Chasing Zebras

There’s a saying in medicine—when you hear hoofbeats, think horses not zebras. The maxim reminds physicians that common things are common. A patient with fever and a cough probably has a viral upper respiratory infection, not anthrax. The aphorism is all well and good, except when the horse is an inexorably progressive, untreatable and inevitably fatal disease, when the horse is ALS. Then you have to be absolutely certain this thing that appears to be a horse is not a zebra in disguise.

Ronnie, a young guy, distressingly young at thirty-five, seemed far too young to have ALS. Most patients develop the disease in their sixties or seventies. But it can strike younger people too. I had seen it in a nineteen-year-old. Anytime a disease, any disease, has atypical features diagnostic caution warnings flare, and onset outside the expected age range is certainly an atypical feature. Lou Gehrig became symptomatic at Ronnie’s age.

Ronnie had a pleasant, engaging manner and a quick smile. I viewed this niceness as a bad sign. Most experienced neurologists will agree ALS has a peculiar predilection to attack nice people and spare mean people.

Ronnie was an in-patient on the neurology service at the VA hospital and the ward team had requested an EMG. I knew of their concern about possible ALS, and the EMG would prove pivotal in his diagnostic evaluation.

Except for his age, things looked all too familiar. When we met in the EMG lab, I asked about his weakness. His faintly vermilion cheeks shone through a two-day stubble that matched his reddish blond hair.

“It started about a year ago in my right hand,” he said, “and it’s been getting worse and worse and now it’s in my left hand.”

“Is there any pain?” I asked.

“No,” he replied.

We were starting off badly—painless weakness is one of the characteristic features of ALS. The disease usually starts asymmetrically, causing weakness and muscle atrophy involving one hand or one foot, spreads relentlessly to the rest of that extremity and to other extremities, then eventually involves the diaphragm, leading to respiratory failure.

The progressive weakness is largely due to degeneration of the motor neurons of the spinal cord. When the disease spreads to the brainstem, which contains the nerve cells that control speech and swallowing, patients develop dysarthria (slurred speech) and dysphagia (difficulty swallowing).

The disease typically runs a course of three to five years from onset to death—sometimes more, sometimes less. It has no effect on the mind. Patients remain excruciatingly aware of the ravages taking place, of the merciless progression, of every lost function. One man described it as having a front row seat at his own dissolution.

“Have you had any leg weakness?” I asked.

“No,” Ronnie said.

This meant he might be destined to develop the dangling arms, or flail arm, variant, in which the patient’s arms and hands become completely paralyzed and useless while the legs and head remain relatively unaffected. The patient becomes helpless, but can still walk, speak and swallow. Eventually, the disease spreads, but the dangling arms phase may last a year or two.

Ronnie’s exam showed the expected weakness, as well as muscle atrophy, in both arms and both hands. There were occasional fasciculations—small, random, focal muscle twitches—in his arms and hands. Fasciculations can occur for other reasons, but in the setting of suspected ALS they are supportive evidence of the disease.

He also had hyperactive reflexes. On tapping each knee with the reflex hammer, his foot shot out too far and too fast. The reflexes were abnormally quick in both his arms and his legs, on both sides. The combination of muscle atrophy and hyperactive reflexes in an extremity is virtually diagnostic of ALS. Nothing else does that, even in a thirty-five-year-old.

ALS is the acronym for amyotrophic lateral sclerosis. The term, first proposed by Charcot, the famous nineteenth century French neurologist, comes as close to perfect as any in medicine because it describes both the clinical and pathological features of the disease.1

Myo is the combining form for muscle and amyotrophic describes the wasting away of the muscles that occurs in the disease. The clinical manifestations of the amyotrophy are weakness and muscle atrophy. Muscle biopsy shows the pathologic manifestations of denervation, the changes that occur when a muscle fails to receive its normal nerve supply.

Sclerosis means hardening, and lateral sclerosis refers to the abnormal firmness neuropathologists can feel when palpating the lateral part of the freshly cut spinal cord. The primary structure occupying the lateral part of the spinal cord is the large white matter tract, the corticospinal tract, that connects the upper motor neurons in the cerebral cortex with the lower motor neurons in the spinal cord.

