Quick Diagnosis of Rare Disease Leads to Remarkable Recovery
By Susan Conova
It is January 2009, and Annalisa Meier keeps asking the same questions over and over:
“How old am I?”
“Where do I go to school?”
“What year is it?”
“What happened to me?”
Her parents, Pilar and Dwight, patiently answer her 20 or 30 times a day:
“You go to Columbia.”
“You were in a coma.”
Annalisa’s therapist struggles to engage her in a conversation, to get her to stay in the moment. She tries to get Annalisa to answer her own questions: How old do you think you are? Where do you think you go to school?
A week passes, and the answers start flowing with a little help. When she says she doesn’t know it’s January, she figures it out when her parents hint that it’s the month before Valentine’s Day.
Many times Annalisa apologizes for getting sick and causing so much trouble. But to her parents, seeing her walk, talk, and think seems like a miracle when they remember the months they spent at NewYork-Presbyterian/Columbia watching over their comatose daughter. Pilar and Dwight know Annalisa still has a way to go, but they no longer have to worry whether Annalisa will live or die, have a full life, or be confined to a nursing home.
Five Months Earlier
It is Sept. 2, 2008, the first day of classes and Annalisa is living her dream of attending Columbia, a hope she had harbored ever since she was a little girl. Her friends and teachers in her high school in Washington, D.C., knew how strong her drive was. She always tried for the top of the class and she always did an outstanding job in her academic endeavors. On the school cross country team, Annalisa wasn’t the fastest runner, but she ran her best in every practice and every race, and her coaches recognized her grit and determination at the end of the season with the Coach’s Award.
She returned to her dorm room after attending her first class at Columbia and called her mother, but during the conversation, Annalisa passed out. She had just tried to explain to her mother that she was drooling in class and couldn’t make herself stop. Annalisa’s speech was slurred, and Pilar had difficulty understanding her.
When Annalisa awakened, she called Pilar again, who “talked” her across campus to Columbia’s student health service, where doctors immediately suspected a neurological problem. An ambulance drove Annalisa a few blocks to St. Luke’s.
Annalisa’s father, Dwight, was in New York City on a one-day business trip, and rushed to the hospital, where Annalisa was awake and talking, but extremely agitated. She pulled manically and uncontrollably at her hair. Her condition worsened, and when she became unable to breathe on her own, the doctors induced a coma.
An MRI of Annalisa’s brain lit up from the intense levels of inflammation, indicating encephalitis. Initially, doctors thought the encephalitis was caused by viral meningitis and that she’d be better in a few weeks. Instead of recovering, however, Annalisa got worse, and nobody knew why.
No bacteria showed up in cultures. None of the antibodies associated with common autoimmune diseases were found. Tests for Lyme disease came back negative.
“I was concerned that she was deteriorating rather than stabilizing or getting better,” remembers Samuel Seward, M.D., the medical director of Columbia’s student health service. “At that point, I thought it couldn’t hurt to get a new set of eyes looking at her. Why don’t we get her to the best neurological ICU in the country?” Late that same night, about a week after she collapsed in her dorm room, Annalisa was transferred by ambulance to Columbia University Medical Center.
The next morning, Kiwon Lee, M.D., assistant professor of clinical neurology and a neurocritical care specialist, stood outside Annalisa’s room and listened to Jennifer McDonald, M.D., then a fourth-year medical student, present Annalisa’s case. Like the doctors at St. Luke’s, he also thought her encephalitis sounded viral. And if the virus didn’t show up in any test, little could be done. At best, Dr. McDonald says, the physicians were hopeful, not optimistic.
But as soon as Dr. Lee walked into her room, Annalisa violently jerked her head to the side, stuck out her tongue, and smacked her lips in a violent, repetitive, chewing motion. “She had this rhythmic movement that’s so classic,” he says. “When I saw that, I was 99 percent sure I knew what we were dealing with.”
