You Are Dr. House

A physician’s assistant from the orthopedic clinic, a talkative, blonde, fifty-something woman, dropped by to ask me to see a patient because of her abnormal gait. I was newly retired from the Army, now working as a civilian contractor at a small Army hospital outside of DC. 

“I saw this patient because of her right foot,” she said. “It was run over by a car because she couldn’t get out of the way. Some kids horsing around. I think she was thirteen. Anyhow, the car started rolling and all the others got out of the way. But not her. Clumsy, I guess. Her foot was crushed pretty badly and she’s had problems with it ever since. She’s thirty-four now.”

“You want me to see her because of her foot?” I said.

“Oh, no, no,” she said. “I was seeing her because of her foot and as she was leaving, I noticed her walking looked pretty abnormal. More than I could explain just because of the foot. No, I think something is wrong with her gait that might be neurologic. Could you take a look at her?”

Tiana came in with her husband a few weeks later. She told me the story about her foot. Then I asked about her walking. 

“What about my walking?” she said.

“They asked me to see you because of the way you walk. Are you having problems walking?”

“Well, yes, but it’s nothing new. I’ve always walked this way. Nothing has changed. My legs are just stiff.”

Tiana’s husband had known her for six years and said her gait had been abnormal for all that time, maybe growing a little worse. She related having pain at times in the thighs and calves, worse with walking, and that her legs often felt weak. She sometimes felt pins and needles in both feet. She denied any problems with her arms or hands. 

I asked if she had ever seen a doctor about her problems walking. She said her parents had taken her to pediatricians when she was small because of her abnormal gait.

“Do you know what they said was wrong?”

“They said I had cerebral palsy.”

I asked about her family history. She told me her father used to drag his feet and walked with a cane. Her mother wound up in a wheelchair, but because of spine surgery. And then she mentioned her older brother. At age 40, her brother was on disability, dragged his feet when he walked, much like Tiana, and sometimes used a wheelchair.

“Do you know what’s wrong with your brother?” I asked.

“They say he has cerebral palsy, too.” she said.

Tiana’s neurologic examination showed she had mild weakness in both legs and marked spasticity in all four extremities. Spasticity refers to an increase in muscle tone with specific characteristics that distinguish it from other conditions causing increased muscle tone. It affects certain muscle groups more than other muscle groups. Spasticity is also velocity dependent, becoming much more pronounced with rapid movements than with slow movements. 

Spasticity occurs with pathology that affects the corticospinal tract, the large white matter tract that originates in the cerebral cortex and conveys signals to motor neurons throughout the entire length of the spinal cord. The corticospinal tract is one of the largest and most important pathways in the entire central nervous system. 

Tiana had abnormally brisk reflexes in both her arms and legs. When I tapped her knees with my reflex hammer, her feet shot out too far and too fast. When I scratched the soles of her feet, her big toes went up, an abnormal finding known as a Babinski sign. 

Brisk reflexes and Babinski signs both indicate corticospinal tract pathology. Her gait showed severe spasticity with “scissoring”—the knees held tightly together, feet on tiptoe and wider apart than knees, the advancing knee sweeping around and in front of the stationary knee with each step, with the trunk swaying side to side to maintain balance.

I explained to Tiana we would do some blood tests and MRIs to look into her problem further. But I already had a pretty good idea, and one thing seemed clear—this was certainly not cerebral palsy. 

The term cerebral palsy originated to refer to children who have neurologic deficits from birth or very early in life. Causes include prematurity, intrauterine infection, congenital brain malformations and perinatal stroke or intracranial hemorrhage. Another cause, less common than once thought, is fetal oxygen deprivation during birth due to such things as maternal hemorrhage, prolonged and difficult delivery, malpresentation and umbilical cord strangulation. 

But physicians often apply the appellation cerebral palsy to any child who fails to achieve normal motor and intellectual milestones for any reason, frequently without much in the way of investigation.

Cerebral palsy has several forms. It frequently, but not always, devastates the intellect. Nowhere is the sparing of the intellect that can occur more dramatically demonstrated than in the TED talk I Got 99 Problems … Palsy Is Just One by a victim of the choreoathetotic form of cerebral palsy, the comedian Maysoon Zayid. 

A third-year medical student with a form of cerebral palsy that often spares the intellect once rotated on my service. She was brilliant. The team always took the elevator as our only concession to her disability. She became a pediatric neurologist and went on to direct the cerebral palsy clinic at a major university medical center. 

One of the most common forms of cerebral palsy causes spastic weakness of both legs, referred to as spastic diplegia. Despite the leg weakness affected patients can walk but have the typical spastic gait with scissoring. The most common cause of this striking gait disturbance is the spastic diplegia form of cerebral palsy. 

But cerebral palsy is not the only cause.

I told Tiana to bring her brother along when she returned for her test results, unofficially, just as a companion. Tiana, a military dependent wife, was eligible for care. Her brother, a civilian, was not. But I could do a quick neurologic exam, off the record, office door closed, and see how whatever he had compared to whatever his sister had.

In terms of neurologic examination, her brother was essentially her twin. Same leg weakness, same spasticity, same brisk reflexes, same gait. Whatever she had, he had.

The MRIs of Tiana’s brain and entire spine showed no abnormality. All the blood tests were normal, including the vitamin B12 and copper levels, critically important in this situation.

After we discussed all the test results, the time came to let them know what I thought. I sat behind my seen-better-days government desk. Tiana and her brother sat side by side across from me, wearing expectant expressions. 

“I’m not sure how to tell you this,” I said, “but neither of you have cerebral palsy.”

Their eyes widened in surprise at this unexpected news, being told a diagnosis they had carried since childhood was wrong.

“What do you think it is then?” asked Tiana’s brother.

“Let me explain. You both know you have spasticity in your legs, right?”

They both nodded.

“When a person has weakness in both legs, as both of you do, we refer to that as paraparesis or paraplegia. When a person has spasticity and paraplegia, we call that spastic paraplegia. Sometimes spastic paraplegia can run in families. You both have it. You both have exactly the same thing. Your neurologic examinations are identical. Your gaits are identical. You have the same condition. You know this is true, right?”

Again, they nodded. Tiana said, “We’ve always known we had the same thing, we just thought we both had cerebral palsy.”

“The problem with that,” I said, “is that cerebral palsy is not hereditary. It does not run in families. The odds of a brother and a sister both having cerebral palsy are remote. Unheard of. No, what you have is hereditary. And your father probably had it too. You told me he dragged his feet and used a cane, right?”

“Yes, he did,” Tiana said. “He died when we were small so I can’t remember much else.”

“Well, from that description and having examined both of you, it’s likely your father had the same thing. There is a condition that runs in families, that is hereditary, and causes spastic paraplegia. It’s called hereditary spastic paraplegia. That is what I think you have. We can do some genetic testing and try to find out for sure.”

Tiana smiled, looked at me and said, “You are Dr. House.”

Hugh Laurie played Dr. Gregory House, the lead character of House, M.D., an American TV show that ran from 2004 to 2012. Dr. House, an irascible, misanthropic, Vicodin-addicted medical wizard and master diagnostician, achieved fame as a precocious and clinically astute medical detective who could figure out difficult cases and ferret out the diagnosis that had eluded other physicians. House had a bad leg and used a cane. I hoped Tiana was comparing me to Dr. House because of his legendary diagnostic skills and not because of his prickly personality.

