A Talented Tumor

Patrick’s thymoma was a talented tumor. So talented it caused his case to be reported in the neurology literature twice, for completely different reasons. A thymoma is a tumor of the thymus gland and most are relatively benign, at worst locally invasive. Not Patrick’s. We battled it together for almost ten years.

I first met Patrick when he was admitted to my service in 1984. I was ward attending for the month, taking care of in-patients, and teaching the residents, interns and medical students. When the rounding team walked in, Patrick, a slender, dark-haired man of about forty with a pleasant manner and an engaging smile, was sitting on the side of his bed and looked fairly normal except for questionably droopy eyelids.

We went over his history and as he talked his speech became a little slurred. His t’s and d’s were no longer crisp, his s’s became sloppy and his r’s lost their trill. He sounded as if he was talking with scrambled eggs in his mouth.

His history involved mostly gastrointestinal symptoms. He would get full quickly when eating, had little appetite, had lost some weight and had chronic constipation. He had also developed intermittent drooping of his eyelids, mostly the left, and difficulty with his speech that would come and go. He reluctantly admitted to some weakness of his extremities. One of the other faculty members had seen him in clinic and raised the possibility of myasthenia gravis, prompting his admission.

“What kind of work do you do?” I asked.

“I’m a farmer,” he replied.

“What do you grow?”

“Mostly potatoes.”

“Where?”

“On the eastern shore.”

As it would turn out, Patrick was a wealthy gentleman farmer who lived on Virginia’s eastern shore, the narrow peninsula that separates the Chesapeake Bay from the Atlantic Ocean. He ran a large potato farming operation with other family members. During many clinic visits to come he would tell me stories about his farm and often brought a gift of a large box of potatoes, big white baking potatoes one time, yams another.

On examination that first day, his eyelids were not clearly abnormal to casual observation. But when I had him look upward for two minutes, he developed ptosis, droopy eyelids, particularly on the left. The left lid drooped down until it nearly covered the pupil. Ptosis that is not present at rest but develops after prolonged upgaze is called fatiguable ptosis. Myasthenia gravis commonly and characteristically causes fatiguable ptosis.

The technical term for Patrick’s type of slurred speech is dysarthria. His speech became more slurred and less intelligible the longer he talked. With counting to 100, by the time he got above seventy he was struggling to distinctly articulate the numbers. Dysarthria that grows worse with prolonged talking is also characteristic of myasthenia. Thomas Willis, the English physician who first described myasthenia gravis in 1672, described a woman in his village who, when she tried to talk for a lengthy period, became “mute as a fish.”

So far, based on the fatiguable ptosis and speech pattern, myasthenia gravis seemed likely. Then things became complicated. On testing his shoulder and hip girdle muscles, Patrick had mild but definite weakness. When he held both elbows out to the side, fists on his sternum, and I pushed down on the elbows, I could break his shoulder muscles, his deltoids, with a modest effort. Clearly not normal. A grimace and soft grunt showed his effort, then he looked at me with wide eyes and a half-smile, disheartened at having been beaten.

I asked him to hold his elbows out again. And again. And again. In myasthenia, extremity muscles become weaker with successive contractions, just as with the eyelids and the voice, referred to as fatiguable weakness. Patrick’s deltoids got stronger with successive contractions. By the fourth or fifth deltoid contraction, I could not break them. He felt encouraged. I stood back puzzled.

“Pick up your knee,” I said.

He raised his flexed left knee, still sitting on the side of the bed. I pressed down and was able to push his knee down into the bed, something I should not have been able to do in a normal adult male. Same with the right. His hip flexor muscles were definitely weak. Back to the left.

“Again, please.”

This time I could still break his hip flexor, but it required more effort.

“Again.”

This time I could break it, but barely.

“Again.”

This time I could not break it.

His hip flexor muscles were increasing in strength with successive contractions, just like the deltoids did. This is the opposite of what is expected in myasthenia gravis.

The condition that classically causes baseline weakness with increasing strength on successive contractions is the Lambert-Eaton myasthenic syndrome, or LEMS. Unfortunately, “myasthenic syndrome” was included in the name because of some resemblances to myasthenia gravis, and it has caused confusion because there are many more differences than similarities between the two conditions. The transient increase in strength after repetitive muscle contraction is known as Lambert’s sign.