Diagnosis: Paraneoplastic Anti-NMDA Receptor Encephalitis
“Classic” is an odd word to describe a disorder that didn’t have a name until 2007 and still isn’t well known.
Of the hundred or so cases of paraneoplastic anti-NMDA receptor encephalitis described in the literature, cases in young women often stem from creepy-looking tumors called teratomas. Loosely translated as “monster tumors” in Greek, teratomas are filled with a mishmash of cells, including bits of skin, hair, and even neural tissue. Centuries ago they were blamed on witchcraft or intimate dealings with the devil. Today, doctors know them as bizarre, but usually benign, growths often found on the ovaries.
|After a week with no diagnosis, Annalisa was transferred to the neurological ICU at New York-Presbyterian/Columbia
where her mysterious illness was identified as anti-NMDAR encephalitis.
What wasn’t known until a few years ago is that the immune system’s response to the teratoma can get out of control. Antibodies generated to attack the teratoma’s neural tissue (in particular, its NMDA receptors) also can slip past the blood-brain barrier and attack the brain. A neuro-oncologist at Penn, Dr. Josep Dalmau, discovered the antibodies in some of his unexplained encephalitis cases and published the findings in 2005, later describing the disease in more detail.
“If Annalisa had shown up a few years ago, we wouldn’t have known what hit her,” says Stephan Mayer, M.D., professor of neurology and director of the neurological intensive care unit at the Neurological Institute. Now Drs. Mayer and Lee see a case about every six months.
Even now, some patients are sent first to psychiatric institutions, since violent mood swings and extreme personality changes are often the disease’s first symptoms.
Looking back, Annalisa’s mother remembers something strange about her daughter in the weeks before school started. “She started getting headaches, she seemed insecure, she became impatient, and she was confused about simple decisions like buying old textbooks instead of new ones,” Pilar Meier says. “It seemed different than just being homesick.” For an independent and outgoing world traveler, it was completely out of character.
Dr. Lee, immediately after seeing Annalisa, ordered a CT scan. A ping pong ball-sized mass, presumably a teratoma, sat on top of Annalisa’s right ovary. A sample of her spinal fluid was sent to Dr. Dalmau at Penn to confirm the presence of antibodies, but even before the results came back, Dr. Leestarted filtering the antibodies out of Annalisa’s blood. Her teratomas (a second was found immediately before surgery) were removed on Sept. 17.
But that wasn’t the end of Annalisa’s illness.
“Human brains are not resilient”
In a strange coincidence, during the time Annalisa lay unconscious in neurological intensive care, the New York Times published an article about another young woman with the same rare condition. One day the 26-year-old was comatose; the next day, after surgery, she was awake, laughing, and talking.
Annalisa, in contrast, hardly seemed any different in the immediate days after surgery. “Unlike other organs, human brains are not resilient,” Dr. Lee says. “The inflammation and neuronal death caused by viruses, autoimmune attack, or trauma leads to neurological deficits that can take months and even years to recover.”
From his experience and a handful of published cases, Dr. Lee knew that most patients pulled through. A few women, like the patient in the newspaper article, wake up immediately after their teratomas are removed. But others struggle years later with significant cognitive problems. And some never wake up.
In the first few days after Annalisa’s surgery, 24-hour EEG monitoring picked up small, but real, seizures that prompted Dr. Lee to stop efforts to bring Annalisa out of her coma in order to protect Annalisa’s brain from irrevocable damage. At other times, a cooling blanket lowered her temperature to reduce the metabolic demands on her brain. Her heart rate fluctuated erratically, racing to 145 one day and plummeting to 20 on another.
The rhythmic facial tics that tipped Dr. Lee to a correct diagnosis continued, along with new wild, repetitive movements she developed in her hands and fingers. Eventually she developed a respiratory infection, a urinary tract infection, and an eye infection. She almost died twice from the complications.