Hereditary spastic paraplegia (HSP) causes progressive degeneration of the corticospinal tracts that leads to lower extremity weakness and spasticity. Investigators have shown that HSP is not one disease, but a group of familial diseases with similar features. Geneticists have found autosomal dominant, autosomal recessive and X-linked forms. As of now, over one hundred known genetic mutations at different loci on various chromosomes can cause the disease.

Tiana’s genetic testing uncovered no abnormality, but the available testing could only screen for a limited number of the many known causative mutations. The negative genetic testing did not rule out the diagnosis. Her workup had shown no evidence of any other disease process and the family history and her brother’s examination made any other diagnosis unlikely. 

A common misdiagnosis in patients with hereditary spastic paraplegia is the spastic diplegia form of cerebral palsy. 

Tiana worked as a CNA, a Certified Nursing Assistant, a job that involves a lot of walking and physical labor. With her brother already on disability, I thought she could qualify if she wished to apply and was willing to help. I found merely watching her walk painful. Imagining her walking up and down the halls of a hospital all day made my joints hurt. 

Tiana had no interest in applying for disability. She made only one request. She wanted me to write her a prescription for a walking cane. She might get around a little better if she walked with a cane—like Dr. House.

The Comet Line

Oil streaked the windscreen as his engine slowly died, a victim of German anti-aircraft fire. As the crippled fighter limped into French airspace, Rex knew he could not make the channel. He scanned the sky for Luftwaffe as his altitude inexorably dropped. The mottled light and dark green of late spring foliage drifted by beneath him. He looked for a clear space to set the plane down. Streaks and globules of oil made mesmerizing abstract patterns difficult to see through.

He banked toward an open field dotted with the viridescent promise of early planting. Barely clearing the hedgerow surrounding the field, he lifted the nose and pulled off the power. The plane sank. The rich black soil looked soft and inviting, certainly compared to the icy waters of the channel. But he knew the ground was anything but soft.

Rex pulled back on the stick and allowed the stall to settle the aircraft onto the ground. The right landing gear hit first, stuck, and whipped the plane into a ground loop. The sudden angular movement slammed the side of his head into the canopy. When the fighter came to rest, he sat stunned but otherwise unhurt.

The sound of a fist banging on the canopy slowly insinuated itself into his consciousness. Rex swiveled his head toward the racket half expecting to see the telltale shape of a Wehrmacht infantry helmet. He wondered if any others had escaped through the ack-ack and swarm of enemy fighters. He hoped the bombers they had been escorting made it through safely.

Peering through the dirty, oily canopy Rex could barely discern the visage of a young man. The planes of the man’s angular face had not seen a razor in some while, and dark stubble clung to his cheeks and chin. White teeth flashed through the bristles. The young man grabbed the outside handle and began to slide the plexiglass canopy open. Still dazed, Rex felt the helping hands begin to extract him from the aircraft. Standing on the wing, he smelled aviation fuel and looked about for flames, but saw none. 

They both jumped to the ground. The young man shouted, “Courir!” Rex knew minimal French but the meaning was clear as the young man raced toward the treeline, the American close on his heels. They crouched, quiet and still, in the heavy underbrush, looking and listening, for a good quarter hour. A handful of villagers advanced toward the downed airplane. 

“Venir,” the young man said, walking deeper into the woods. Rex followed, hoping he was not being duped and led into Nazi clutches. A short walk led them to a field on the outskirts of a village. The young man crept to the nearest haystack and excavated a hidey-hole, then signaled Rex to join him.

Rex crawled into the scooped-out space. “Reste,” the young man whispered, motioning toward the ground with open palms. He then covered the entrance with armfuls of hay. 

As the sun’s light bled from the sky, the young man returned and extricated the flier. Hunched over, they slipped through the gloaming toward the village. They crouched behind a lichen-incrusted stone wall. They could barely make out the figure of a woman pushing a cart full of laundry, head down, almost at a trot. 

With the laundress out of sight, Rex and the young man leapt over the wall and ran toward the slanted doors behind the nearest house. The young man lugged a door open, and he and Rex went down the steps leading to a coal cellar. Decades of coal dust had stained the white stone walls a dirty gray. A large pile of coal lay in one corner. 

When the young man pulled the door shut, the darkness rendered them both functionally blind. As their eyes adjusted, the young man again whispered, “Reste, reste” and put his finger to his lips. He then walked toward the stairway leading up and into the house, looking back to ensure Rex understood he should stay where he was. 

The young man returned later with bread, cheese, and a bottle of wine. The famished pilot set into the food, leaving only scraps. He then sat on the floor and leaned back against the wall. Safe and satiated, he soon fell asleep. 

Hours later, he heard the door at the head of the stairs open and a shaft of light danced across the cellar. The door closed and flickering candlelight illuminated two figures coming down the stairs, one his savior, the young man, the other a woman. The pair crossed the cellar toward Rex, who stood to meet them.

“Henri,” the young man said, sticking out his hand. 

“Rex.”

Henri gestured toward the woman. “Andrée.” 

“People call me Dédée,” said Andrée Eugénie Adrienne de Jongh in quite decent English. “It’s my code name. It means little mother. They also call me The Postman. You are now a parcel. We’re members of the Resistance and we will take care of you.” 

Rex felt overwhelming relief to learn he had landed in the hands of the Resistance. “Thank God,” he muttered. 

“We’re part of The Comet Line, or Le Réseau Comète,” Dédée said. “My job is to get my children to Spain. Our collaborators there will take you to Gibraltar. You can travel from there back to England. We will hide and feed you. We can concoct convincing false identity papers and outfit you with civilian clothes. We have exfiltrated dozens of Allied soldiers and downed airmen. Trust us and we will get you out.”

Leaving several candles, Dédée and Henri climbed the stairs and went back into the house. Rex fired a match and lit a candle, then resumed his seat on the floor, leaned against the wall, and took a long pull from the bottle of wine. So close, he thought. Only of handful of missions to reach two hundred combat flight hours and a ticket home. What rotten luck.

Feeling the wine, Rex blew out the candle, rested his head against the wall, closed his eyes, and soon felt the warm arms of sleep enveloping him. He awoke to light streaming through a small window high on the cellar wall. Coal motes danced in the sunbeams. Henri appeared with coffee, a croissant, butter, and jam. Rex wondered if he had ever tasted anything so good.

An hour later, Dédée appeared. “I have someone working on your passport and other identity papers. Are you carrying any military identification?”

“ID card and dog tags.”

Dédée scrutinized Rex’s ID card and glanced at his dog tags. “German spies have succeeded in infiltrating the Comet Line on a few occasions. We must vet those we help to be certain they are who they say they are. Tell me the capital of Kentucky.”

Rex’s eyebrows knit and a vertical line flashed above the bridge of his nose. “Louisville. No, wait, might be Lexington.”

“At least I know you’re not a spy.”

“How do you know that?”

“German spies all know the capital of Kentucky is Frankfort. Americans never know that. There are other useful questions. We might ask someone from New York who plays center field for the Yankees. And there’s the typo on your ID card.”

“What typo?”

Dédée held out the ID card and pointed. “See here at the very top. It says NOT A PASS—INDENTIFICATION ONLY. When Nazi spymasters make fake American ID they always correct the spelling error. Gives their agents away immediately.”

“Damn. I never noticed that.”

“So, your ID card and your ignorance say you’re not a spy. We need to get rid of your ID card. Too dangerous to have on you. The Germans found your plane and they’re sniffing around. We’ll sew your dog tags into the cuffs of your trousers when your civilian clothes arrive. The Germans regard Allied service members in civilian clothes or without military identification as spies subject to execution. But you can’t very well escape in uniform. Still having your dog tags might help make the case you are not a spy.”