Both myasthenia gravis and LEMS are disorders of neuromuscular transmission. Muscles contract because electrical signals, nerve impulses, travel along intramuscular nerve twigs and arrive at a neuromuscular junction. The junction consists of an expansion of the intramuscular nerve twig, called the terminal bouton, a synaptic cleft, just a microscopic space, and a specialized area on the muscle cell called the end plate, which is studded with receptors for the neurotransmitter acetylcholine.

A nerve impulse arriving at the terminal bouton causes the release of acetylcholine, which diffuses across the synaptic cleft, then binds to an acetylcholine receptor molecule on the muscle end plate, triggering a muscle action potential. Muscle action potentials in turn produce muscle contraction.

Neuromuscular transmission is the mechanism whereby thoughts from the brain cause muscles to contract. Diseases that disrupt this process are called neuromuscular transmission disorders or diseases of the neuromuscular junction and include myasthenia gravis, LEMS, botulism, magnesium intoxication and the side effects of certain drugs.

There are two types of neuromuscular transmission disorders. Those affecting the terminal bouton of the intramuscular nerve twig are termed presynaptic. These conditions interfere with the release of acetylcholine. Botulism is a classic example. Disorders that affect the muscle end plate are called postsynaptic. Myasthenia gravis is a postsynaptic disorder due to an autoimmune attack on the end plate acetylcholine receptors; LEMS is a presynaptic disorder due to an autoimmune attack on the terminal bouton’s acetylcholine release sites.

The hallmark of both presynaptic and postsynaptic neuromuscular transmission disorders is muscle weakness. Beyond the weakness, there are disease-specific quirks that provide clues. Bulbar muscles are those innervated by the brainstem (the brainstem, especially the medulla oblongata, is sometimes referred to as the bulb), and include the muscles of the head and face, including the extraocular muscles that move the eyes, the eyelids, the muscles of facial expression, and the muscles of the mouth and throat including the muscles that control speech, swallowing and breathing.

Myasthenia gravis characteristically causes prominent bulbar muscle weakness, LEMS much less so. Patrick’s degree of bulbar involvement was much more to the degree expected in myasthenia gravis than LEMS. But myasthenia gravis should not cause increasing strength with successive contractions—that was typical of LEMS, in fact highly suspicious for LEMS.

The literature had long contained mention of a rare “overlap syndrome,” referring to patients who had features of both myasthenia gravis and LEMS. Might Patrick have an overlap syndrome?

I pulled out my hammer and tapped his reflexes. There was barely a twitch. His reflexes were diffusely underactive. In myasthenia gravis, the reflexes should remain normal but underactive reflexes are typical of LEMS.

Because of all his gastrointestinal symptoms, we came back later in the day to carry out some autonomic testing. The autonomic nervous system is responsible for all the vital but unconscious, vegetative functions that we are not aware of, such as breathing, digesting and much more. His early satiety and constipation suggested the possibility of an autonomic nervous system problem. Dysautonomia, dysfunction of the autonomic nervous system, is common in LEMS. Those patients often have impotence, dry mouth and constipation.

His blood pressure was normal sitting and standing. Then we had him do a Valsalva maneuver, exhaling against a closed glottis, like straining to have a bowel movement. There is a complex blood pressure response to Valsalva that is divided into phases. In phase IV, the blood pressure should rise markedly. Patrick’s did not. The absence of rebound overshoot on Valsalva was abnormal and suggested dysautonomia.

We placed one of Patrick’s hands in a pan of ice water for one minute. This cold pressor test should cause the blood pressure to rise. Patrick’s did not. As we neared completion of the cold pressor test, Patrick’s eyebrows knitted and his other hand fisted, but his blood pressure budged not one point. We held it for another 30 seconds. Still no rise. Released, he held up his dripping wet, frozen, tingling, aching hand and stared at it, incredulous that such a simple test could have been so painful. We did sweat testing that seemed to show hypohidrosis, a lack of normal sweating.