“There were times when we didn’t even know she would survive,” remembers Dr. McDonald, who had become close to Annalisa’s family and frequently visited them between shifts to make sure they understood everything about Annalisa’s condition. “We were looking for some sort of meaningful brain activity, but with her movement disorder it was hard to tell. If she squeezed your hand, it didn’t necessarily mean she was doing it on purpose.”
“The first sign that maybe someone was in there”
Several weeks after her surgery, Annalisa came out of her coma but was still only minimally conscious. To her parents, Annalisa at times showed signs she understood what was going on around her, who people were, and what was being said.
Every day for a few minutes, Annalisa opened her eyes, looked at people in the room, and followed them with her eyes as they moved around.
But these moments – which thrilled Dwight and Pilar – only happened when family members were in the room. It wasn’t until the middle of November that the unit’s doctors and nurses saw Annalisa respond: She held up two fingers, raised her thumb, and stuck out her tongue on command. “It was the first sign we had that maybe someone was in there,” Dr. McDonald said.
Her parents hoped it was the breakthrough they had been waiting weeks to see. The next day, at one in the morning, Annalisa’s heart suddenly stopped and restarted on its own seconds later as doctors and nurses scrambled to help. It was clear there would be more ups and downs.
“Her brain was still in the process of healing and it sent incorrect signals to the system controlling heartbeat,” Dr. Lee says. He recommended a course of chemotherapy to suppress Annalisa’s immune system and help dampen her body’s response to the remaining anti-NMDAR antibodies in her brain.
A nurse suggested physical therapy, an idea Pilar thought was crazy, since Annalisa resisted when people tried moving her arms and legs. It turned out to be an inspired idea. “The therapist learned that Annalisa loved basketball, so she’d say, ‘I’m going to lift your hand and you’ll pretend you’re shooting a basket,’” Pilar said. “That was the first time Annalisa didn’t resist. Every time she had physical therapy after that, she responded.”
As the end of November approached, Annalisa’s doctors and parents made plans to move her to a rehabilitation facility. But there was no doubt she was still not fully conscious. Though she often responded to her mother’s commands, she didn’t always do so. She rarely responded to commands from doctors. And because of pain associated with a recently contracted eye infection, Annalisa stopped opening her eyes. It made it even more difficult to know whether she was responding to stimuli or not.
Dwight and Pilar shared their frustration with friends: “We want Annalisa to return to consciousness more than anything, yet it hasn't been like in the movies, where someone or something flips a switch and full consciousness returns like turning on a light. The process is more akin to trying to coax a flickering flame (the instances of ‘almost-consciousness’ we share with her from time to time) into a full blown fire (constant, dependable consciousness).”
In late November 2008, Annalisa was discharged to National Rehabilitation Hospital in Washington, D.C. “If you looked at her when she left,” recalls Dr. Lee, “you’d never think she’d be going back to college.”
A Return to the NICU
In June 2009, Annalisa returned to the NYP/Columbia. As she walked through the corridors of the hospital and spoke with the doctors, nurses, and therapists who had spent hours with her every day, many didn’t recognize her at first.
“When they did, there were a lot of tears,” Pilar says. “It brought back all of the good and bad memories for us, but we’re very glad we visited. It was important to us to show the people who cared for Annalisa the fruits of their labor. And seeing the joy among the nurses made us feel very grateful. Everyone said this is what they live for.”
After three months in the rehab hospital and many more months of intensive outpatient day therapy, Annalisa is nearly fully recovered, mentally and physically. She has taken salsa lessons, played tennis, attended lectures at her neighborhood bookstore, audited classes and took classes for grades at George Washington University, all in preparation for returning to Columbia in the fall of 2010.
“When I started my career a number of years ago, recoveries like Annalisa’s weren’t supposed to happen,” Dr. Lee says. “People didn’t stay in an unconscious state for months and then make a complete recovery. That’s what we’re learning with these patients. That’s what keeps us going.”