Rex had not been without his ID card and dog tags since starting basic training. He would feel naked without them but saw the wisdom in Dédée’s advice. 

“Another thing,” Dédée said. “Once we start the trip, be careful not to act too American. No chewing gum. No jingling the change in your pockets. If you smoke, grip the cigarette in the customary European way, between your thumb and index finger.”

After Dédée left, Rex spent the next several hours alternating between pacing laps around the cellar and sitting down leaning against the wall. Too anxious to nap, mind racing, he could not sit for long. Luckily, he didn’t smoke. No risk of giving himself away with such a simple thing as holding a cigarette wrong. 

Henri returned mid-afternoon with bread and cheese, accompanied by a man carrying an armful of clothes: cotton shirt with a wide collar, gabardine trousers, light moleskin jacket, brodequins, and a tweed newsboy cap. 

“I’m Jacques Donney,” the man said. “One of the founders of the Comet Line. They also call me Father Christmas.”

Donney handed the clothes to Rex and Rex handed over his flight suit and combat boots. In his new outfit, he stood for inspection and drew a grin and a thumbs-up from Henri. “You could pass for a native, I should think,” Father Christmas said.

Henri tapped on his own wrist and pointed at Rex. Finally understanding, Rex pulled up his sleeve, revealing a Bulova wristwatch. Henri stared at the timepiece with a frown, then held out his open hand. With a sigh, Rex removed the watch and dropped it into Henri’s palm. After Henri left, Rex resumed his pacing and sitting, feeling both bored and worried. He wished he had some idea of the time.

The light faded from the small window throwing the cellar again into darkness. Rex thought about the many hours devoted to flight training and wished his instructors had devoted more time to training in escape and evasion. 

Dédée returned by candlelight escorted by Jules, a bearded, older man wearing a beret. Dédée explained that Jules would take Rex on the first leg of his journey to Spain as soon as the forger finished his identity papers. She would meet him in Paris.

An hour later, Henri appeared and said, “Venir. Photographier pour passeport.” Although challenged by Henri’s accent, Rex understood the gist of the message. Wearing his new clothes, Rex accompanied Henri on a fast, furtive midnight run to the home of a photographer. 

After three more days in the cellar going crazy with boredom, Rex tucked his new passport into the pocket of his moleskin jacket. He was now Emile Barbier. The pilot walked out of the house to begin his bolt to freedom.

Jules and Rex mounted bicycles and pedaled toward the nearby village of Machault. A Comet Line helper there provided food and the two men shoved off on the next leg of their trip, the one hundred forty kilometer ride to Reims, which would take the rest of the day. Rex wondered if the French of any Nazis they might encounter was any better than his.

His speculations were tested at a checkpoint outside Reims. A German guard speaking pidgin French and Jules speaking pidgin German jabbered past each other while Rex remained quiet and unobtrusive. The guard approached Rex. His unlined face and hesitant manner suggested he belonged in school, not the military. “Reisepass, bitte,” he said, holding out his hand. 

“Emile” swallowed his panic, smiled at the guard, and handed over his passport. The young guard walked back to his partner, who stood by a large sign reading HALT! Together they peered at Rex’s passport. The guard returned, stared intently at Rex, then Jules, then Rex, handed the passport back to Rex and said, “Thanks.” Rex caught himself before blurting out “you’re welcome.” The guards stood back and waved them through. 

Jules and Rex spent the night in a safe house in Reims. The next morning, they pointed their bikes southwest and began the day-long ride to Paris. Virginia d’Albert-Lake, an American expatriate, her French husband, and their helpers filled the bellies of the exhausted travelers and bedded them down on pallets in the basement. Not long after breakfast the next morning, Dédée appeared. She and Jules chattered in French, then she turned to Rex.

“No trouble on your trip, I hear,” she said.

“Only the calluses on my arse,” Rex said.

“So, you speak any French?” Dédée asked.

“Minimal. I can ask where the bathroom is and tell someone I need a doctor. That kind of thing.”

“Well, don’t even try it. Your accent would be a dead giveaway. We’re taking the train from here. Once aboard stick your head in a newspaper and try not to interact with anyone.”

The following day, Rex and Dédée walked toward the imposing facade of the Gare du Nord train station. Rex hauled open one of the heavy doors and followed Dédée inside, into a scene of pandemonium. They stopped and took in the chaos. German soldiers filled the train station, every platform packed, long lines at every ticket window. A tall man wearing a red beret walked past, shaking his head, muttering, “Catastrophe, catastrophe.”

Dédée left Rex standing by a column and walked toward the ticket windows. She was gone so long, Rex began to wonder if he’d been abandoned. Worry mounting, he had started to consider contingency plans when Dédée reappeared and handed him a ticket. On their platform, they inched along in a crowd of gray uniforms toward the train car. They took their assigned seats in a car half full of Wehrmacht soldiers. An officer wearing the uniform and dual lightning bolt insignia of the Waffen-SS occupied a facing seat.

Rex pretended to read his newspaper as the train raced through the countryside toward Tours. Dédée stole glances at the SS officer, who leafed through a sheaf of papers. His gaze eventually flicked up and their eyes locked. He smiled at the attractive young lady, reached for his cigarette case, and offered her a smoke and a light. He tried to start a conversation in German, then English, but she pretended to understand nothing. The smoke tendrils of their cigarettes interlaced and floated upward as Dédée stared out the window. The car reverberated with the boisterous laughter and conversation of the soldiers. 

The SS officer leaned forward, tapped Rex’s knee, motioned for him to follow, then walked toward the restrooms at the back of the car. Rex glanced at Dédée, who continued to look out the window, then rose and followed the officer. After a moment, Dédée stood and ambled behind the two men. 

In the restroom, the German officer tried to engage Rex in conversation, but his French was no better than Rex’s and the American shrugged and stared back blankly. Rex could gather the man was trying to ask about Dédée. Frustrated, the German raised a hand as if to strike, then muttered dummkopf and stormed out the door, nearly knocking Dédée over. 

Rex relaxed a bit when the train pulled into Tours and the SS officer gathered his things and moved toward the exit. About half the soldiers left with him. Rex and Dédée rode on. Most of the remaining soldiers disembarked at the next stop. With no one within earshot, Rex, speaking just above a whisper, asked Dédée to tell him more about the Comet Line. 

Dédée, a nurse and a commercial artist, explained the line stretched almost 2,000 kilometers from Brussels to Gibraltar, through occupied France and Franco’s ostensibly neutral but fascist Spain, both awash with secret police as well as Germans and German sympathizers. She had made over twenty Comet Line runs. She started the escape route with her father, Frederic, financed by selling her small jewelry collection. The line accepted financial support from the British but insisted on operational independence. Most of those in the cadre of helpers were women.  

“And where exactly are we headed?” Rex asked.

“To a farm house near the Spanish border. There we’ll meet the Basque guide who’ll escort us over the Pyrenees to the British Consulate in Bilbao. There a diplomat will pick you up and drive you to Gibraltar. 

“At first, we said goodbye to our escapees in northern Spain and depended on them to find their way to Gibraltar. But we were infiltrated and betrayed. Men were captured and turned over to the Germans.  A man who helped start the Comet Line, Arnold Deppé, was betrayed by an informer and captured. A Belgian collaborator who infiltrated our operation betrayed another of our founders. We worry particularly about the Geheime Feldpolizei, the Wehrmacht’s secret police. Now, we put escapees directly into the hands of the British.”

