Maddie* couldn't stop crying. The first few days after her stroke, it had made sense. She had led a charmed retirement, with annual trips across the country, time with family and an active life. Now everything was in flux. A week before, Maddie, who was in her late 70s, had woken up unable to use half of her body. Her husband called an ambulance, and a diagnosis was reached within hours. Maddie had suffered a blockage in the blood vessels supplying her brain stem, affecting the pons, a region that conducts messages from higher centers of control and consciousness down to her body. At the hospital, she began to undergo a rush of frightening tests to evaluate the cause of her stroke and the risk of having another. She figured it made sense to cry.

A few days later, when Maddie was transferred from the stroke unit to the rehabilitation service, she was feeling more hopeful. Her risk of further strokes had been minimized with drugs to regulate her blood pressure, cholesterol and clotting. She could hear that her speech, initially slurred, returning to clarity. On the stroke unit, the emphasis had been on stabilization, but in rehabilitation, the goal was improvement. Maddie felt ready to work on her recovery.

Even with the hope of rehabilitation, though, the tears continued. Maddie cried when her husband came in and when he left. She cried during therapy meetings and medical updates. She cried through eating and bathing. The only time she did not weep was while she slept. Most oddly, Maddie cried even when she did not feel sad.

On the stroke unit, the crying had been annoying. In rehabilitation, it was downright disruptive. Maddie's therapy sessions were impeded by bouts of sobbing that invariably led the befuddled therapists to cut short their work with her.

Was It Depression?

Maddie's doctors worried she was having a recurrence of depression, which had plagued her in the past but was well controlled by an antidepressant. About a third of stroke patients experience new or worsened depression, for reasons ranging from functional loss to metabolic changes in the brain. Maddie worried, too, remembering the bleakness of her depression. Because of the complexities of her case, doctors asked for a consultation from a resident psychiatrist. That is when I was called in.

During our first meeting, Maddie spoke eloquently about the progress she had made since her stroke. Her words resonated with hope, which is unlike patients with depression. Maddie believed she would get better and return to the life she had enjoyed. But throughout our conversation, she would suddenly start sobbing. She spoke through the cracked refrain of her weeping, which seemed incongruous with the content of her speech. She even bawled through a description of her grandchildren.

Credit: Hanna Barczyk

When I asked Maddie whether she felt depressed, she replied, “I'm confused about why this is happening. I don't think so.” Additionally, she did not meet other criteria used to diagnose depression, such as loss of interest in usual activities, poor sleep and appetite, low energy and weak concentration. Maddie was experiencing extreme, uncontrollable expressions of sadness without the accompanying emotion. In a sense, this was the opposite of depression, in which a person may feel despair within but appear blank or detached to others.

An Underdiagnosed Disorder

I recognized Maddie's condition as a relatively common, though vastly underdiagnosed, disorder called pseudobulbar affect (PBA). PBA is characterized by involuntary bursts of emotional expression—most often crying or laughing—independent of actual emotion. It can occur in many neurological disorders, including amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), multiple sclerosis, Parkinson's disease and stroke. All told, it affects an estimated two million to seven million people in the U.S., according to a 2011 study published in Advances in Therapy. In this same study, the great majority of patients who tested positive for PBA received either no diagnosis or an alternative diagnosis from their clinicians. Only half of symptomatic patients received any treatment, and for many, their treatment was based on a mistaken diagnosis.

PBA is caused by the disruption of an emotional expression circuit spanning several brain regions. Cortical structures responsible for higher emotional-intellectual function, such as the frontal lobe, produce the emotional context for expression and send it to the brain stem and cerebellum. The cerebellum acts as a gatekeeper, inhibiting or allowing the impulses to pass to the pons, where they are executed as laughter or tears. When Maddie's stroke injured her pons, she lost the integrity of the inhibitory circuit from the cerebellum that allowed her brain to regulate emotional expression.

Because Maddie had been treated for depression earlier in life, her diagnosis had been confounded—a common situation. As the 2011 study showed, PBA is routinely unrecognized or mistaken for other psychiatric disorders. Adding to the confusion is the issue, confirmed by a 2010 study in the Journal of Neurology, that people with PBA experience decreased quality of life and social isolation, which may further muddle diagnosis by contributing to psychiatric symptoms such as depression and anxiety.

For Maddie, the diagnosis was liberating. PBA is one of the most profound examples of disjunction between emotion and expression, something universally relatable: nearly everyone has had the experience of a misconstrued facial expression or tone. For Maddie, these disconnects became so frequent and intense that she wondered whether she could still recognize her emotions. Understanding that her crying was the consequence of her stroke allowed Maddie to trust her thoughts and feelings again.

When I sat down with Maddie and her husband to explain her diagnosis, they quickly asked about treatment. In 2011 a failed ALS medication called Nuedexta won Food and Drug Administration approval for treating PBA. Nuedexta, the rebranded combination of the common cough medicine dextromethorphan and the malaria medicine quinidine, works by blocking glutamate, one of the major excitatory neurotransmitters in the brain, in a way that seems to regulate the aberrant signaling in the affected pathway. Unfortunately, because of potential drug interactions with antidepressants, Nuedexta was a risky choice for Maddie. Yet I felt there was another class of medications that might help her brain regulate itself: another antidepressant.

When I told Maddie and her husband that I hoped to try a second antidepressant, they were baffled. “I thought you told me that you didn't think I was depressed?” Maddie asked me, with obvious concern. I explained that before Nuedexta came to market, doctors often prescribed an off-label treatment for patients with PBA: selective serotonin reuptake inhibitors (SSRIs), which are antidepressants that work by increasing serotonin in the synapses between neurons. It just so happened that Maddie's antidepressant worked through another mechanism, involving the neurotransmitter norepinephrine. We agreed to leave her original medication alone to do its job and to try a low-dose SSRI aimed at her PBA.

Shutting Off the Waterworks

Although both PBA and depression may respond to medications that increase serotonin in the synapses, the responses are distinct. Depression takes weeks to respond, possibly because the increase in serotonin has a number of secondary effects that are responsible for the mood changes. In contrast, PBA can respond in days. After five days on medication, Maddie was experiencing crying jags fewer than one time a day.

Maddie completed several weeks of rehabilitation, constantly gaining strength. When I came to see her, she savored the chance to speak. Her clear consonant laugh erupted at just the right moments to make me smile. I saw Maddie cry once more in her final days in the hospital; she was gazing at her weak left arm and pondering what a day at home might now be like. The tears streaming down her face reflected the true sadness and fear of that moment. We sat together, sharing in her hardship, before she looked up and said, “At least I'll get to be with my grandchildren again,” her tears drying, her lovely smile breaking through.

*Not the patient’s real name.