ALS causes degeneration of both the upper and the lower motor neurons. Degeneration of the upper motor neurons causes the lateral sclerosis felt by the pathologist and the spasticity and hyperactive reflexes found on clinical examination. Degeneration of the lower motor neurons causes the denervation seen by the pathologist in the muscle biopsy and the weakness and muscle atrophy found on clinical examination. Amyotrophic lateral sclerosis concisely describes all of these features. Since it causes degeneration of the motor neurons, ALS is also referred to as motor neuron disease.

ALS is known popularly as Lou Gehrig’s disease because Lou Gehrig developed it late in his baseball career. ALS has claimed many famous victims—politicians, entertainers and athletes. But none so famous as Lou Gehrig.

A careful analysis of his baseball statistics showed that the disease may have begun in 1937, certainly by 1938, and probably started in his legs.2 The first manifestation was a decline in singles and doubles. He still had the arm power to hit home runs, but could not reach first base on a marginally hit ball and had lost the leg speed for a double. He kept working to get his legs in shape. The Yankees kept him on the roster even as the disease ravaged him, until he finally benched himself in May, 1939, when he considered himself a burden to his teammates. After all, he was the legendary Lou Gehrig.

He died in 1941 at the age of thirty-seven.

We know that certain diseases can mimic the clinical picture of ALS.3 Some of these mimickers are treatable. The evaluation of an ALS patient includes a search for conditions known to mimic it, but all of them are rare, all of them are zebras. Almost inevitably the search proves futile—all the tests are normal. But in Ronnie’s case I got teased.

His EMG showed diffuse denervation—loss of nerve supply—consistent with ALS. His initial labs showed an elevated serum calcium concentration. Not extremely high, only a little high. On repeat, it was high again. But it did not remain consistently high and was never extremely high.

Among the various causes for an elevated serum calcium, a prime consideration in an apparently healthy young man is hyperparathyroidism, overactivity of the parathyroid glands. The parathyroid glands control calcium and phosphate metabolism by secreting parathyroid hormone. There are four parathyroid glands, two on each side, located behind the thyroid gland in the neck. The most common cause of hyperparathyroidism is a benign tumor, an adenoma, of one of the glands.

I was riveted on Ronnie’s calcium levels, largely because of papers written by a neurologist, Dr. Bernie Patten, in Houston. Papers with titles like: Severe neurological disease associated with hyperparathyroidism; Phosphate and parathyroid disorders associated with the syndrome of amyotrophic lateral sclerosis; Neuromuscular disease in primary hyperparathyroidism; and Motor neuron disease: retrospective study of associated abnormalities.4-7

The last paper included discussion of the discovery that patients with hyperparathyroidism may have features resembling ALS. During residency, following leads in Patten’s papers, I had gone rummaging in the musty old stacks of the UCSF library and pulled a 1949 paper by Carmine Vicale from the Presbyterian Hospital in New York.8

Vicale reported muscle weakness in 21 of 33 cases of parathyroid adenoma. The essential features of the syndrome he described—weakness, muscle atrophy and hyperactive reflexes. The paper contains this line: “ . . . it most closely resembles amyotrophic lateral sclerosis, because there is atrophic muscular weakness with overactive deep reflexes.” No joke.

Damn right Ronnie’s calcium levels had my attention. But nobody else’s.

The lab documented slightly elevated urinary calcium excretion. Ultrasound examination of his neck showed no evidence of a parathyroid tumor. No CT or MRI of the neck available then.

The typical patient with hyperparathyroidism has more dramatic and sustained calcium elevations. The endocrinology consult team brushed me off. I upped the conversation from resident level, to fellow level and finally attending to attending. I showed them the papers about the potential association between ALS and hyperparathyroidism. They did not think he had it and offered no further suggestions.

Ronnie began to haunt my personal time. He went with me on runs, kept me company in the car, helped me spawn schemes.

These were the days before the internet, before Google and email. I wrote Bernie Patten, describing the case, including all the lab values, asking if I was off base worrying about hyperparathyroidism in this patient. He just egged me on.

I conspired to seek a second endocrinology opinion, not easy to do on an in-patient in your own hospital. From the library, I retrieved Cecil’s Textbook of Medicine and Harrisons Principles of Internal Medicine, found the names of the physicians who had written the sections on hyperparathyroidism and wrote them letters with the lab values and case details. They graciously made suggestions about additional testing but our endocrinologists again expressed no further interest in the case and offered no assistance. They now clearly viewed me as a pest.