Our bedside autonomic testing suggested that Patrick did in fact have dysautonomia. Myasthenia gravis should not cause dysautonomia. So, here I had a man who by clinical bedside testing had classic signs of myasthenia gravis but who had other signs that were much more typical of LEMS.

At the end of the first day, my impression was that Patrick had an overlap syndrome. The ward team ordered a battery of tests.

On rounds the next morning I said, smiling, “Patrick, you know it’s usually not good to be an interesting case to a neurologist.”

He laughed and said, “Well, do you know yet what’s wrong with me?”

I explained that he had evidence of two different conditions affecting the junction where his nerves communicated with his muscles, and that we had ordered a slew of tests to try to get to the bottom of it.

“OK, Doc, I just hope you can fix it,” he said.

The acetylcholine receptor antibody level in his blood was markedly elevated, proving beyond doubt that Patrick had myasthenia gravis. There is now an antibody test for LEMS but it was not available at that time. A striated muscle antibody test was positive; this test is often abnormal in patients with thymoma. The blood work also showed a positive antinuclear antibody, the lupus test, at a significantly elevated titer of 1:8000, although he had no clinical evidence of lupus.

A test was done by administering a drug called edrophonium intravenously. Edrophonium blocks the enzyme that degrades acetylcholine, acetylcholinesterase, and temporarily enhances the effects of acetylcholine at the end plate. A myasthenic patient’s strength may improve dramatically. Droopy eyelids pop open. Wheelchair-bound patients stand and walk. The test is often positive in myasthenia gravis but in Patrick’s case it was negative.

Barium and endoscopic studies showed a dilated stomach with delayed emptying and decreased peristalsis, all consistent with dysautonomia affecting the gastrointestinal tract.

A CT of the chest showed a mass in the anterior mediastinum, the space just beneath the breastbone, in front of the heart, consistent with a thymoma. There is an association between thymoma and myasthenia gravis. Thymoma occurs in approximately 10% of myasthenia gravis patients, mostly in older males. Conversely, over 50% of patients with thymoma have myasthenia and myasthenia is not uncommonly the presenting manifestation of a thymoma. Myasthenia occasionally makes its appearance after removal of a thymoma. The first to report an improvement in myasthenia gravis after removal of a thymoma was the pioneer cardiothoracic surgeon Alfred Blalock in 1939.1

The thymus gland is a part of the immune system. It lies in the anterior mediastinum. Lymphocytes are a type of white blood cell involved in immune system function. There are two types of lymphocytes: B cells and T cells. Immunity is divided into humoral and cellular components. B cells produce antibodies and are involved in humoral immunity. T cells are involved in cellular immunity. Circulating antibodies can effectively combat microbes that live and divide outside host cells. Cell mediated immunity provides defense against microbes that have already entered host cells.

Both B and T cells are produced in the bone marrow. Immature T cells migrate from the bone marrow to the thymus, where they mature and are trained to react to foreign agents but not to self. Once mature, the T cells migrate to the lymph nodes throughout the body for storage.

In response to a foreign invader, such as a virus, both B cells and T cells proliferate and become either memory cells or effector cells. The memory cells persist to ensure a quicker response to future invasions. The B effector cells produce antibodies that eliminate invaders. Among the many types of T effector cells are helper T cells and cytotoxic T cells. The helper T cells produce signaling proteins that promote antibody production in B cells. Cytotoxic T cells target cells that have already been infiltrated or infected, destroying the cell and the invader in the process.

The thymus is large and active during childhood and adolescence, reaching its maximum size at about puberty, while it is busy training T cells. Once this job is done, the thymus rapidly involutes and is replaced by fat and fibrous tissue, leaving the anterior mediastinum in a normal adult mostly empty.

Patrick then had an EMG, an electromyogram, which includes nerve conduction studies and, when evaluating a patient for a possible neuromuscular transmission disorder, a procedure called repetition nerve stimulation. The physiology of neuromuscular transmission is complex and dynamic. It involves the release of acetylcholine from the nerve terminal, diffusion of transmitter across the synaptic cleft, interaction of transmitter with the acetylcholine receptor followed by degradation of the acetylcholine by acetylcholinesterase. All this happens in a matter of milliseconds.

