John Galbraith Simmons – Brain Blogger Health and Science Blog Covering Brain Topics Wed, 30 May 2018 15:00:03 +0000 en-US hourly 1 Locked-In – Lesson for Stroke Awareness Wed, 07 Nov 2012 12:00:51 +0000 After he suffered a stroke in 2005, Tony Nicklinson developed locked-in syndrome, a rare condition that left the middle-aged Brit fully paralyzed from the neck down. He lived on, mentally alert but wholly incapable of taking care of himself. He could not walk, feed himself or brush his own teeth. Devastated when a British court refused to allow him to commit assisted suicide, Nicklinson stopped eating or accepting fluids. He developed pneumonia, refused antibiotics, and died this past August 22, 2012.

Although news bulletins focused on his legal efforts to be permitted to commit assisted suicide, Nicklinson’s tragic disability — seven years of what his wife called a “living nightmare” — also bears upon stroke awareness and the availability of the emergency treatment that too few people know about or receive — the clot-busting drug, tissue plasminogen activator (tPA). Locked-in syndrome has something to say to everyone at risk for stroke. So does tPA.

In 2005, Stephan Mayer MD, together with colleagues at the Columbia University College of Physicians and Surgeons, reported on a unique case of heroic treatment to prevent locked-in syndrome in a stroke victim.

tPA and a Case of Locked-In Syndrome

Mayer’s patient, the pastor of a well-known church in Manhattan, suffered from a “stuttering course” of brainstem ischemia that lasted days. He first went to the emergency room some 10 hours after he began to experience facial numbness and right-side weakness. A history of neck pain suggested a vertebral dissection, or tear in the lining of the main artery that supplies blood to the brain. Transferred to the neurointensive care unit (Neuro-ICU), his symptoms were varied and ominous. First the left arm would become weak, afterwards the right; then one side of his face would become paralyzed. To insure he could breathe, he had to be intubated.

“We realized he was in the early stages of an evolving basilar artery syndrome,” recalls Mayer, “the final result of which, in the worst case, you infarct your whole pons and become locked-in.” Patients who end up in a complete locked-in state remain conscious but are completely paralyzed save for the vertical gaze. The condition is widely recognized as a fate worse than death.

Over two days Mayer presided over the patient’s disrupted “low flow state” in the occluded basilar artery of his brainstem. He administered heparin, an anticoagulant, and artificially raised his blood pressure but neither measure had any appreciable effect. An angiogram showed blood seeping into the basilar artery and small fragments of clotted blood. Occlusion of both vertebral arteries shut down the possibility of a mechanical solution such as angioplasty.

Suddenly, on the second day in the ICU, the patient became totally quadriplegic. Efforts to reverse it failed. Mayer went to the patient’s wife.

“I said, ‘We’re losing him. He’s going to develop this locked-in syndrome. We’ve got to try something.” He added: “The one thing I can think of doing is giving tPA.”

Were circumstances less than extraordinary, that meant breaking all the rules. “Forget the three hour [time window for giving tPA]; this ischemic process had been going on for two days.” Mayer was purposely keeping blood pressure high, at around 220 systolic, another contraindication. So was the anticoagulant he administered. Finally, a diagnosis of arterial dissection was not an approved use for tPA, which raised genuine concern for catastrophic hemorrhage.

“Look,” Mayer told the patient’s wife. “It’s high risk. But I don’t know what else to do. It’s a total roll of the dice and probably won’t work. But otherwise you’re going to just stand around and watch this guy become locked-in.”

With her approval, he administered tPA.

“I’ll be damned,” Mayer recalls. “About an hour later, he started to improve. He started to move both sides.” Sensation and movement fully returned. Within days he would walk out of the hospital.

“From a biological point of view, he was thrombosing [developing blood clots],” recalls Mayer. “By giving the tPA, it was just enough to open everything up.”

Mayer and his colleagues went on to write up the case, published in Neurocritical Care. They hoped to illustrate and underscore that, “Sometimes, when you’re facing certain doom, you can roll the dice, break the rules, as long as you have eyes wide open about the risks and benefits.”

