cells they infect, or cancer cells. They trigger an immune response that starts with white blood cells scooping up the antigens and delivering them to lymph nodes. There, B-cells are exposed to the foreign antigens. The B-cells make and then release antibodies designed to latch onto the viruses, bacteria, or rogue cells that created the antigens.

The antibodies attach to the targets’ surfaces and act like flags. Other parts of the immune system, T-cells in particular, spot the flags and destroy what they have latched onto.

In a healthy immune response, those antibody flags tag what’s foreign or problematic. In an autoimmune response, the antibodies tag healthy cells. That’s what was happening in Brooke’s central nervous system.

B-cells making the antibodies meant to flag teratoma cells got into her brain, and the antibodies they created then hooked onto her brain cells’ NMDA receptors – hence the name anti-NMDA receptor encephalitis. Her immune system then went on the attack.

So: IVIG worked for Brooke by neutralizing the misguided antibodies the teratoma triggered and otherwise modulating the immune system. But there was still the matter of the teratomas. As long as they remained, the dangerous immune response would continue.

Removing ovarian teratomas and starting a clinical trial for anti-NMDA receptor encephalitis

Brooke had surgery to remove the ovarian teratomas within hours of her arrival at UCHealth University of Colorado Hospital. The question then was what to do next.

IVIG is for acute treatment. Second-line, longer-term treatments have included monoclonal antibodies such as rituximab that plant flags on B-cells for the immune system to destroy, but whether and how well that works for patients over the long run is still an open question. That’s in part because, despite autoimmune encephalitis being an ancient health problem, the NMDA receptor’s role in what would become known as anti-NMDA receptor encephalitis wasn’t identified until 2007. Until the root cause was known, targeted therapies had to wait.

But by May 2023, a clinical trial for anti-NMDA receptor encephalitis had just launched. Brooke became the first patient enrolled in CIELO, a study spanning 79 locations around the world investigating the effectiveness of satralizumab, a monoclonal antibody that works indirectly to suppress B-cells. Piquet leads Colorado’s CIELO site for that study as well the local enrollment for one just launched, called ExTINGUISH. It’s testing a monoclonal antibody called inebilizumab that targets B-cells directly and includes patients with autoimmune encephalitis driven by either the NMDA receptor or the LG1 receptor.

Involvement in clinical trial aids ongoing monitoring of autoimmune encephalitis

Neither Piquet not Brooke knows whether Brooke has been on satralizumab or a placebo for the past year and a half (it’s a double-blind study). But the trial has benefitted Brooke either way. About a year after she left the hospital, Lance noted that she seemed off.

“We’d be having a conversation, and she’d just stop and stare at something in the house,” he says. “I’m like, babe. Babe. Babe – are you OK?”

Piquet, who was meeting with Brooke monthly, also noticed a change. Teratomas rarely recur, but an MRI scan showed that it was happening with Brooke. She chose to have a hysterectomy.

“We caught that because we had her under the microscope, basically, in that clinical trial,” Piquet says.

Nearly two years after imagining a comedy show that wasn’t, Brooke feels she’s slowly improving, she says.

“For the most part, I feel back to being myself,” she says.

But her energy flags, particularly after social events. She needs a lot of rest. She tried going back to her job at Starbucks in the spring, but it proved to be too much.

That’s typical for those recovering from autoimmune encephalitis, Piquet says. There can also be anxiety and PTSD around hospitalizations they don’t really remember (Brooke’s recall of that month in UCHealth Greeley Hospital remains scant). Because the recovery timeline can extend as long as five years, Brooke may see continued improvements, and she is doing much better than many who go untreated. They can end up with chronic seizure disorder and serious long-term cognitive problems, Piquet says.

Brooke is thankful to have recovered as she has so far.

“I’ll take a little short-term memory and a little anxiety over everything else that could have happened,” she says.