The train rocked on through the night to the soporific, clickety-clack melody of the rails. The travelers’ heads began to nod. 

They awakened to deceleration and squealing brakes as the train pulled into Bayonne. Rex and Dédée stepped down onto the station platform, glancing surreptitiously for their helpers. A boy of perhaps twelve strolled past, eyes darting about, and jerked his head. Rex and Dédée followed. 

The boy suddenly stopped. Two German guards at a security checkpoint blocked the exit from the train station. The boy turned into a short hallway and stopped outside the door to the men’s room. He motioned for his charges to follow and ducked into the restroom. 

The boy strode to a window and tried to open it. The window would not budge. Rex stepped forward, inserted his strong fingers into a handle at the window’s bottom, braced himself and pulled upward. The window didn’t move. He placed his hands beneath the top rail and pushed. The window creaked and slid open a few inches. He repositioned his feet, crouched a bit, braced his elbows against his torso and shoved. The window slid open. Rex helped the boy and Dédée through, then followed. 

The trio walked down the cobblestone streets of Bayonne, then turned down an alley where they found bicycles leaning against a building. Outside town they slowed and rode gingerly through the inkiness toward the village of Anglet and the home of Elvire de Greef and her family, all pillars of the Comet Line. 

Dédée introduced Rex to Elvire and her teenage daughter Janine. “Elvire’s nickname is Auntie Go. She’s helped many men escape. Tomorrow night our guide will come. His name is Florentino Goikoetxea. He’s a smuggler wanted by both the French and Spanish police. Florentino knows the Pyrenees like his mother’s face, even at night.”

Florentino brought canvas shoes, espadrilles, for Rex and Dédée, a quieter way to travel. He asked Rex to rid himself of any French or British money. If caught in Spain, they could at least avoid charges of currency smuggling.

“The border is treacherous,” Florentino said. “It’s guarded by both French police and Franco’s Guardia Civil, as well as German soldiers. But I know their tricks and routines. I know where they patrol and when. They’ve never come close to catching me. Follow my instructions and I’ll get you through.”

Florentino, Dédée, and her parcel left just before midnight in a light drizzle, walking toward the first hurdle, the mountain Xoldokogaina. They walked along a dirt road beside a raucous, rock-strewn mountain brook and began the climb toward the summit, following winding footpaths known only to smugglers. The rain soon soaked their espadrilles. They fought their way up the mountain, in the dark, in the drizzle, helping each other through difficult passages. 

At the summit, Florentino said, “Stay close,” and the travelers began their descent along a deep ravine beside a stream, navigating over slippery rocks in the blackness. Wet shoes on slick stone made for challenging footing as they dropped toward the Rio Bidasoa. The Bidasoa marked the border. On the other side lay Spain, and freedom.

The river surged with snow melt, straining at its banks. Florentino and Dédée respected the stream’s danger. An escapee and a Comet Line guide had drowned trying to cross it.

Eyeing the raging river, the trio walked toward a suspension footbridge upstream. The rope-sided bridge swayed and juddered in the wind, creaking and groaning. A searchlight played along the span at regular intervals. Unable to see but wary of missing slats, with Florentino leading and Rex trailing, they stepped carefully across the span, towards the far bank, towards Spain, towards liberation. 

They tried to cross quickly, timing their sprint to avoid sweeps of the searchlight. One of Dédée’s feet slipped through the gap made by a missing slat, causing her to fall heavily on her rump, one leg dangling toward the river. Rex and Florentino heard more than saw her fall. Taking care to avoid the same fate, the two men made their way to the terrified woman and lifted her out of the predicament.

“Are you all right?” Rex asked.

“Yes, but that scared the crap out of me,” Dédée said. “Wish we could cross during the day, but that would be too dangerous.”

Finally off the bridge, the trio began to climb toward the next peak, Pagogana. The ascent proved steep and difficult. They hauled themselves up by grabbing roots, small trees, and bushes, leaving cuts and abrasions on their hands. As fingerlets of pink and ochre laced the eastern sky, they walked along a ridge, then steeply down toward a safe house in the Spanish village of Ergolen. 

At the safe house, they enjoyed a breakfast of sausage and eggs. They removed their wet espadrilles, dried their feet, tended to blisters, and rested. After nightfall, they walked along the road toward Oiartzun. 

A black car, engine off, barely visible, sat on the shoulder of the road. Florentino walked carefully toward the car, until he saw the diplomatic plates. He tapped on the driver side window and the startled man inside peered out at the guide he had met so often along this stretch of road. The exhausted travelers piled into the car and began the one-hundred-kilometer drive through the lovely Basque town of San Sebastian and toward Bilbao and the British consulate. 

At the consulate, Dédée introduced Rex to Nigel Robinson, the diplomat who would drive Rex to Gibraltar. They walked to Nigel’s car at the curb in front of the embassy. Dédée said goodbye to Rex and wished him luck, then watched the taillights of Nigel’s car fade into pinpoints and disappear in the traffic. 

The next morning, Dédée began her return trek. She stopped in San Sebastian to meet with another British diplomat, alias Monday, who treated her to dinner in a restaurant overlooking the beach and the bay. After the meal, Monday slipped Dédée a pouch containing several hundred pounds sterling to fund Comet Line operations.

The following day, Dédée and Florentino began the thirty kilometer walk to the French hamlet of Urrugne, back across the mountains, back across the Rio Bidasoa, their destination the safe house operated by Frantxia Usandizanga, a widow with three young children. Dédée knew but paid little attention to a villager named Donato, a villager on the Nazi payroll. 

After a good meal and catching up with Frantxia, the exhausted Dédée retired. The following morning as Frantxia and Dédée sipped coffee, strident knocking erupted at the door and ten German soldiers barged into the house. Barking unintelligible orders, the soldiers handcuffed and arrested the two women. 

Frantxia’s children never saw her again.

Two weeks later, a handcuffed and shackled Dédée, a guard at each elbow, trudged toward the entrance of Fresnes Prison, south of Paris. Next stop: Ravensbrück concentration camp for women. The Vichy press had crowed over the high-profile capture of the leader of the Comet Line. 

Fresnes featured a large mens’ and small womens’ prison. As the guards led Dédée to her cell, the women in all three tiers of the cellblock began to chant: “Dédée, Dédée, Dédée.”

The recognition rained down on Andrée de Jongh, later Countess De Jongh, hero of the Resistance.

Something Fishy Going On

One afternoon a 52-year-old man, a recently retired military intelligence analyst, came to the Walter Reed neurology clinic complaining of the tingles. Scott had already seen several physicians, including two civilian neurologists, and gotten no answers. Lindsey, one of the residents, saw the patient first and presented the case to me. 

Scott looked ex-military: trim, short-haired, neatly dressed. He recounted additional unusual symptoms present for the past several months. Holding his hands out and spreading his fingers, he described having intermittent but frequent numbness and tingling all over, but especially in his hands and feet, as well as fatigue and aching pain in his muscles. He went on to describe a symptom that sounded a bit crazy. He apologized first.

“Sorry, I know this sounds nuts. But I have been having this numbness and tingling that runs up my face in a strip from my chin, up across my forehead, over the top of my head and down into my neck. Comes and goes. It’s really weird.” He held his thumb and forefinger about two inches apart and made a sweeping motion from his chin up over the top of his head. 