The contrast in outcomes between Mayer’s case and that of Tony Nicklinson also points to the importance of stroke awareness and knowing about the use of tPA to treat stroke, now recommended within 3-4.5 hours of symptom onset.

“I’m already dead – don’t mourn for me,” were Tony Nicklinson’s last words before he died after seven years of unmitigated suffering. When Stephan Mayer’s patient, who was about 60 years old at the time of his stroke, left the hospital after beating incipient locked-in syndrome, he took up a new email address. Its username: notdeadyet.


Janjua N, Wartenberg KE, Meyers PM, & Mayer SA (2005). Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA. Neurocritical care, 2 (3), 296-9 PMID: 16159079

Zivin JA, Simmons J. tPA for stroke: the story of a controversial drug. New York: Oxford University Press; 2011.

Image via olly / Shutterstock.

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Into the Looking Glass – Stroke, tPA, and Avoiding a Fate Worse Than Death Sun, 04 Nov 2012 12:00:15 +0000 Stroke, a major cause of death and the leading cause of adult disability, can leave victims unable to walk, talk, eat or take care of themselves. To treat stroke while it’s happening, the “clot-busting” drug tPA (tissue plasminogen activator) has been proven to save brains from damage and reduce or even completely avoid disability. Patients require a CAT-scan to assure diagnosis and the drug must be administered within 4.5 hours after onset of symptoms. In today’s medical environment, that shouldn’t be an overwhelming obstacle.

Although appropriate for almost 9 in 10 strokes — those that are ischemic, or due to blood clots — only a small fraction of potentially eligible patients, not more than about 4-8%, receive tPA.  Consider this:

It’s safe and effective…so few patients get it. As a drug for a major and life-threatening disorder, tPA was shown to be effective with a 11-13% absolute benefit (cancer drugs that provide a 2% absolute benefit are routinely approved).

It’s a one-time drug…yet so became the target of a muckraking campaign. Unlike drugs such as Vioxx, which were prescribed for daily use to masses of patients only to show unanticipated adverse effects, tPA for stroke is usually given once, intravenously. But its approval nevertheless incited journalists to campaign against it as dangerous and ineffective. Such charges lingered for years after post-approval studies confirmed the original results of randomized trials, which were supported not by the drug industry but by a branch of the National Institutes of Health.

Neurologists never had a drug to treat stroke before…so they were reluctant to use this one. Many neurologists might have been expected to be early adopters but initially only a few were enthusiastic. Neurologists were not accustomed to treating strokes as the emergencies they demonstrably are, and  many remained skeptical for years. Most have been by now been convinced, but tPA has been the most controversial drug ever used in neurology.

Emergency physicians were accustomed to using tPA… yet with stroke they didn’t want to. When the drug was first FDA-approved, ER doctors often used it for heart attack (most commonly due to clots, like stroke). But when it came to a brain disease, many (despite their reputation as cowboys in the ER) were fearful and concerned about their diagnostic acumen. A few created and many bought into the efforts to impugn tPA as overhyped by its manufacturer, Genentech, presumably in cahoots with the American Heart Association.

Stroke victims don’t know about tPA. Although controversies over the drug are now largely past, their legacy has been persistent lack of stroke awareness among the general public, with only a small minority of potential patients and their families or colleagues knowing the symptoms of stroke,  the importance of time-to-treatment, or the simple instruction (Call 911). So it is that, although FDA-approved for stroke since 1996, tPA today reaches only a fraction of nearly 800,000 new stroke victims annually in the United States. About 50% are potentially eligible.


Adeoye O, Hornung R, Khatri P, & Kleindorfer D (2011). Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke; a journal of cerebral circulation, 42 (7), 1952-5 PMID: 21636813

Zivin JA, Simmons J. tPA for stroke: the story of a controversial drug. New York: Oxford University Press; 2011.

Image via andkuch / Shutterstock.

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