One of my outside consultants suggested an empiric neck exploration to look for a parathyroid adenoma. I approached the surgery service about exploring Ronnie’s neck. The surgery attending, a full professor who had been at the institution for decades, would later become the Chair of Surgery and then Dean of the MCV School of Medicine. I was just a young assistant professor. Only an adept medical politician rises to the rank of Dean. He remained collegial but no dice.

There was nothing further to do. Ronnie grew weaker and weaker, gradually wasting away, his voice reduced to an incomprehensible whisper. All ALS patients eventually reach a point requiring a decision regarding ventilatory support. In such a young man and with this lingering doubt in the air, he agreed to tracheostomy and a ventilator.

For some strange reason, the disease spares two groups of motor neurons: those that control the eyes and those that control the bladder. They placed Ronnie in a four-man room for chronic ventilator patients on the pulmonary service elsewhere in the hospital. I would drop by to see him from time to time.

He eventually lost all voluntary movement except for the ability to move his big, blue eyes and flex his right big toe. The quick smile disappeared; his lips hung slack and toneless. I do not know to this day whether we missed a case of hyperparathyroidism masquerading as ALS. Probably not, considering the lack of a serious tease from that zebra again from a legion of ALS patients over the next 35 years.

But other zebras taunted me, like lead poisoning.

While Ronnie lay wasting away on the pulmonary service, suffering through the bag of bones stage of terminal ALS, a diminutive, talkative, Italian grandpa, Antonio Pellegrino, came to my neuromuscular clinic at the VA one afternoon for suspected ALS.

I struggled to get his story because he would talk about anything but his physical symptoms: the weather, sports, his grandkids, the traffic, how long it had taken him to find a parking spot. Voluble, loquacious, garrulous, no adjective can do justice to the talkativeness of the man. He was very animated—smiling, constantly gesticulating, waving and pointing his fingers, dramatizing his accented English as if he were conducting an orchestral score of his conversation.

Mr. Pellegrino was simply one of those people who never has an unuttered thought. Kellyanne Conway burst onto the political scene in 2016 as an adviser to the Trump campaign and instantly became notorious for her devoid-of-content, double-speak loquaciousness. Dan Rather, known for his Texas witticisms, said, “That woman could talk the legs off a table.” So it was with Mr. Pellegrino.

The patient’s clinical picture appeared typical for ALS, and I saw no reason to question the diagnosis. But something came up in his history. Part of the medical history is the social history and part of the social history includes asking about the patient’s occupation. Plus, I often inquire about occupation even when it’s not strictly required, as when doing an EMG, because it helps me get to know the patient and makes the day more interesting. You never know what you might hear or who you might meet.

A professional photographer advised me during his EMG to never believe what I saw on a magazine cover and explained some of the trickery they use. I saw the engineer who built the space shuttle runway. He told me it is so vast a Cessna 172 can take off across it, and not even need the whole width of the runway. I’ve met writers, detectives, chefs, judges, professional musicians and retired generals.

I asked Mr. Pellegrino, “What do you do for a living?”

“I’m retired,” he said.

“Retired from what?”

“I was a painter.”

“You were an artist?” I said, hopefully, sensing trouble.

He laughed. “No, I wasn’t an artist.”

This must mean he had been a house painter. I knew a problem would inevitably arise, as I looked at this seventy-three-year-old man who probably spent much of his career handling paint while it still contained lead. Only under relentless pressure did manufacturers finally remove lead from house paint in 1978.

The suspicion about a link between ALS and exposure to lead dates back to the eighteenth century. The original paper on motor neuron disease by Aran, in 1850, cited Gerard van Swieten, a prominent eighteenth-century Dutch physician, as having been the first to note a possible association.9 (Patten, personal communication) Three of Aran’s eleven patients had been exposed to lead and two had overt lead poisoning.

