Left, Science Source/Photo Researchers; right, Dr. P: Marazzi/Photo ResearchersIn the New York Times on the 7th of November 2008:
White blood cells (left) in the patient's spinal fluid suggested an infection; an X-ray of a teratoma with a tooth (right).
White blood cells (left) in the patient's spinal fluid suggested an infection; an X-ray of a teratoma with a tooth (right).
Brain Drain By LISA SANDERS, M.D.
This happened a year ago:
“Dr. Rachel Clark could see the patient through the glass walls of the Massachusetts General Hospital intensive-care unit. A young woman lay on the bed, unconscious. The girl’s mother sat next to her, stroking her head. Just minutes earlier Clark’s pager called her to this ward filled with the sickest patients. The text read: “Unresponsive patient in the I.C.U. Possible Gyn etiology. Please respond asap.” As she made her way through the hospital, Clark, a first-year resident in obstetrics and gynecology, tried to imagine what kind of problem would lead critical-care specialists to call on her to help with a patient in a coma.
“The 26-year-old woman fell ill two months earlier, her mother told Clark. It started with a headache — the worst of her daughter’s life. Her mother took her to the emergency room near their hometown in rural Maine. The doctors there thought it was a migraine and gave her something for the pain. It didn’t help.
“Over the next 10 days her daughter saw six different doctors, had many blood tests and scans and tried a dozen medicines. No one had a diagnosis or a cure.
‘There’s something wrong in my head,’ the young woman kept repeating. ‘It’s just not right.’
“On their last trip to the emergency room, her daughter went crazy. She was talking to people who weren’t there. She was afraid, paranoid. Then suddenly she became violent, lashing out at everyone around her. ‘They told me she was having a psychotic break, that she probably had schizophrenia,’ her mother reported, the horror of that night still audible in her voice. The patient was taken to a psychiatric hospital. A few days later she developed a fever and was sent to yet another hospital. There she had a seizure. After that, she never woke up. She was finally transferred to Massachusetts General in Boston. But even here the doctors had found no answers.”
“The young woman had a history of migraines but was otherwise healthy. She took no medications. She worked in an office and lived with her parents. On exam she no longer had a fever. Her eyes were sometimes open, but she was completely unresponsive, even to pain.”All investigations drew a blank and out of desperation, the team ordered a CT scan of her body. A tiny cyst was found on her left ovary: A TERATOMA.
One resident was creative to suggest that this tiny cyst, known as a teratoma, could be the cause of her coma.
“Clark searched the medical literature, eventually finding an article, published just months earlier, that described 12 women with what the paper’s author called ovarian teratoma encephalitis. The women had headaches and psychiatric symptoms and became comatose. Each was ultimately found to have a teratoma. Remarkably, most of these women recovered fully once the cyst was removed. Clark was amazed.
Ovarian teratoma encephalitis is so rare that it is still not well understood, but the author of the paper theorized that these particular tumors — which have the potential to grow any type of cell in the body — develop primitive brain cells. Somehow the immune system mistakenly identifies these cells as “foreign” and makes antibodies to destroy them. These antibodies go on to attack the same kind of cells in the brain.
Clark said she felt certain this was what the patient had.
“But the other doctors caring for the patient were skeptical. Every year thousands of patients develop some kind of encephalitis. It’s quite likely that some small percentage of these patients will have one of these common cysts, and yet, for most, the two conditions will be completely unrelated. There have been only a handful of cases that have linked a teratoma and encephalitis over the past 11 years. The odds of this patient falling into that category were infinitesimally small.”
“But Clark persisted. A sample of the patient’s blood was sent to the author of the paper to have him look for the antibody he found in his patients. If that test was positive, then they would take out the tumor.”
“For the next two weeks, Clark checked for the results daily. She eventually discovered that the blood was never tested. Clark almost cried with frustration. While they had been waiting for these results, the patient became even sicker.”
“Another OB-GYN, Dr. Rebecca Kolp, was now in charge of Clark’s team. Clark sought out the doctor and described the patient and what she’d found in her research. She told her about the lost test. Should they wait another two weeks, or should they operate now?”
“Kolp thought about it for only a moment. The intern made a strong case, and although it seemed an unlikely diagnosis, Kolp thought it was worth the risk. Would the girl’s mother be willing to let them operate on her daughter? The mother agreed to the operation immediately. The girl had been sick for so long and seemed only to be getting worse. That afternoon, Kolp removed the tumor.”
“The next morning it was still dark when Clark arrived at the I.C.U. As she entered the patient’s room she called out the young woman’s name in a hushed voice. No response. The doctor checked the surgical site — it looked fine — and then tried once more to rouse the young woman. No change. Her heart sank. In the paper she’d read, recovery was rapid — often within hours of the operation.
“At rounds, Clark told Kolp that the patient was no better. The attending physician was disappointed but not surprised. They had done all they could. But later that morning Kolp phoned Clark. ‘Rachel, you’re not going believe this,’ she reported excitedly.
‘Your patient is awake.’
“Rachel Clark was elated. Just a few months into her residency, she diagnosed a rare disease, one that she figured she would never see again.”
“A year later another patient arrived with the same story of headache, psychosis and coma. A CT scan revealed a teratoma, and she was operated on the next day. This patient also recovered. It’s worrisome, Kolp said. ‘It makes you wonder how many other woman are languishing out there who might be saved.’”It is incredible how closely my teratoma case (as described in The Cockroach Catcher) mirrored Dr Rachel Clark’s cases. Now, after thirty years, the mystery of why my patient was in coma after surgery is solved!
