The Art of Diagnosing:
by Maryann Brinley
This regular feature is designed to highlight case histories from the files of UMDNJ physicians. Our narrative comes from the records of Lawrence I. Golbe, MD, professor of neurology, UMDNJ-Robert Wood Johnson Medical School. Aspects of the case have been changed to protect the patient’s privacy. An individual’s ability to remain independent, despite a progressive, incurable neurologic illness, relies upon a cocktail mix of pharmaceuticals. Balancing those drugs’ benefits and side effects is a high-wire act that few doctors can pull off. Golbe is among the world’s leading experts on movement disorders like Parkinson’s disease (PD) and progressive supranuclear palsy (PSP).
Most of us can’t wait to fall into bed for a good night’s rest. But, like Shakespeare’s poor Hamlet, who wailed, “To sleep, perchance to dream — ay, there’s the rub,” this patient’s sleep was under attack — and so was his wife.
Our patient started having symptoms of Parkinson’s at 62. They consisted of a tremor in his left hand that soon spread to the rest of his body. Two years later, he had difficulty walking and shuffled a little. Still working as a salesman, he started to have trouble with manual dexterity by the time he sought Lawrence Golbe’s expertise. At that point, in 2000 and four years into this disease, he explained to Golbe that it was taking a long time to perform simple daily chores like shaving or cutting up his food during meals. He also needed his wife’s help to button a shirt.
Previous doctors had started the man on four different medications. “The age at which Parkinson’s begins will dictate which drugs are likely to produce side effects. It’s a real balancing act with a lot of empirical trial and error. My patients — and we have about 500 with movement disorders — call constantly so we can adjust medications,” Golbe says. “Younger patients tend to get more involuntary movement with levodopa. Older ones with dementia will have more hallucinations with agonists like pramipexole or ropinirole. During regular routine appointments, I talk about potential symptoms and also have patients tell me what’s going on in their lives. I listen for anything that sounds unusual. Managing these cases is not like taking care of some cut-and-dried problem. There has to be a lot of human interaction.”
Golbe decided to discontinue two of the drugs the patient was taking. “His degree of control was adequate at that point on levodopa / carbidopa and pramipexole.” However, in 2004, his Parkinson’s grew worse so Golbe readjusted medication again, adding a third drug, entacapone, keeping in mind that these pharmaceuticals interact and each has different side effects.
It wasn’t until an appointment in July 2005 that the patient’s wife brought up new, rather strange conduct: her husband was gambling compulsively.
“Like any behavior, gambling is the product of a lot of sparks and soup,” Golbe explains — with the sparks being the electrical and the soup being the chemical activity in the brain. Pramipexole mimics the neurotransmitter dopamine. In Parkinson’s, this neurotransmitter is deficient. Dopamine, which regulates muscle control, is also closely involved with reward behavior. “The good feeling” that comes from satisfying some kinds of urges involves a squirt of dopamine in the brain.” Our patient, who had led a rather sober life, was now experiencing exaggerated dopamine-like squirts. This gave him intense satisfaction from winning at gambling and led him to withdraw large sums at the cash machine so he could buy lottery tickets. “He had found it very satisfying to do these compulsive things as never before.” So Golbe reduced his pramipexole. “When I spoke with his wife by phone two weeks later, she said the gambling was under control.”
The march of the pathology of Parkinson’s disease has only recently been described in the medical literature and within the last three to four years, according to Golbe. In fact, what led to the recent, more detailed understanding of this pathological progression was Golbe’s own breakthrough research in the 1990s, which found a relationship between the protein alpha-synuclein and PD. He had led the clinical portion of the project that found that a mutation in the gene for alpha-synuclein was the cause of one form of hereditary PD. Others soon found that Lewy bodies, spherical clumps of previously poorly characterized material in the brains of all PD patients, were composed principally of alpha-synuclein.
“When you stain the brain of somebody with Parkinson’s using antibodies directed against alpha-synuclein, you see aggregates of alpha-synuclein not just in the form of Lewy bodies but also in strands called Lewy neurites,” he explains. In the early stages of this disease, you can spot these signs in the olfactory tract, too. That’s why the sense of smell can be impaired very early on, even years before other symptoms occur.
“Simultaneously, the march of Parkinson’s will start in the very lowest part of the brainstem, in the medulla, the dorsal motor nucleus of the vagus nerve, where reflexes in many organs are controlled.” This nerve goes all the way to the intestines, the heart, and the blood vessels, which is why some individuals with PD experience low blood pressure, bladder problems, acid reflux, constipation and other disparate symptoms. The part of the brain which controls conventional motor indicators of PD — the ones most commonly associated with Parkinson’s — is only one small area, the substantia nigra, which isn’t reached by the disorder until the middle of its course. From there, it will travel to the limbic system, where depression often results, and then to the cerebrum where thinking may be affected.
The non-motor signs of Parkinson’s are very important but don’t always respond to medications. “We treat the depression with medication, of course, but there is no good evidence that it works very well.” There may also be problems with temperature regulation where people are unable to tolerate cold or break into overheated sweats similar to menopausal hot flashes. In just a few minutes, clothes can be drenched. Weight loss can occur and typically, an average size person will lose 20 to 30 pounds over a period of six to 12 months before stabilizing. “This drop is not due to eating less or difficulty swallowing but due to a change in their bodies’ weight thermostat. Because sleep is controlled by many different areas of the brainstem, including some which are low on the brainstem, this march up from the medulla toward the center of the brain can hit the sleep area before you actually see traditional motor features of Parkinson’s,” he says.
In July 2006, during a routine visit, the patient’s wife reported that once or twice a month, he shook and punched her during the night without awakening.
Research has identified four distinct stages of sleep, one of which is rapid eye movement (REM), the phase associated with dreaming. REM is characterized by rapid heart rate, distinct brain waves, increased electrical brain activity and, normally, atonia or paralysis of the voluntary muscles. Sleep disorders that involve real activity, like sleepwalking or periodic limb movement, don’t actually occur during REM. However, in the case of Parkinson’s, that restful paralysis of REM sleep can be interrupted by a syndrome known as REM behavioral disorder (RBD). During RBD, patients’ bodies can become rigid as muscles tighten, flex and contract at the same time the heightened electrical activity of a dream is taking place. People may physically act out what’s happening inside their heads. “Patients never remember waking up or actually moving but will tell you the next day they were having a violent dream. The disease has made it difficult to disconnect the part of the brain where dreams originate from the part of the brain controlling movement.”
Usually seen in men over 60, RBD can force someone to run, fight, dance, fall out of bed, bump into furniture, chase or even beat up a sleep partner. It occurs in men, not women, though PD affects both sexes equally. Why men act out their dreams and women don’t isn’t clear. Some evidence suggests that these RBD midnight flashes of madness can be precursors, or early warning signs, of undiagnosed Parkinson’s.
Meanwhile, this man was lucky to have access to Golbe’s clinical experience. Shaking his wife violently while remaining asleep was an obvious giveaway for Golbe. “I treated him with clonazepine [an antidepressant with anti-seizure effects]. This is the standard treatment for RBD. I have other patients with RBD and it almost always takes care of the problem and it worked for him,” Golbe says. And also for her.
For our patient, it had all been a bad dream. Unfortunately for his wife, it had been a nightmare come true.