For repetitive stimulation studies, a small disc electrode affixed to the muscle surface records the muscle action potential, which has a certain amplitude that remains fairly stable under normal circumstances. If the nerve supplying a muscle is stimulated repetitively while recording the muscle action potential, the size and stability of the action potential may vary depending on the rate of stimulation.

In a normal individual, the amplitude remains the same whatever the rate of stimulation but with a neuromuscular transmission disorder the amplitude may vary. At a slow rate of stimulation, the amplitude will remain the same. But at a rate of 2-3 stimuli per second, transmission begins to fail and the amplitude begins to decrease in a characteristic and predictable fashion. This “decrement” at 2-3 stimuli per second looks the same in both myasthenia and LEMS.

Then the patient is asked to isometrically contract the muscle strongly for about 10-15 seconds and there the two conditions behave differently. This brief, isometric contraction causes a flood of calcium into the terminal bouton and increases the release of transmitter. In myasthenia, the decrement disappears and the muscle action potential amplitude may increase slightly. In LEMS, the decrement disappears and the muscle action potential amplitude increases dramatically—doubling, tripling, even quadrupling. This “incrementing response” is very striking.

Patrick’s EMG, done by Bob Leshner, showed the expected decrement at slow rates of repetitive stimulation. After brief exercise, it showed the dramatic incrementing response characteristic of LEMS.

It was now clear that Patrick had an overlap syndrome. Not only was there clinical evidence of both a presynaptic and postsynaptic disorder but the acetylcholine receptor antibody was present in his blood, proving myasthenia gravis, and now the repetitive nerve stimulation studies showed the pattern characteristic of LEMS. His CT showed a probable thymoma. The tumor was likely producing antibodies against both the presynaptic and the postsynaptic membranes. There was also a positive antinuclear antibody but no clinical evidence of lupus. It was just another autoantibody in the tumor’s repertoire.

And Patrick’s thymoma wasn’t done yet.

A critical function of the thymus is to train T lymphocytes to distinguish between foreign agents and self. The thymus normally produces mature, functional T cells and induces self-tolerance. Thymic malignancies may cause a loss of self-tolerance and result in autoimmune disorders, most notably myasthenia gravis but also including systemic lupus erythematosus, pernicious anemia, autoimmune thyroid diseases and others.

Exactly how thymomas lead to the loss of self-tolerance is unclear. One possibility is that thymoma derived T cells are immature and lack sufficient self-tolerance for normal function.2 Another is that autoimmunity is linked to genetic aberrations caused by high cell proliferation rates. Another is that the normal balance between T helper cells and T suppressor cells gets out of balance in favor of the helper cells. The B cells get too much help. Whatever the mechanism, the thymic education process gone awry results in the induction of autoimmune disease.

A new term, thymoma associated multiorgan autoimmunity (TAMA) was coined to describe a disorder that involves the skin and other organs. It illustrates dramatically the extent of autoimmunity possible with a thymoma.3

I went by to catch Patrick up on his test results and for the first time met his wife, Connie, a pert, personable brunette bejeweled just shy of ostentatiousness. I would never have picked her from a crowd as a farmer’s wife. Potato farm must be doing well, I thought.

I explained that he had a tumor in his chest that was making antibodies to his neuromuscular junctions, which were causing his weakness and other symptoms. It would have to come out. He agreed. “Where do I sign?” he said.

The thoracic surgeons were able to attain gross total removal of the tumor. Pathological examination confirmed the tumor was a thymoma. His postoperative course was uneventful until a routine, follow-up chest x-ray two weeks later showed a small accumulation of fluid near the base of his left lung. Further evaluation showed an enlarged spleen. The spleen is a fist-sized organ that lies in the left upper quadrant of the abdomen just under the diaphragm. It is part of the lymphatic system.

Thymomas are typically indolent, slow-growing tumors that may spread locally. The most common metastatic sites are to the pleura (the lining of the lung), the pericardium (the lining of the heart) and the diaphragm. Extra-thoracic metastases are rare. Aoki, et al, in 2018, reported a case of an isolated splenic metastasis and stated that to their knowledge no patient with an isolated splenic metastasis from a thymoma had been previously reported.4 It is that rare.