Famous neurologic pioneers, such as Dr. Kinnier Wilson and Sir William Gowers, wrote about a possible association between lead and ALS at the turn of the twentieth century. Over the years, papers appeared with titles such as: Chronic lead intoxication mimicking motor neuron disease; Motor neurone disease and exposure to lead; and Amyotrophic lateral sclerosis and metallic toxins.10-12

Some of these papers described patients who responded to treatment to remove lead from their systems. In 1974, Dr. Lewis P. Rowland, an esteemed neurologist then Chairman of Neurology at the prestigious Neurological Institute of New York at Columbia University served as senior author of a paper titled Reversible Forms of Motor Neuron Disease: Lead “Neuritis.”

The paper reported a patient who appeared to have ALS but who had evidence of lead poisoning and improved after treatment to remove the lead.13 As an aside in that paper, Dr. Rowland mentioned reviewing seventy-nine cases of autopsy proven ALS and finding two house painters who suffered attacks of abdominal colic attributed to lead intoxication.

The heavy metals are elements with a high atomic number that occupy a cluster in the periodic table. For medical purposes the heavy metals include lead, arsenic, mercury and cadmium, because of their toxicity to humans.

A standard method to screen for possible lead intoxication is to collect a twenty-four-hour urine for heavy metals. The lab then determines the concentration of the elements in each milliliter of urine. Knowing the total amount of urine, it then calculates how much of each metal the patient excreted in twenty-four hours. We have reference values to know whether or not the excretion falls within the normal range.

However, in the face of serious concern about lead intoxication, a twenty-four-hour urine for heavy metals is inadequate, does not cut it, is just going through the motions. A standard part of the workup for ALS for years, decades, included twenty-four-hour urines for heavy metals but nobody really considered lead intoxication even a remote possibility in most patients.

I happened to know a lot about lead poisoning because of where and when I went to medical school. At the Medical College of Georgia, the possibility came up often. Before the outbreak of lead toxicity due to contaminated water in Flint, Michigan, in 2014, people generally thought of lead poisoning as something associated with kids ingesting contaminated paint chips in old houses. But in Georgia, in the late 1960s, on the Internal Medicine service, we saw patients with lead poisoning from drinking moonshine.

Lead is a multisystem toxin. It came up as a possible diagnosis in patients with such common conditions as chronic renal failure, anemia, peripheral neuropathy and gout—especially gout. Any medical student caring for a patient with gout could count on a question during attending rounds about saturnine gout. Saturnine as in dark, as in moon, as in moonshine, as in Saturnalia, or maybe because most of the drinking occurred on Saturday night. Whatever the etymology, saturnine gout is gout due to lead toxicity.

Talk on rounds would sometimes turn to how lead could get into moonshine. Seems the moonshiners took care to use copper pipes when building their stills but would join the copper pipes with lead solder. The distillate flowing through the pipes would then leach the lead from the solder. Now, sellers offer solid copper stills online. Some moonshiners would use a lead lined car radiator as a condenser in the still or store the illicit liquor in a radiator. This is not something of purely historical interest. Patients continue to show up in ERs with lead poisoning from drinking moonshine.14

Because of experiences from medical school and intern days, I did not consider simply checking a blood lead level, or a twenty-four-hour urine for heavy metals, an adequate workup for Mr. Pellegrino. After an acute episode of intoxication, the body removes the lead from the circulation and sequesters it in the tissues and bones. Hides it away.

The half-life of a compound refers to the time required for its concentration to decrease to half of its original value. Scientists often use the half-life in reference to radioactive isotopes. The half-life of plutonium-239 is 24,300 years. Lead has a half-life of about thirty days in the blood.15 From the blood, it diffuses into the kidneys, liver, bone marrow and brain before settling in the bones. The half-life in bone can run several decades. Increased bone turnover due to aging, menopause, immobilization, osteoporosis and various diseases and medications may then release lead back into the circulation.

Making a diagnosis of lead intoxication in the chronic phase, when the lead is sequestered, requires a process called chelation, done by administering calcium EDTA (ethylenediaminetetraacetic acid). EDTA binds the lead, removing it from its hiding places, and carrying it to the kidney for excretion in the urine.

Diagnostic chelation involves collecting a baseline twenty-four-hour urine collection, then administering a dose of EDTA and repeating the twenty-four-hour urine collection. An increase in lead excretion by a certain amount proves the patient harbors a significant body burden of lead. If the diagnostic chelation is positive, the patient undergoes a series of therapeutic chelations, five-day courses of EDTA to remove the lead, separated by equilibration periods and intermittent diagnostic chelations to assess the current body burden.