That kind of bizarre symptom, not typical of any organic neurological disorder, often elicits eye-rolling behavior in physicians, who immediately discount it as psychological. The possibility of a disorder I had read and heard about but never seen entered my mind, and I asked a critical question, "Have you had anything unusual happen with hot and cold things?"

He looked startled for a moment, then said, "Yes I have, but it sounds so crazy I haven't told anyone, even my wife. When I get in the shower, no matter how hot I turn the water it feels cold. And if I turn the water to cold to see if I can feel that, the cold seems to hurt and feel hot. My hot coffee never seems more than lukewarm. It's really strange."

I posed another critical question, "Do you like seafood?"

Scott related a particular fondness for seafood. He was not the sort of picky, reluctant seafood eater who stuck to lobster, shrimp and scallops, a crustaceanophile. No, he embraced all marine life as potentially edible. Yes, he had eaten grouper. Yes, he had eaten snapper. Were some unusual fish offered at a good seafood restaurant he would likely try it. Barracuda had never presented itself on a menu but if it did he would enjoy some. 

The travel history sometimes becomes important, particularly when faced with an unusual constellation of symptoms or findings. Diseases not endemic to a particular locale may show up unexpectedly because the patient has contracted the condition on a trip, then become symptomatic on returning home. In the age of jet travel, diseases can spread widely and quickly. Ebola virus has a restricted geographic distribution but American physicians had to treat several cases after infected travelers flew home. 

Scott had visited Florida in the past few months but could not recall having eaten seafood while there.

I told him, "I'm beginning to think you may have ciguatera intoxication."

I explained that ciguatoxin, a marine toxin that lurks in the plankton around coral reefs, causes ciguatera intoxication. The little fish eat the plankton, big fish eat the little fish, and so on up to the biggest fish. The ciguatoxin accumulates with each step up the food chain and is present in the highest amounts in large predator fish, such as barracuda, grouper, snapper and amberjack. These are some of the major offenders in a long list of fish that can harbor ciguatoxin. The toxin is tasteless, odorless and colorless. A fish containing ciguatoxin looks, smells and tastes perfectly fine. Cooking does not affect the heat stable toxin.  

Ciguatera intoxication occurs mostly in the tropics. A seafood-loving traveler to the Caribbean had best take care. Ciguatoxin-bearing barracuda became such a problem in south Florida at one point the city of Miami passed an ordinance forbidding restaurants from serving barracuda inside the city limits. Outside the city limits you were on your own. 

The patient does not even have to travel. Sometimes the disease comes to him because fish these days travel, too. Grouper caught off Saint Croix can arrive in Omaha the next day. 

Over several visits, after talking with his wife and perusing his memory banks, the story slowly emerged. He had eaten grouper in a restaurant in Arlington, Virginia. After ingestion, ciguatera typically causes abdominal pain, nausea, vomiting and diarrhea. Scott had developed the GI symptoms within a few hours of eating the grouper and the sensory symptoms began within the next couple of days. He had not made the connection. Why should he? Who expects to develop a tropical disease after eating out in Arlington? Except he did.

The CDC reported six outbreaks of ciguatera poisoning involving twenty-eight people in New York City between August 2010 and July 2011, thirteen from eating barracuda, fifteen from eating grouper. Avoiding consumption of all reef fish is the only sure-fire way to prevent ciguatera. Especially in the days of apparently widespread fish fraud, when what appears on a diner’s plate may not match what the restaurant prints on its menu, what should a seafood lover do? There are no good answers.

Ciguatera is a clinical diagnosis.1 There are no confirmatory tests. Testing the suspect fish source can sometimes confirm the diagnosis, but that opportunity had long since passed. Scott underwent blood tests and some electrical studies of his nerves and muscles—all normal.

Nerve cell membranes have channels through which the sodium and potassium ions that control membrane excitability pass. The flux of these ions controls the membrane potential. Gates control access to the ion channels. With depolarization of the membrane to threshold level, the sodium ion access gates fly open and sodium rushes into the cell, depolarizing the membrane and producing an action potential. 

Ciguatoxin paralyzes the sodium channel gates in the open position. The nerve cells become irritable, firing constantly, never able to rest because the toxin has rendered the cell membranes unstable and hyperexcitable, skittish and jittery, discharging with minimal provocation or firing spontaneously. It’s like having all your nerve endings exposed and constantly overstimulated. A miserable condition. 

Scott, a smart guy, started reading and concluded the symptoms of ciguatera he found sounded a lot like him. We began empiric treatments using agents that block the sodium channel in an attempt to stabilize the hyperexcitable membranes of his sensory nerve cells. He failed to respond to several different medications. There was not much else to do. 

Ciguatera usually causes an illness that resolves in a few days to a few weeks, but some cases become chronic and leave the affected patient suffering for months or years. It appeared Scott would fall into that latter group, doomed to endure cigua-aggravation for a long time.

He began to look for help elsewhere, seeking reassurance about the diagnosis and suggestions regarding treatment. Very few physicians in the world know much about ciguatera intoxication; most doctors have not even heard of it. 

Scott tracked down a tropical medicine specialist in Australia who had seen a lot of ciguatera and published on the topic. He managed to get in touch with the expert, who told Scott he absolutely agreed with the diagnosis of ciguatera intoxication but had nothing to offer in terms of therapeutic suggestions. The patient gradually improved a little but remained fairly symptomatic at followup. 

Daily rounds, or ward rounds, accomplish the work of patient care and involve literally walking around and seeing individual in-patients in the hospital. In a teaching hospital setting, ward rounds typically include the attending physician and the residents, interns and medical students who make up a ward team. 

Grand rounds is a weekly teaching conference, a sit-down affair, usually a lecture, for all the ward teams and others in the department. A visiting professor from out of town or another department often speaks at grand rounds as a subject matter expert. 

Scott, although not a professor, or even a physician, had become an expert on ciguatera intoxication and knew more about it than most doctors. Considering the impressive level of his autodidacticism and his personal insights into the condition, I asked him to give grand rounds. The idea of a patient lecturing to a roomful of doctors produced some blowback but curiosity won out. 

The grand rounds went well. The patient proved articulate, knowledgeable and organized. I stood by to provide backup but he needed no help. He gave a very good lecture, as good as any grand rounds. Never before or since have I attended a grand rounds with a patient as the guest speaker. Perhaps we should do it more often. 

In addition to the scientific content, he described the experience of living with ciguatera intoxication, the daily travails of dealing with the weird sensory symptoms, the fatigue and the muscle aches. Try to imagine, for just a moment, not being able, for the rest of your life, to enjoy a hot shower. He provided a personal perspective no physician or scientist could, and the audience was richer for it. 

I may have had grouper a few times before seeing Scott. Never again.

Sleep Apnea and the Sword Swallower

Polysomnography (PSG), commonly known as a sleep study, is a test in which multiple (poly) recording leads are attached to the patient in order to record (graph) sleep (somn) patterns. The use of PSG to study sleep was introduced by a group of innovative clinicians at Stanford University in the 1970s. They brought the world's attention to obstructive sleep apnea (OSA), now recognized as a very common condition. 