But the situation was too suspicious. A thymoma removed only two weeks before. An enlarged spleen. A fluid collection in the lung adjacent to the enlarged spleen. The spleen was removed and showed metastatic thymoma. Patrick’s tumor was unusually aggressive. Radiation and chemotherapy were not standard treatments at the time and the disease was apparently eradicated.

A month later he returned to clinic, bearing a box of yams and a big smile.

“How are you feeling?” I asked.

“Much better,” he replied. “I’ve gained back some of the weight I lost. The constipation is gone. I feel stronger. Thinking about easing back into work.”

“I see no problem with that. Just don’t go crazy with it.” I learned later how hard the work was during harvest season.

He returned for visits every few months and continued to do well, growing stronger and more energetic. A year after removal of the thymoma and the subsequent splenectomy he was asymptomatic except for mild, occasional fatiguability. Examination showed no ptosis or dysarthria, normal strength and reflexes and normal autonomic function. He was in remission.

I thought we had as convincing and well documented a case of myasthenia gravis-LEMS overlap syndrome as had ever been reported, and one that was unique because of its relationship to a thymoma, so together with one of the residents we reported the case.5

Sometimes a tumor will hibernate, enter a dormant phase. An apparent cure may be an illusion, a trick. The reasons are unclear. I have seen it most often with breast cancer and melanoma, which may lie low for years before again raising their ugly heads. Patrick’s thymoma was playing such a game.

After a couple of years during which he was essentially asymptomatic, the weakness slowly returned. Repeat scans of his chest showed no evidence of tumor recurrence. Repeated searches for metastatic disease were unrevealing. He was treated with prednisone and with pyridostigmine, an oral drug that blocks the effects of acetylcholinesterase.

When the prednisone failed to completely control his symptoms, I gave him the more powerful immunosuppressants, azathioprine and cyclosporine, while trying to taper and minimize the prednisone dose because of its terrible side effects. We often use these drugs in patients with myasthenia gravis and Patrick was not doing any worse than many of my other myasthenics. He did not go into respiratory failure, myasthenic crisis, so things could have been much worse.

I continued to see him every few months. During harvest season, he often brought potatoes. Connie was usually with him, always the best dressed woman in the waiting room, turning heads. We talked about other things—their latest trip, their family, my family. He invited me to visit them on the eastern shore.

About five years in, Patrick developed severe right flank pain. X-rays showed a lesion in one of his ribs. A biopsy showed metastatic thymoma. It had finally raised its head. There were no other metastases we could find. Focal radiotherapy relieved the pain and he was soon back at work.

Tangier Island is a picturesque fishing and crabbing village in the middle of the Chesapeake Bay, accessible only by boat or small airplane, famous for its soft-shell crabs. It is a gotta see destination for Virginians. Neurologists are drawn there because of Tangier disease.

People with Tangier disease have a deficiency of a lipoprotein that causes a deposition of cholesterol, most famously in the tonsils, causing them to turn orange. It is a hereditary disorder, discovered and described by NIH researchers among the isolated population of Tangier Island in the 1960’s. Neurologists want to visit Tangier Island in hopes of seeing the renowned orange tonsils.

Rhonda and I decided to visit Tangier Island. The best way to get there is by a one-hour ferry ride from Onancock, Va. And Onancock is only about 15 miles from Patrick’s house. No way was I going that close to Patrick’s without stopping by.

Patrick and Connie came onto the porch to greet us as we pulled into the circular drive of the large, colonial house on a sunny, summer afternoon. The porch was like a garden of well-tended plants, sitting on the deck and hanging from the arches. We walked into a spacious interior of beautiful, glossy hardwood floors. We sat in the living room, which was a little formal but still comfortable. It did not turn into an office visit. We talked about people things—his farm, our families, the rich history of the eastern shore. Stayed about an hour.

In the driveway, leaving, Patrick and I started to shake hands, but the goodbye became one of those half-shake, half-hug guy things, then finally just a plain old hug.

About nine years in, Patrick left a message that the muscles in his legs were twitching uncontrollably. When I saw him a few days later, the muscles of his calves and shins were alive with fasciculations and myokymia.