My comment about the case was:
“I have often wondered if it would be such a disservice to mankind if doctors were not so understanding of the psychological side of things.The possibility of a serious illness being missed is of course a major concern when a patient seeks help for one reason or another. To put psychological conditions at the top of the list of possible diagnosis is dangerous.”I can well understand what a difficult position Dr Rachel Clark found herself in, to be the lone voice against traditional thinking in the diagnosis of a tricky case. We need such courage amongst our young doctors, but for their own good, perhaps not during their finals viva!
To remember our eminent yet formidable Professor of Medicine, Professor MacFadzean: One Patient One Disease.
Hospital Medicine: Pride & World Class in Pennsylvania!
In medicine, truly new discoveries are uncommon and with the emergence of guidelines and protocols it has become even more difficult to make new discoveries. It has taken over 30 years before I could understand what happened to my Teratoma patient. Luckily for her, the treatment she received would have been in line with what we know now of the condition.
Hospital Medicine indeed has its important place and most important of all in the discovery of new conditions and establishing diagnostic and treatment programmes.
It is perhaps timely to remind the next generation of Bright Young Things that become doctors to remember that psychiatric symptoms presented by a patient may indeed be the presentation of a neurological condition.
This is more so for bizarre combinations of psychiatric and other symptoms. It was in the last five years or so that much progress has been made on what is now called Anti-NMDA Receptor Encephalitis.
Who knows, one day medical scientists might be able to decipher the most difficult of psychiatric conditions: Schizophrenia. Bright Young Psychiatrist might have noticed that Clozapine, one of the most effective drugs for schizophrenia has a marked effect on the immune system.
In the mean time
might have something they could be proud of: the discovery of this new neurological condition. Pennsylvania
For now, my patient’s parents’ prayer has been answered.
Anti-NMDA Receptor Encephalitis
NEW ORLEANS — A mysterious, difficult-to-diagnose, and potentially deadly disease that was only recently discovered can be controlled most effectively if treatment is started within the first month that symptoms occur, according to a new report by researchers from the Perelman School of Medicine at the University of Pennsylvania. The researchers analyzed 565 cases of this recently discovered paraneoplastic condition, called Anti-NMDA Receptor Encephalitis, and determined that if initial treatments fail, second-line therapy significantly improves outcomes compared with repeating treatments or no additional treatments (76 percent versus 55 percent). The research is being presented at the American Academy of Neurology's 64th Annual Meeting in
. New Orleans
565 cases! Not so rare!
The condition occurs most frequently in women (81 percent of cases), and predominately in younger people (36 percent of cases occurring in people under 18 years of age, the average age is 19). Symptoms range from psychiatric symptoms, memory issues, speech disorders, seizures, involuntary movements, to decreased levels of consciousness and breathing. Within the first month, movement disorders were more frequent in children, while memory problems and decreased breathing predominated in adults.
My patient was under 18 and presented with catatonia symptoms. She later lose consciousness and was ventilated.
"Our study establishes the first treatment guidelines for NMDA-receptor encephalitis, based on data from a large group of patients, experience using different types of treatment, and extensive long-term follow-up," said lead author
Maarten Titulaer, MD, PhD, clinical research fellow in Neuro-oncology and Immunology in the Perelman School of Medicine at the . "In addition, the study provides an important update on the spectrum of symptoms, frequency of tumor association, and the need of prolonged rehabilitation in which multidisciplinary teams including neurologists, pediatricians, psychiatrists, behavioral rehabilitation, and others, should be involved." University of Pennsylvania
The disease was first characterized by Penn's Josep Dalmau, MD, PhD, adjunct professor of Neurology, and David R. Lynch, MD, PhD, associate professor of Neurology and Pediatrics, in Annals of Neurology in 2007. One year later, the same investigators in collaboration with Rita Balice-Gordon, PhD, professor of Neuroscience, characterized the main syndrome and provided preliminary evidence that the antibodies have a pathogenic effect on the NR1 subunit of the NMDA receptor in the Lancet Neurology in December 2008. The disease can be diagnosed using a test developed at the
and currently available worldwide. With appropriate treatment, almost 80 percent of patients improve well and, with a recovery process that may take many months and years, can fully recover. University of Pennsylvania
In earlier reports, 59 percent of patients had tumors, most commonly ovarian teratoma, but in the latest update, 54 percent of women over 12 years had tumors, and only six percent of girls under 12 years old had ovarian teratomas. In addition, relapses were noted in 13 percent of patients, 78 percent of the relapses occurred in patients without teratomas.
As Anti-NMDA Receptor Encephalitis, the most common and best characterized antibody-mediated encephalitis, becomes better understood, quicker diagnosis and early treatment can improve outcomes for this severe disease.
The study was presented in a plenary session on Wednesday, April 25, 2012 ET at 9:35 AM at the American Academy of Neurology's annual meeting.
[PL01.001] Clinical Features, Treatment, and Outcome of 500 Patients with Anti-NMDA Receptor Encephalitis
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Of 100 patients with anti-NMDA-receptor encephalitis, a disorder that associates with antibodies against the NR1 subunit of the receptor, many were initially seen by psychiatrists or admitted to psychiatric centres but subsequently developed seizures, decline of consciousness, and complex symptoms requiring multidisciplinary care. While poorly responsive or in a catatonic-like state, 93 patients developed hypoventilation, autonomic imbalance, or abnormal movements, all overlapping in 52 patients. 59% of patients had a tumour, most commonly ovarian teratoma. Despite the severity of the disorder, 75 patients recovered and 25 had severe deficits or died.
Cahalan's new memoir is called Brain On Fire-My Month of Madness.