Removing lead is a long, complex process.

All this went through my mind in a flash when I thought Mr. Pellegrino might have been a house painter. Then he upped the ante.

“No, I was a sign painter,” he said, smiling. “My specialty was small signs. Like painting names on doors, or the name of a business on a window. Sometimes I did the detail work to finish a big sign, like the small lettering and the little curlicues and flourishes. You had to have a steady hand.”

“I guess you handled a lot of paint,” I said.

“I had to keep a sharp point on my brush, so I would dip the tip of the brush in the paint, get just the right amount on it, then touch it to my tongue. Touching the brush to my tongue helped to sharpen it. Then I would paint.”

“You touched the brush to your tongue?” I asked, aghast.

“Sure did. That might have been my secret, how I got such fine details.”

A typical child with pica might eat paint chips during its toddlerhood, maybe a couple of years. It seems the lead contaminated chips taste sweet, so kids can acquire a taste and go looking for them. Consider the damage that can do. And here I had a man who may have ingested lead contaminated paint almost every day for decades.

Case 2 in Campbell, et al’s 1970 report of lead associated motor neuron disease described a woman who had worked with lead pigments and glazes during fours years of art school, beginning at age 18, and “admitted to sucking her paint brushes to keep a fine point on them.” 11 They postulated this four-year exposure to lead resulted in ALS developing eighteen years later. Her exposure was trivial compared to my little Italian grandpa.

The lab found no elevation of Mr. Pellegrino’s blood lead level, expected because he had not suffered any exposure since his retirement from sign painting several years before. I knew if he harbored any lead in his body, the evil molecules had hidden themselves in his bones and soft tissues. I admitted him for a diagnostic chelation.

Lead poured from his body like rain from a Florida thunderstorm. The lab technicians double checked and recalibrated their equipment, then repeated the assays and calculations. There was nothing wrong with their equipment. Mr. Pellegrino had an astronomical body burden of lead.

We admitted him every four to six weeks for therapeutic chelations over the next year. The intermittent diagnostic chelations showed a falling body lead burden, but his ALS progressed relentlessly. The disease paid us no mind. It considered our efforts minor obstacles in its path and flicked us aside like the 1932 Yankees did to all their competition. That was the year Lou Gehrig hit four home runs in one game and Babe Ruth hit his memorable called shot home run in game three of the World Series.

Eventually, diagnostic chelation showed no more mobilizable lead in Mr. Pellegrino’s system. It was gone. The disease had reached a point where dysarthria made him even more difficult to understand, and his wasted hands lay in his lap when he spoke. No more conducting.

We missed his visits to clinic after he died. He was an entertaining patient, a delightful man.

His autopsy showed the classic neuropathology of ALS. We had successfully removed all the lead and it had not affected the course of the disease. Whether the lead might have directly affected the motor neurons, or induced the motor neuron degeneration, which then pursued its typical course, or whether the ALS and the patient’s body lead burden had nothing to do with each other, we will never know. In a paper in 2001, Dr. Rowland commented that there had not been a convincing report of heavy metal induced motor neuron disease for twenty-five years.16

The next zebra to come loping over the horizon was a condition called multifocal motor neuropathy (MMN). Researchers from Johns Hopkins University coined the term in a 1988 paper describing two patients with a disorder involving the motor fibers of multiple peripheral nerves in the upper extremities, sparing sensory fibers.17 Both patients had presented with painless, progressive, asymmetric upper extremity weakness and both were initially though to have ALS. But their nerve conduction studies showed striking abnormalities never seen in ALS.

We perform motor nerve conduction studies by recording the electrical signal from a muscle after stimulating the nerve that innervates the muscle at two or more points. The size, or amplitude, of a muscle’s resulting electrical signal depends, in part, on the number of nerve fibers supplying the muscle.

Imagine a group of ten sprinters at the starting line of a one-hundred-yard dash. The starter fires his pistol. A snapshot at the ten-yard line would show a tightly grouped pack of runners. Their density might translate into a hypothetical electrical signal of a certain size. Because of variations in footspeed, a snapshot at the finish line would show a more spread out group of runners. Their decreased density might translate into a hypothetical electrical signal of a slightly smaller size.