Fasciculations are spontaneous, isolated muscle twitches. Most normal people have them occasionally, particularly in the calf muscles and the small hand muscles. They are made worse by fatigue, anxiety and particularly by excessive caffeine.

Myokymia is also a spontaneous, isolated muscle twitch similar to a fasciculation. Normal, healthy people occasionally have myokymia too, most often as an annoying, persistent twitch in one eyelid.

Fasciculations and myokymia look similar in the way they ripple the skin, but are quite different when recorded with an EMG needle. Myokymia is associated with a very characteristic and unusual electrical discharge called neuromyotonia.

Issacs syndrome is a condition in which patients develop widespread fasciculations and myokymia with neuromyotonia on EMG, due to an autoantibody attack against the potassium ion channels of motor nerves, causing the nerves to spontaneously discharge.

Patrick sat in a chair in my office, heels together, knees akimbo, looking down at his quivering calves, small muscle contractions flitting randomly and incessantly from place to place and said, “It never stops. That’s some crazy shit.”

His EMG showed widespread fasciculations, myokymia and neuromyotonia. He had developed Isaacs syndrome. The thymoma, hiding somewhere, was now making a new autoantibody, this time to his motor nerve potassium ion channels. Or maybe pesky circulating memory cells were somehow responsible. A condition affecting ion channels is referred to as a channelopathy.

We treated Patrick with plasmapheresis, a procedure that removes the patient’s plasma, and the evil humors it contains, and replaces it with substitute fluids. The pathogenic antibodies are flushed down the sink, cleaning the plasma. He improved substantially and got on with his life except for having to undergo periodic maintenance plasmapheresis, several times a month, like being on dialysis.

Some years later, talking with one of my favorite former fellows at a meeting, it turned out she knew of two similar cases of neuromyotonia due to an autoimmune channelopathy, one in St. Louis and one in Pittsburgh. One of the other cases was also due to a malignant thymoma. We joined forces and reported these cases.6 This was the second time Patrick’s case was reported in the medical literature, fourteen years after the first case report about his overlap syndrome.

His thymoma had now produced at least three different autoantibodies—against the presynaptic membrane of his neuromuscular junctions, causing LEMS; against the postsynaptic membrane of his neuromuscular junctions, causing myasthenia gravis; and against the potassium ion channels of his motor nerves, causing Issacs syndrome. A talented tumor. Not until thymoma associated multiorgan autoimmunity was described in 2019 had one individual been reported with a thymoma producing so many autoantibodies.3

Patrick had been doing well at his last follow-up visit, about a year after the Issacs syndrome developed, taking low dose prednisone and immunosuppressant medications and receiving periodic plasmapheresis. He continued to work, mostly in a supervisory role.

One day, nearly ten years after I had first met Patrick, I received a message to call Connie.

“Hi, Connie. How are you? How is Patrick?”

“I’m not so good right now. Patrick died.”

It was like a punch in the gut.

“What happened?” I asked.

“Our daughter was getting married and we were all happy. The ceremony was planned for a Saturday afternoon. Patrick was getting dressed. He was going to wear a nice navy-blue suit. He was in our bedroom, standing in front of the dresser, tying his tie, and he had a heart attack. He just died right there. It was shocking. We called 911 and the ambulance came right away but there was nothing they could do. He was already dead. They told us it was sudden cardiac death. We were all devastated.”

“Oh my God, Connie. I don’t know what to say. I’m devastated, too. You know Patrick was special to me.”

And he was. Sometimes the doctor-patient relationship evolves into a different dimension, beyond just the medical care involved, particularly over the course of a long illness and many visits. A unique bond develops at times.

But when a patient dies there are often mixed feelings. There is the sense of loss and bereavement but mixed with it there can be a little guilt and apprehension over whether the physician might bear some responsibility—for having missed an abnormal lab value or x-ray finding for instance, or perhaps for having prescribed a drug that caused a side effect. Could the physician have done something, or failed to do something, that contributed to the patient’s death?

There was none of this with Patrick. He was doing well from a neurological standpoint. He and I had together battled the thymoma successfully for a decade and were in a state of equipoise with it. He had an ordinary heart attack. I had not done or failed to do anything.

I was free to be bereft.