The experience also has led Columbia physicians to start investigating the best course of treatment for anti-NMDAR encephalitis. “Is it best to get rid of the patient’s antibodies as soon as possible? Is there a reason to wait before suppressing the immune system?” Dr. Lee says. “We think the sooner we can get rid of the antibodies the better, and the more aggressive we are the better, but we don’t really know.” Dr. Lee is collecting information from all the cases seen at NYP/Columbia in the past few years to try to answer these questions.
For Annalisa, the visit was surreal. She doesn’t remember anything about the weeks she spent in the hospital’s intensive care and step-down units. “It’s amazing to me that people who didn’t know me – the custodians, the therapists, all the doctors and nurses – all went out of their way to help me,” she says. “I had the feeling I was blessed, well-cared for, and loved.”
By Pilar Meier
On New Year’s Eve, 2008, when Annalisa learned to speak again, her first words were “Columbia College.” The goal of returning to Columbia has been the driving force for her recovery.
In the summer of 2010, Annalisa completed the final step of her roadmap back to Columbia. She attended a summer session, successfully took two creative writing course, lived independently in a dormitory, played tennis and pick-up basketball games, shopped for groceries, did laundry, and functioned well on her own. Annalisa still sometimes struggles with her short-term memory and can become confused, but coping strategies that she learned during rehabilitation help her deal with these situations when they arise. Annalisa hopes and expects to continue to improve as she resumes her life. She believes more than ever that she is here for a reason, and someday hopes to make a difference in the world, in international relations, conflict resolution, journalism, law, or…(still to be determined).
Annalisa joins Columbia College’s Class of 2014 as a freshman this fall. Getting to this stage of Annalisa’s recovery has been a two-year process, but it all began when she was correctly diagnosed and then, literally, kept alive at NewYork-Presbyterian Hospital. The incomparable medical care that she received was the foundation of everything she has accomplished since, and will accomplish in the future. Annalisa, the Meier family, and the entire extended family (including Castillo, Srs., Castillo Jrs., Rodriguez, Prebulas, Bakers, and Bergers, all of whom watched over Annalisa in NewYork-Presbyterian at some point) will always be grateful.
AN INCREASE IN CASES?
When Dr. Lee first saw Annalisa in the neuro ICU, he immediately suspected paraneoplastic anti-NMDAR encephalitis from his previous experiences with the disorder. But they’ve all been recent experiences, which makes some of Annalisa’s doctors wonder if the syndrome is something new and on the rise.
“I never saw these cases in my training, and once you see this movement disorder, you never forget it,” Dr. Lee says. “I’ve spoken to people with 40 and 50 years of experience, and they’ve said they never saw anything like it in the past. I think it’s something new, but it remains to be seen.”
Though the syndrome may turn out to be a common cause of encephalitis in young adults and children, Penn’s Dr. Dalmau believes it is simply becoming more recognized by clinicians. “When you look back at some older descriptions of mysterious cases of encephalitis, you realize they could have been describing anti-NMDAR encephalitis,” Dr. Dalmau says. “It’s like the story of the blind men and the elephant. A few different aspects of the disease have probably been described in the past, but now we know the whole elephant.”
What both doctors agree on is the need for more awareness about the disorder, particularly among psychiatrists, who are often the first physicians to encounter patients with anti-NMDA receptor encephalitis.
“It’s scary to think there are probably a few young women out there who’ve been diagnosed with a psychiatric disorder and locked up,” Dr. Lee says. “It’s important to understand that the disorder is still very rare, but it’s potentially fatal. For young people with sudden mood and personality changes, especially young women, doctors should suspect anti-NMDAR encephalitis.”
Columbia’s student health director says Annalisa’s experience has put his entire staff on alert. “Since Annalisa, we have had our antennae up looking for more cases,” Dr. Seward says. “And, indeed, roughly a year later we had another case. With Annalisa fresh in everyone’s minds, the diagnosis was confirmed rapidly, and I am happy to report the student is doing very well. I expect we’ll see an increasing number in the future.”