PART ONE BROKEN BRAINS
1 Case One
Massachusetts, October 2012
When neurologist Jed Barash was growing up in Orange, Connecticut, his fatherâs copy of the New England Journal of Medicine appeared in the mailbox every Thursday without fail. The arrival of the signature red-and-white NEJM marked the passing of Barashâs childhood as regularly as a metronome. Fifty-two weeks a year, 600,000 people around the world receive their copy of the worldâs most prestigious medical journal. Itâs considered essential reading for medical professionals, including Barashâs father, an anesthesiologist. The journalâs standards are exacting, the editorial process excruciating. To be published in its pages is a sign of professional success and a passport to credibility.
In the fall of 2012, the normally staid NEJM issue that appears in Barashâs mailbox includes an attention-grabbing title: CHOCOLATE CONSUMPTION, COGNITIVE FUNCTION, AND NOBEL LAUREATES. A Swiss-born author presents data revealing âa surprisingly powerful correlation between chocolate intake per capita and the number of Nobel laureates in various countries.â Switzerland tops the list. The burden of proof is high for such surprising claims. But this article is no more than a spoof designed to highlight a common mistake: jumping to the conclusion that when two things are associated, one causes the other. Some journalists miss the point and present the findings as proof that eating more chocolate makes you smarter. In this case it would be an inconsequential mistake. But when it comes to making decisions that affect human health, getting it wrong is dangerous. Figuring out the true relationship between two associated phenomena is something Barash will come face-to-face with in the months and years ahead.
On the first Friday of October, Barash leans forward in his chair and stares at the MRI scan on his monitor. Heâs looking at the brain of a young man admitted to the hospital last night, and the image is so strange and beautiful that he knows something has to be wrong.
âWhoa,â he says out loud to his empty office. âThis is weird.â
Floating brightly against the darker background of the rest of the brain are two C-shaped structures tucked on either side of the central fluid-filled cavity. Together they make up the hippocampusâthe place that holds the keys to memoryâand the intense glow is a distress signal from many millions of cells. Some mysterious, marauding force has laid waste to just this tiny region, leaving the rest of the brain unharmed. Barash looks out his door to the still-quiet waiting room up on the seventh floor at Lahey Hospital & Medical Center in Burlington, Massachusetts, just outside Boston. Then he looks back at the monitor.
Last nightâs phone call from nearby Winchester Hospital requesting permission to transfer this patient suddenly makes more sense. The distraught 22-year-old had recently overdosed. He was dragging one leg and repeatedly asking his mother if he was dying. Winchester is a smaller hospital that handles routine emergencies like a broken wrist or an appendicitis, but when patients with complex conditions or unexplained symptoms come in, the staff will often send them over to Lahey, a facility that has hundreds of specialists and more equipment. With the high-quality image in front of him, Barash can see what the Winchester staff could not, and it explains why the patient was acting strangely.
In ten years of medical training, Barash has reviewed thousands of scansâbrains shrunken from Alzheimerâs disease, brains dotted with tiny broken blood vessels, brains with tumors in different sizes, shapes, and locations. In every case, no matter what the damage looked like, it was pretty clear what was going on. But what Barash sees on the screen in front of him is strange and alien, belonging to no category he can imagine. It looks like someone took a page out of his medical school neuroanatomy textbook and deliberately highlighted the brainâs memory center.
He reexamines the MRI, scrolling up from the base of the skull through the familiar soft gray brain structures until the hippocampus comes back into view. It seems certain that this patient will fail the memory tests theyâll give him today, and the damage has triggered Barashâs interest in strange cases and rare brain diseases. He believes more in chance than in destiny, but still, he thinks, itâs almost as if his years of study and obsession have guided him directly to this moment, sitting in this office, looking at this startling image.
The care of this patient is now with his colleague, Yuval Zabar, a neurologist Barash admires for his intellectual curiosity and ability to run through every diagnosis that could possibly explain a patientâs symptoms. Itâs Friday, the final day of a week being on call, and Barash is allowed to leave for the weekend at noon to make up for the last seven nights of fragmented sleep. But instead of heading for home, Barash turns off the monitor, pulls on his white doctorâs coat, and heads down to 6 West to join the neurology team on their daily rounds. He has to see the patient for himself.
Between the patient, his mother and grandmother, and the doctors, there are more than half a dozen people in the cramped hospital room. Barash chooses an out-of-the-way corner from which to watch the examination. This is his preferred mode, to observe rather than be observed, and it doesnât bother him that he wouldnât stand out in a crowd. Born, raised, and educated in New England, 33-year-old Barash is solidly built and stands just shy of six feet, with a broad forehead, short brown hair, and a face that would look incomplete without his glasses.
James Maxwell Meehan, boyish and handsome enough to play the leading role in a romantic comedy, is sitting up in bed looking puzzled. On the whiteboard on one wall someone has written the following:
âMax, you are at Lahey Hospital in Burlington.â
âYou overdosed the night before last.â
âYou are having trouble with your memory.â
Maxâs mother, Laura, explains that Max keeps asking her, his sister, and his friend the same questions, so theyâve written the answers on the whiteboard so he would stop.