I was introduced to OSA in a lecture by Dr. William Dement, who almost single handedly invented the specialty of sleep medicine. In the lecture he showed dramatic video of affected patients. In OSA, the upper airway becomes lax and intermittently obstructs respiration during deep sleep. The patient awakens many times during the night because of respiratory obstruction. Because of these sleep interruptions, nocturnal sleep is of poor quality, leading to fatigue and excessive daytime sleepiness. A cardinal symptom is obstreperous snoring. Many people snore, especially men. But in OSA the snoring reaches the point where the bed partner wears earplugs, or goes to sleep in another room, or banishes the patient to the sofa. Affected patients are usually overweight men with short, thick necks.

The patient before me in 1980 was a poster child for OSA: obese, with a short, thick neck and a small chin, unable to stay awake. History from his wife confirmed obstreperous snoring and excessive daytime sleepiness. PSG was then only available in a few university medical centers. Small town America had to make do. 

Though we generally credit Dement for alerting the world to the existence of OSA as a syndrome, Charles Dickens described it the Pickwick papers in Joe the Fat Boy, who would “go on errands fast asleep,” and snore as he sat at a table. And medicine for years recognized an obesity-hypoventilation entity called Pickwickian syndrome. 

A CPAP machine is a device that blows a steady stream of air into the throat to prevent it from collapsing during inspiration, preventing respiratory obstruction. Home CPAP machines, now the standard, first-line treatment for OSA, had not yet been invented.

On seeing an OSA patient these days, a PSG would be done to confirm the diagnosis and determine the optimal CPAP pressure, after which the patient would be fitted with a CPAP device for home use. None of this technology existed when I saw my Pickwickian man. None of the other modern therapies for OSA, such as oral appliances and surgery had yet been developed. The only treatment available was tracheotomy, a hole cut into the lower neck, an irreversible, disfiguring procedure. 

In casting about for some way to treat the patient short of tracheotomy I had an idea. When I tell my wife I have an idea, she occasionally says “Luuceee,” using the tone and inflection Desi Arnaz used to address Lucille Ball on the I Love Lucy show when Lucy would tell Desi she had an idea. Many of Lucy's ideas were quite harebrained, and many episodes of the show revolved around the consequences when Lucy would try to put one of her ideas into action.

What followed with this patient might have qualified for an episode on the Lucy show.

An oral airway is a hard rubber or plastic device used for temporary control of the airway, as for resuscitation efforts before placement of an endotracheal tube, or brief periods when a patient may be unconscious and need breathing support. Many sizes are available, pediatric and adult. The usual adult airway is about 4 inches long and is curved to fit along the tongue and press it down into the floor of the mouth, preventing the back of the tongue from interfering with airflow into the lungs. The front of the airway protrudes slightly from between the lips and is often taped in place.

The gag reflex is an involuntary contraction of the muscles of the mouth and throat when a foreign object is inserted into the back of the throat. Most people have experienced the activity of the gag reflex, such as when a doctor inserts a tongue blade to examine the throat. If the tongue blade goes in too far, the patient gags. We sometimes deliberately cause gagging to check for the integrity of the reflex. It is not usually possible to voluntarily suppress the gag reflex, the response is automatic and involuntary.

But some individuals learn to suppress the gag reflex under certain circumstances, and can then tolerate the presence of a foreign object in the throat. If I could train the patient to suppress his gag reflex, then perhaps he could learn to insert an oral airway at bedtime, tape it in place and be able to sleep without respiratory obstruction. But how could he learn to suppress the gag reflex? What sort of people learn to control their gag reflex. There are the obvious erotic implications, but I was not about to go there. Under what other circumstances do people learn to suppress the gag reflex, I thought.

Aha, sword swallowers.

Those people insert large, heavy metal objects into their throats and down their gullets, or at least appear to. How do they learn to do that? I need to talk to a sword swallower. How the heck do you find a sword swallower. This was not a simple proposition pre-Google.

I started by looking up circus in the yellow pages.

When I finally reached someone who knew something about the circus my first question was whether sword swallowing was an illusion, a trick, perhaps a collapsible blade. Masters of the sleight-of-hand can appear to accomplish amazing feats. Was sword swallowing some sort of magician trick? My circus insider assured me it was not, that those swords were real, that people did indeed insert them down their throats. He did not really know any details about how they learned to do it but suggested I talk with one of the practitioners of the art. How do you find a sword swallower? Find a circus and just show up? The circus guy told me that the Ringling Brothers circus was then in winter quarters just outside Sarasota, Florida. 

A few calls later and I was talking to a sword swallower, a pro, a real circus performer. I explained the nature of my call and what I was trying to find out. He graciously agreed to brief me on the ins and outs of sword swallower training. 

"You start with coat hangers," he explained. He went on to describe how the first stage involves inserting a straightened out coat hanger down the throat. "Isn't that difficult?" I asked. "Of course it is. But with patience and persistence you get used to it. I could walk around all day with a coat hanger down my throat and it wouldn't bother me." I tried to picture going about daily affairs with a coat hanger sticking out of my mouth, the other end deep in my gullet. 

Once a trainee can tolerate a single straightened out coat hanger the ante goes up. First the coat hanger is bent to form a double strand squeezed tightly together. Then the strands are widened. Then multiple straight coat hangers taped together, adding hangers gradually until there is a large wad. Each stage takes days to weeks. But by gradually increasing the size of the object and learning how to gently maneuver it down the throat the performer learns to suppress the gag reflex. 

Learners also deliberately trigger the gag reflex by putting other objects down the throat: fingers, spoons, whatever blunt object will work. By gagging over and over they desensitize the reflex. Mastering the trick is difficult and it can take years to learn to swallow a real sword. Then they try to swallow more than one; the world record is fifty-two. Why anyone would want to do this is a mystery to me.

Injuries are not rare. Severe sore throats are common from trauma to the pharynx. Such a "sword throat" is an occupational hazard. As many as a third of sword swallowers eventually suffer a laceration of the throat or a perforation of the esophagus. Major gastrointestinal bleeding occasionally occurs. The Sword Swallowers Hall of Fame lists twenty-nine deaths from sword swallowing injuries over the past one-hundred and fifty years. Sword swallowers helped physicians develop the technique of bronchoscopy in the 1930s. 

George the Giant. the stage name for George McArthur from Bakersfield, Ca., set the official record for the longest sword ever swallowed, thirty-three inches. At seven feet three inches, George has a significant edge in height. He is also a fire eater as well as holding the record for most bricks broken on a man lying on a bed of nails. 

After he had explained sword swallower training, I thanked him and started to say goodbye.

Then, "Let me ask you a question." There was an obvious need to hear him out. He had helped me, and I should try to help him if I could. He went on.

"I am six feet seven inches tall. Theoretically, I should be able to swallow a thirty-five inch sword and set the world record but whenever I try there is a point where I encounter resistance and the sword will not go in any further." 

I tried to visualize the anatomy. Not a gastroenterologist or general surgeon, the best I could think of was that the sword was refusing to pass through the lower esophageal sphincter or impacting the lower part of the stomach.  

He continued, "When I reach that point the sword just stops and won't go in any further, do you think it would be OK if I push?"

A flurry of questions flashed through my decision making centers related to the anatomy, what little I knew about swords, my medicolegal exposure and how fast he might bleed out if he did push. 

I told him that pushing was a supremely bad idea and could result in disaster. When I started to explain the anatomy and the consequences of a GI tract perforation, it quickly became apparent he knew these things as well I did. The real question was what risk he was willing to take to attain sword swallower glory and only he knew the answer.  

When the OSA patient returned for follow-up I told him about my sword swallower consult and how he might go about deconditioning his gag reflex and learning to sleep with an oral airway. I got him a pediatric airway to start with but he could never get the hang of it. It was simply impractical. 