If the ten-yard line represents the wrist and the finish line the elbow, the size of the electrical signal should not decrease by more than 20% between the wrist and the elbow. We refer to this as physiologic temporal dispersion. It is normal and expected because not all the individual axons that make up a peripheral nerve conduct impulses at the same velocity, like variations in footspeed among the runners.

Now imagine that halfway down the track, three runners collide and fall in a heap, all spraining an ankle, all unable to continue. They never finish the race. Only seven runners cross the finish line. The hypothetical electrical signal at the finish line becomes much smaller than could be attributed to variations in footspeed. This is analogous to the phenomenon of conduction block, in which a localized disease process affecting some axons renders them unable to conduct an impulse. The size of the electrical signal at the elbow decreases by more than 20%.

The clinical situation is naturally more complicated than this parable, but it illustrates the basic concept. Distinguishing between temporal dispersion and conduction block became critical in the clinical decision making involving ALS patients.

The patients in the Johns Hopkins paper describing MMN had conduction block in the involved nerves on nerve conduction studies. Conduction block on nerve conduction studies does not occur in ALS. Ever. The Hopkins patients also had high titers of antibodies to a chemical component of their peripheral nerves, a ganglioside called GM1.

The Johns Hopkins patients did not respond to treatment with prednisone or plasma exchange, the standard treatments for a neuropathy causing conduction block, but did respond to Cytoxan (cyclophosphamide). So, the Hopkins researchers had reported two patients initially thought to have ALS, who had conduction block on nerve conduction studies and antibodies to GM1 ganglioside, and who responded to treatment with Cytoxan.

The only problem is that Cytoxan is a very toxic drug. Nasty stuff. First used as chemotherapy for conditions such as leukemia in the 1960s, it has many unpleasant side effects. It can make your hair fall out, kill your white blood cells, rot your liver and cause bladder hemorrhage. Not to mention the nausea and vomiting. These are only a sample off the full list of side effects.

In the late 1980s and 1990s, papers appeared with titles such as: Chronic multifocal demyelinating neuropathy simulating motor neuron disease, Multifocal motor neuropathy mimicking motor neuron disease and Motor neuropathies mimicking amyotrophic lateral sclerosis/motor neuron disease.21-23 In a large Irish study, the most common ALS mimic was MMN.3 Understandably, neurologists became a bit obsessed with not missing MMN in patients who appeared to have ALS.

The AANEM convened a panel to develop consensus criteria for distinguishing between temporal dispersion and true conduction block. The head of the panel and lead author of the paper that followed was Dr. Richard K. Olney, the Director of the ALS Treatment and Research Center at UCSF.24 Rick was a stellar physician and researcher and an esteemed colleague, highly regarded yet unpretentious and always amiable. Everyone considered Rick Olney a nice guy.

The AANEM conduction block paper appeared in 1999. In 2003, Rick noticed problems with his right leg. His doctors thought he had a lumbar disk herniation and he underwent surgery, but the weakness progressed and Rick soon knew he had ALS. Legs again. Like Gehrig.

Physicians he had trained cared for Rick in the ALS center he had founded. Even as his own illness progressed, he continued to study it.25 He enrolled as the first patient in a clinical trial he had designed before his diagnosis. Rick Olney died in 2012, at age sixty-four. The AANEM honored his memory by creating the Richard K. Olney lecture, given annually at its association meeting.

Rick survived eight years. The disease treated another ALS researcher, Dr. Lisa Krivickas of Harvard, less leniently. Lisa and I knew each other as colleagues on the Board of Directors of the American Board of Electrodiagnostic Medicine, our certifying organization. She made it only a little over two years from the time she told us in a board meeting she had ALS until she died. Lisa was forty-five. The disease had taken her mother when Lisa was young. She devoted her life to fighting it only to have the disease assassinate her in the prime of life.

In 2017, Dr. Rahul Desikan, a prominent researcher in the field of neurodegenerative diseases, including ALS, at UCSF, found he had ALS. He died in July 2019 of rapidly progressive ALS.

It almost seems as if the disease is an evil, sentient entity intent on tracking down and eliminating the specific people trying to find a cure for it.

And sometimes, when it comes to these zebras, even when you win, you lose.