A resident-in-training begins the examination by interviewing Laura and Max to find out what brought him into the hospital. A few nights earlier, Max went to one of his favorite bars in Bostonâs Back Bay, where he danced and drank for hours. Back at his boyfriendâs apartment, he injected what he thought was pure heroin and passed out. It wasnât such an unusual night for Max, but according to his boyfriend, when Max woke up the next morning on the couch he complained that his left leg felt numb, and when he tried to stand up he fell over. A few minutes later, when he decided to stand up again, he fell over. Maybe his leg had fallen asleep, he figured. After another little while, he couldnât say how long, he realized it was morning and he ought to get up. But then he noticed that his leg didnât seem to be working. It occurred to him that maybe heâd slept too long on one side and pinched a nerve. Nothing made sense. Every few minutes, the realization that his leg felt paralyzed seemed like a horrible new discovery. Max started sobbing. Itâs not unusual for people who have overdosed to be confused and disoriented afterward, but Max found himself in a kind of limbo, a never-ending present.
âItâs just very odd,â his mother says. âHeâs fine. Heâs himself, he still has the same sense of humor. We even showed him that Ainât Nobody Got Time For That video on YouTube to distract him, and he laughed like he always does at silly things. But then we showed it to him again, and he laughed like it was the first time.â
Zabar, an experienced neurologist in his mid-forties, takes over the examination from the resident. Zabarâs thick head of hair is showing the first signs of gray, and he has the harried attitude of a man aware that his phone or pager is likely to buzz again within the next five minutes. Most patients appreciate the care he takes to explain things clearly and the way he doesnât sugarcoat bad news.
âMax, Iâm going to ask you to remember a few simple words.â Zabar looks him squarely in the eye to make sure Max is paying attention. âThe words are purple, velvet, honesty.â
Zabar pauses between each word to give Max time to register.
âCan you repeat those words back to me now?â he asks kindly.
âPurple. Velvet⊠honesty,â says Max.
âGood.â
Zabar gives Max a piece of paper with three figures on itâa triangle inside a circle, a skinny rectangle capped with a semicircle that looks like a mushroom, and the letter L. Below each shape is a wordâpride, hunger, station.
âI want you to copy these three shapes and three words just as you see them.â Zabar needs to make sure Max is paying attention and can follow directions.
Max copies them correctly, but when Zabar gives him a blank sheet of paper and asks him to re-create the shapes and words, he canât remember them.
âOkay. Now, can you tell me the three words I asked you to remember earlier?â
âPurpleâŠâ Max stops.
âAnything else?â
âThatâs all I remember.â
Barash picks up on Lauraâs growing anxiety. Sheâs trying to get a read on the room, but the resident, intern, and medical student are all focused on Zabar, who, wearing a poker face, presses on. He hides a pen, a crumpled piece of paper, and a cup around the room while Max watches. Several minutes later, when he asks Max to point them out, Max doesnât even know what heâs talking about. Barash finally catches Lauraâs eye and tries to give her a comforting look. From the damage to the hippocampus that theyâd seen on the MRI scan, the official diagnosis confirms what was almost a foregone conclusion: anterograde amnesia. Max still knows who he is and remembers everything that happened to him before he overdosed. But he canât form a single new memory. Every moment of the last few days has disappeared.
Zabar regularly sees patients with memory problems, and theyâre often elderly. Some have had strokes or brain tumors, but most suffer from dementia. Maxâs memory loss reminds Zabar of people with advanced Alzheimerâs disease, but aside from the fact that heâs much too young for that, his brain scan doesnât match the diagnosis. In Alzheimerâs, some brain regions, including the hippocampus, tend to be smaller than usual, a sign of slow, insidious destruction. But in his twenty years as a neurologist, Zabar has never seen a case like this one. Aside from the damaged hippocampus, blood flow in the rest of his brain is normal. The only significant health problem Max has is drug use, both legal and illegal: tobacco, alcohol, marijuana, cocaine, ecstasy, LSD, and heroin. The standard urine toxicology screen run on any overdose patient detects opioids, corroborating Maxâs account that he had injected heroin. After leaving Maxâs room, Barash and Zabar stop in the hallway to talk over the case for a few minutes. Even though it seems likely that the drug or a contaminant is in some way responsible, neither one of them can fathom why only the hippocampus is injured.
Barash heads back to his office to hang up his white doctorâs coat and check his e-mail one last time before heading home. Aside from colorful socks, he dresses traditionally, favoring button-down shirts with the sleeves rolled up, a tie, chinos, and comfortable shoes. Heâs two months into his first job as a full-fledged attending neurologist. Since heâs new and thereâs no space left in the main neurology pod on 7 West, heâs been assigned a tiny windowless office that was recently vacated by the chaplain. Itâs right off the waiting room, where a loud printer just outside the door ejects copies throughout the day. Visitors often assume heâs a secretary and step into his office to ask for directions.