"Luuceee."

Only in my line of work could you start with a question about how to manage a sleep apnea patient and end up learning the world record for swallowing a sword.

Moribund

Moribund

The most frightening thing about covering the ER is the kids, especially the little kids. And what I knew about pediatrics as a senior medical student covering the ER as an unlicensed, pretend ER physician at Aiken Memorial Hospital in Aiken, South Carolina wouldn’t have filled a thimble. Pediatrics was not a required third year rotation and I had not elected to take it in the fourth year. I had learned what little I knew from reading and study. And from almost a year of experience in the ER. I knew that a small child with a deadly serious illness might not look very sick. A child with meningitis might only seem listless with a little fever, in contrast to an adult who would have a high fever and a stiff neck. I lived in fear of missing a case of childhood meningitis.

One relatively quiet evening, the two ER nurses, Christie and Brenda, and I were sitting in the main treatment room chatting when the door burst open and a young black woman rushed in carrying a child of about three who hung limply across her arms. The woman’s face wore an expression of panic. Her voice was urgent as she pleaded, “Please help her. She’s real sick.”

Christie leapt from her seat pointing at the gurney, “Lay her there.”

I said to Brenda, “Call the pediatrician,” then began to examine the child.

The first thing that burst into my consciousness was how cool and clammy she was, almost like touching a corpse. She was completely flaccid, like a rag doll. Had her skin been less dark I would probably have seen the cutaneous lesions immediately, but I didn’t. Her pulse was thready and barely detectable. Christie tried to obtain a blood pressure, shook her head and said, “Nothing.” She was in circulatory collapse. In shock. Her respirations were shallow and sporadic. She was moribund, at death’s door.

As I tried to sort out what to do first, intubation, start an IV, the pediatrician appeared as if by magic. He quickly assessed the situation, then said, “Peds ward, quick.”

He wanted to go to the treatment room on the pediatric ward where he would have all the equipment needed: pediatric size laryngoscope and endotracheal tubes for intubation, pediatric IV sets and, most important, pediatric nurses. I scooped the child up and began to run. She was completely limp in my arms, head lolling. The pediatric ward was on the second floor. I took the steps two at a time. She stopped breathing as I ran through the door to the pediatric ward, the pediatrician holding the door open.

She was in full cardiopulmonary arrest as I laid her on the table in the treatment room. I started mouth to mouth respirations while one of the nurses began chest compressions, one hand on the tiny sternum. The other nurses and the pediatrician began preparations for inserting an endotracheal tube.

This was my first and only personal experience with real live mouth to mouth resuscitation. It’s a good thing because I’m not sure I would have been able to do it again, since after the first few breaths she vomited copious, acrid, sour fluid into my mouth. What do you do in that situation? You spit it out, clear the patient’s airway and resume rescue breathing.

The pediatrician managed to insert the endotracheal tube and we ran the code for about an hour but it was useless. She was gone. Close inspection afterwards showed what looked like scattered hemorrhagic skin lesions. 

Afterwards I was drained and finished my ER shift like a zombie. I felt morose over losing the little girl and exasperated with her mother for waiting so long to bring her in.

A couple days later, my beeper lit up with an Aiken number. It was the pediatrician.

“Bill, that kid we ran the code on. All of the blood cultures are growing meningococcus. She had overwhelming meningococcemia. You and all of your family members need to take chloramphenicol for ten days.”

This diagnosis at least explained how the child had gotten into such an extreme state before her mother brought her in to the hospital. She was infected with the bacterium Neisseria meningitidis, commonly referred to as meningococcus. Neisseria meningitidis is the feared cause of deadly meningitis that often occurs in outbreaks in crowded settings such as day care centers, college dormitories and among military recruits, usually involving older children and adolescents. Many organisms may cause meningitis, but when the average person hears the term meningitis this is the disease they are thinking of. Although meningococcal disease often occurs in outbreaks, most cases are sporadic, especially in young children. Children younger than 5 have poor immunity against meningococcus.

The cardinal signs of meningitis include fever, severe headache and neck stiffness. The diagnosis is straightforward when all these elements are present. But disease, any disease, often presents atypically in the very young and the very old. Even children with meningitis severe enough to cause status epilepticus, repetitive seizures, may not have the classic signs and symptoms of acute bacterial meningitis. (1)

In meningococcemia, the organisms grow, proliferate and circulate in the bloodstream, spreading the infection widely throughout the body so that it involves multiple organs. Most meningococcal infections cause meningitis but some produce meningococcemia as a primary infection, with or without coexistent meningitis. In meningococcemia, the infection can rapidly reach a fulminant, overwhelming state. The fatality rate for meningitis alone is 4-6%, but for meningococcemia it may rise as high as 40%, often leaving survivors with devastating complications. Neisseria meningitidis is a uniquely virulent organism.

Meningococcemia may evolve into a fulminant form and produce circulatory collapse, septic shock, within hours of onset. (2) Herrick, in 1919, said, “No other infection so quickly slays.” (3) Not even Ebola kills as rapidly as fulminant meningococcemia.

Some cases of fulminant meningococcemia with rapid demise are due to a condition called Waterhouse-Friderichsen syndrome, in which low platelets and impaired blood clotting lead to large and small hemorrhages into the skin. The small hemorrhages are called petechiae and the large hemorrhages purpura. Recognizing the hemorrhagic rash is often difficult in dark-skinned patients. In Waterhouse-Friderichsen syndrome, a major contributor to the morbidity and mortality is hemorrhagic necrosis of the adrenal glands leading to severe, acute adrenal failure. Waterhouse-Friderichsen syndrome occurs in 10-20% of children with meningococcemia.

In our case, the child may very well have appeared well or only slightly sick that morning, perhaps listless with a runny nose and low-grade fever, nothing that would have prompted a visit to the doctor. In the first 4-6 hours, meningococcemia tends to mimic a viral upper respiratory infection, before entering a rapidly progressive phase. She may have grown more listless through the day, perhaps vomiting, before abruptly becoming unresponsive and going into septic shock. It’s not that this mother was neglecting her child. No, meningococcus can kill quickly. It could have happened to anyone.

At that time, my family was my wife, Robbie, and two sons, ages 4 and 14 months. The Aiken pediatrician thought all four of us should take chloramphenicol for ten days. There are many other choices for post-meningococcal exposure antibiotic coverage now, but in the spring of 1970 the choices were penicillin and chloramphenicol, and chloramphenicol had the edge in potency against a very virulent organism.

The problem was chloramphenicol’s reputation. The drug was widely feared and seen as the antibiotic of last resort in most clinical situations because of its tendency to cause bone marrow suppression and aplastic anemia. Chloramphenicol is toxic to the bone marrow and predictably causes a drop in hemoglobin above a certain cumulative dose. The most serious, fortunately rare but sometimes fatal, side effect is aplastic anemia. In aplastic anemia, the bone marrow stops producing blood cells of all types: red blood cells, white blood cells and platelets. Examination of the bone marrow shows pancytopenia — all the cells are gone. Lack of red blood cells causes anemia; lack of white blood cells predisposes to infection; lack of platelets causes abnormal bleeding. Untreated, the majority of affected patients die from one of these complications or from transformation into a lymphoproliferative disorder, such as leukemia or lymphoma. Chloramphenicol is featured prominently in any list of the causes of aplastic anemia.

All this was bad enough. I had also heard of something called gray baby syndrome due to chloramphenicol. I did not know much about gray baby syndrome but it just sounded bad. I did not want my baby turning gray.