Many patients referred to the Richmond VA hospital come from the nearby, small VA hospital in Beckley, WV. I called some of these Beckley patients my mountain men, for many were large, bearded fellows who looked as if their usual daily dress could easily have been buckskins.

One of my mountain men had MMN. He had severe, bilateral, asymmetric, upper extremity weakness particularly prominent in his finger extensors. On holding his arms out straight, his fingers would droop, different fingers to different degrees on the two hands, like some complex gang sign. There was no atrophy, and no fasciculations or upper motor neuron signs. Nerve conduction studies showed conduction block. The lab reported the presence of GM1 antibodies at an impressive titer. The clinical picture fit MMN. It did not look like ALS.

And he responded to Cytoxan, without major complications or side effects. The weakness essentially resolved. He returned for follow-up about every 3 months. I would walk into the exam room and ask, “How are you doing?” In response, with a big grin, he would just hold out his hands, fingers all straight, like little soldiers snapping to attention, in formation, nobody drooping. We would check his labs at each visit, and over the course of about three years everything had been fine, rock solid.

Then, after one visit, his complete blood count report showed an unusual abnormality. With Cytoxan, the usual hematologic side effect is a depression of the white blood cell count. With this report, my mountain man’s white cells looked fine. Not so his red cells. He had anemia and microscopic examination of the blood smear showed immature red cells called ringed sideroblasts mixed with the normal red blood cells.

One of the fortunately rare side effects of Cytoxan is that it can cause malignancy. Strange that a drug used to treat malignancies can then cause malignancy, but it can. He underwent an evaluation by the hematology service. They concluded the anemia and sideroblasts were a manifestation of a condition referred to as myelodysplasia, which had been induced by the Cytoxan therapy. Myelodysplasia often evolves into leukemia. He could receive no further Cytoxan treatment. Hematology declared it absolutely contraindicated.

I had found and successfully treated a case of MMN, and the therapy had caused the patient to develop a condition that posed a greater threat to his life than the MMN had. Great.

In my semi-retirement job in private practice, I agreed to work in a worried and upset patient for a neuromuscular consult. One of my partners had seen her for leg weakness and ordered an EMG, which had been done by another of my partners. Someone I trusted.

The study showed a picture suspicious for motor neuron disease. The EMG report communicated this impression in the usual carefully worded clinical language. The patient’s family physician received a copy and then apparently told the patient she had ALS. This is a far cry from how we usually work up and eventually ease into breaking the bad news to an ALS patient. The patient, in distress, called my partner who had ordered the EMG and I agreed to see her expeditiously.

She was, unfortunately, a nice lady. She had dark, reddish-brown hair and hazel eyes. Her legs had already grown so weak she needed a walker. Her attire showed concessions to difficulty with mobility. I suspected she had once been a snappy dresser.

“Excuse me,” I said. “I’m going to get someone to help me move you to the exam table.”

I soon returned with a nurse, who took one elbow as I took the other. The patient still had enough leg strength to step onto the footstool and hoist herself with a little help onto the exam table. The nurse and I removed her sneakers and socks and rolled up the legs of her sweatpants.

The leg weakness was obvious, both to her and to me. But, although she did not realize it she also had slight weakness in her arms and hands. Fasciculations danced and rippled across her shoulders and chest. A close look revealed them in her calves as well. She had abnormally brisk reflexes in both the arms and legs. I already knew her EMG had shown denervation in all four extremities. There could be little doubt about the diagnosis.

She had already been told she had ALS and the situation demanded I tell her this was probably correct. Then we went over the work-up. I told her certain conditions could mimic ALS and what they were, but that they were rare, that they were zebras, but we would test for them.

I told her I had been looking for a zebra for many years and not found one. And I told her about the new treatment we had for ALS. Then newly approved by the FDA, edaravone appeared to slow progression of the disease by about one-third. I suggested she get the testing done, then seek a second opinion. Balancing hope and honesty. Difficult.

All her testing was normal. She had ALS. A couple months later, she sent me a card. It read:

“Hope all is well and that you are cool. Would like to thank you for your kindness and gentle ways with me. I shall remember you for sure. I’m most sorry I could not be a zebra for you. Good luck on fighting the dragons. From an auburn horse.”