Driving home to Lexington from the hospital that afternoon, Barash is so wrapped up in puzzling over the mystery and reliving the events of the day that he barely registers the familiar suburban landmarks along the wayâthe mall, the movie complex, the gas station. He imagines how heâll describe the case to his wife, Gillian Galen, how he met a patient who couldnât remember more than the previous few minutes, a guy who canât go home and tell someone the story of his own day.
Dr. Galen, slender, green-eyed, and levelheaded, is a psychologist and an excellent observer of human nature. She understands the mindâand Barashâwell enough to understand his fascination. They discuss it in their standing-room-only kitchen as they share a pizza and he drinks his Friday-night ginger bourbon fizz.
âHis MRI was just insanely weird,â Barash says.
âWeird how?â
âLike something completely scorched his hippocampus.â
âBoth sides?â
âBoth sides, and he was toast. Like, two days after an overdose he should be fine, but he was confused. And he wasnât confused in the classic sense of confusion. He literally was just not⊠he wasnât able to move forward in time. He was stuck. He kept going back to the same thing, telling his mom the same thing, asking Zabar the same question within a few minutes. Itâs a classic amnestic syndrome.â Barash stops to imagine. Heâs used to seeing people with advanced Alzheimerâs whose memories are as bad as Maxâs, but what would it be like to be so young and just wake up that way one morning?
âThatâs so sad. Will he get better?â Gillian asks.
âWe have no idea. Never seen anyone like him before,â Barash says, âbut itâs not gonna be sunshine and rainbows.â
One week after the overdose, on Maxâs twenty-third birthday, he returns to Lahey. As they do in most major teaching hospitals, the neurology team has weekly grand rounds, when doctors present interesting cases. The entire department can attend, including nurses, physician assistants, medical students, interns, and residents, and everyone is encouraged to weigh in. Zabar has decided to present Maxâs case.
Barash takes a seat among fifty or so other people crowded into the windowless, poorly lit neuroscience conference room. Paintings of distinguished neurologists and neurosurgeons line the wood-paneled walls. Max is seated at the head of the aisle with several rows of chairs on either side for the audience. Zabar stands at a podium and gives a brief overview of Maxâs case. Then, with Maxâs permission, he examines him, running through cognitive tests like the ones heâd given him in his hospital room a week earlier. He also tells Max a simple story, which he comes back to now and then, asking Max to repeat it at greater and greater time intervals. Max is cooperative, but his memory remains profoundly impaired. He is, in the words of neurologists, âdensely amnestic.â
When the exam is over, Max leaves, and Zabar displays his MRI on the screen behind him. The image captures the moment of acute damage, when some uncountable number of neurons would have only recently died, trapping water that would normally have been pumped across the cell membrane. Zabar dives into the case review.
âThe thing that is really striking to me,â says Zabar, âis that this signal is so bright that it looks like a stroke, but this person is so young. He has no risk factors for stroke. Heâs not immunosuppressed, and thereâs no evidence of any other infection like HIV, Epstein-Barr virus, or herpes.â
One of the stroke specialists in the audience takes advantage of a break in Zabarâs rapid-fire delivery.
âI have never seen a scan like this. I mean, it does look like a stroke. The intensity is there, but Iâve never seen a stroke that just took out the hippocampi bilaterally and not surroundingâŠâ
Barash asks the question hanging in the room. âYeah, why would it just be the hippocampus on both sides?â No one answers, so he continues in his quiet, rumbly voice. âItâs so perfect, itâs so localized. Whatever happened, there was clearly an affinity for just that area.â Usually grand rounds end with a clear understanding of the diagnosis or, if not, ideas to explore further. But today the discussion goes long and the meeting ends with a conundrum; what happened inside Maxâs brain?
If anyone at Lahey has the expertise to figure it out, it would be head neuroradiologist Juan Small. Heâs written four books on radiology and is known for his ability to sort through every possible explanation for an abnormal brain scan. And heâs careful about drawing inferences. Small couldnât attend the grand rounds presentation, but wordâs gotten out about a highly unusual case, and he keeps a list of them to help medical students learn how to make difficult diagnoses. Now he sits in his darkened basement office and calls up Maxâs imaging data on his large monitor.
Small selects the view that shows Maxâs brain from the base of the skull through to the crown of his head. Slowly, he scrolls up through the soft gray landscape. The familiar contours of the eye sockets begin to appear. Everything looks as it should until two islands of white emerge, complete, perfect, and intensely bright. I donât know what this is, he thinks. Heâs used to seeing tiny white dots in the hippocampus, each one representing dead neurons. They are the telltale signs of a stroke. But he has never seen the entire territory laid waste, and he reviews some ten thousand scans a year. Small scrolls back and forth a few more times, confirming the scope of the damage. I donât know what this is, he thinks again. And not only that I donât think anybody knows what this is. Maxâs brain scan is in a category all its own. Small adds it to his list, although he wonât have an answer when his students ask for the correct diagnosis.
Back in his tiny office after grand rounds, Barash turns his focus to preparing for a full slate of afternoon patients. The complete lack of daylight deprives him of any sense of time. The office is spare, with a desk, two chairs for visitors, a file of scientific papers heâll probably never have time to read, and the computer monitor. Diplomas and three picture...