Robbie and I discussed our situation. I did not tell her every gory detail, kept gray baby syndrome to myself. There was no need to scare her to death. The word meningitis conjures up fright enough. I was scared aplenty for the two of us, afraid of the disease, afraid of the treatment. I decided to get another opinion, maybe even two.

Only a couple of months before, I had done a one-month rotation on the Infectious Disease (ID) service. ID was a subspecialty of Internal Medicine and we spent most of our time roaming around the hospital doing consults and recommending which antibiotics to use in various situations. The Chief of the Division of Infectious Disease was Dr. William Chew, who was an experienced and stellar clinician and an inspiring teacher. I had gotten to know him well enough to drop by his office for a chat. He listened to the story attentively, then said, “I think it would be OK if you took penicillin yourself for ten days. Don’t give your family anything but minimize your contact.”

That meant not holding my baby or hugging my son for ten days. Normally, one of the first things I did when I got home in the evening was sit down with the baby in my lap. That would have to stop temporarily. Small price to pay.

I talked to another faculty member, a junior faculty member, not as experienced as Dr. Chew. She seemed uncertain, then recommended we all take penicillin for ten days.

Decision time. The Aiken pediatrician thought we should all take chloramphenicol. But two medical school faculty members were telling me penicillin was sufficient, so I was not going to expose us to the risks of chloramphenicol. In the end, I took the penicillin and stayed away from the rest of the family for ten days, holding my breath the whole time.

Nothing happened. We were all fine. The little girl was an isolated case, not part of any outbreak, and I did not catch it. But it was a tense and stressful ten days. Every ache, every pain, every kiddie cough and sniffle set us on edge. The last dose of penicillin felt like emancipation.

And the story proves the lesson, once again: it never hurts to get another opinion.

References

1. Chin RF, Neville BG, Scott RC. Meningitis is a common cause of convulsive status epilepticus with fever. Arch Dis Child. 2005;90:66-9.

2. Tabacco J, Suniega E, Sarabchi F, Mitsani D. Fatal meningococcemia. J Community Hosp Intern Med Perspect. 2012 Jan 26;1.

3. Herrick W. Extrameningeal meningococcus infections. Arch Inter Med 1919; 23: 409-18.

Little Men with Big Teeth

This story won first place in the 2022 F. Scott Fitzgerald Literary Festival Short Story Contest. Here are the judges comments. “The story uses the diagnostic language familiar to physicians to advance a complex discussion of the nature of human suffering. In examining Mrs. Fuller, the story's protagonist walks readers through the medical history of diagnosing dementia, presents a treatise on the nature of psychedelic drugs, and reveals both intriguing and mundane facts about neurological disorders. It's a challenging, deceptively warm story that uses heady clinical language to depict the exacting and ultimately empathetic nature of good and caring physicians. This story may at first seem as cold as any other fact-based diagnostic assessment, but the magic of the piece is that, at heart, it's about one person attempting to understand and assist someone who is in clear pain.”

It appeared as a reprint in the Glint Literary Journal in December 2025 and you can read it here: https://glintjournal.wordpress.com/glint-16-creative-nonfiction-william-campbell

He’s Not an Intern

I went to medical school because I wound up in the wrong line on the first day of college. Hard to believe such a momentous decision could hang on such a triviality. Whatever plan I had for college involved nothing more than a general education, certainly not, as my Mom wanted, following in the footsteps of my Methodist minister father. That I rejected.

The high school guidance counselors suggested trying for Emory. It was academically within reach and, as a church-affiliated school, offered scholarships to the children of Methodist ministers. Even though it was an expensive private school otherwise beyond my family’s financial means, a scholarship made it feasible, as long as I earned some money to help support myself. Emory accepted my application.

The first real day of college was registration, held in the gymnasium, a cavernous, old building with all the basketball hoops pulled back out of the way, the bleachers folded back against the walls, the floor ringed with tables and a mob of people milling around, mass chaos, noise and confusion. I joined a long, snaking line that I thought, in the pandemonium, was the correct line for generic, ordinary college. After standing in the queue for what seemed like forever, I finally reached the head of the snake only to discover it was the line intended for students wishing to sign up for the pre-med curriculum.

Although my memory banks remain foggy on the exact discussion at the registration table that day, I know I walked into the gym with no thought of becoming a pre-med student. I know I refused to go to the back of a different line. I know that when I walked out of the gym, I had officially become a pre-med student. Turned out everybody at Emory was pre-something. Pre-dent, no thanks. Pre-law, hell no. Pre-theology, double hell no. So, I stuck with pre-med.

Then it became about the competition. Mostly friendly, not always. My South Georgia high schools had prepared me poorly to go up against the smart, much better educated, big-city kids from Atlanta and Miami, even New York and Boston.

I kept second guessing the decision to stay in that pre-med line, wondering if I really wanted to go to med school. What I really wanted to do was fly. I’d been obsessed with airplanes since boyhood, able to explain the Bernoulli principle and how a jet engine worked at age ten. Model airplanes sat everywhere in my boyhood room and hung on fishing line from the ceiling, all carefully painted and decaled. I could easily tell the difference at a glance between all the WWII fighter planes, knew all about General Claire Chennault and the Flying Tigers. My grandfather had treated me, at about age twelve, to a sightseeing flight that more or less sealed the deal. What I really wanted was to go to flight school. Maybe.

In my sophomore year, I found out about the Marine Corps early commissioning program. They made it easy. Sign on the dotted line and you became a U.S. Marine, stayed in school, did Marine ROTC, went to basic training the next summer, went to Officer Candidate School the following summer and went to flight school on graduation. Sounded attractive. I could become a Marine aviator. My boyhood aspirations realized. They would help pay for school.

I completed the application forms. Put the forms in an envelope. Put on a stamp. Put on my game face. Walked to the nearest mail dropbox. Put the envelope up to the slot.

Pulled it back. Stared at the slot. Walked up to the corner and back to the dropbox. Stared at the slot. Back to the corner. Back to the dropbox. Back to the corner. Back to the dropbox. Back to my dorm room. Had I mailed those forms then, in 1964, I would probably have become not only a Marine Corps aviator but John McCain’s cellmate.

Having to work made it tougher. But I hung in. Then, junior year, came organic chemistry. Organic broke a lot of people. The year before I took it, a tough prof taught the course. Quizzes with a class average in the 30’s were common. I had a roommate from Hong Kong, new to the U.S., who took organic that year.

Steve struggled with English, especially with colloquialisms. He came back to the dorm room after an organic quiz one day asking, “What this mean ‘lose my ass.’ Everybody say ‘lose my ass.’ Please explain.” I slipped into my role as Steve’s Professor of Patois and explained the meaning of his latest encounter with college slang.

The following year, Emory brought in a visiting professor from Agnes Scott College, across town. The way Dr. Clark taught it, though far from easy, organic made sense. Still, the ranks of med school aspirants thinned after organic.

The university discouraged students from working during the first year, so my first college job was as an admissions clerk at Emory University Hospital as soon as freshman year ended in June, through that summer and for the next academic year. The job itself was not bad. The challenge was kicking out of bed on a Saturday or Sunday morning while everyone else slept in, especially after a late, hard partying and drinking night. The only sound accompanying my footfalls out the door at 6:30 A.M. was the snoring of my classmates. Learning to drink was part of the curriculum and the lessons were sometimes brutal.

I craved involvement in patient care and applied for a position as an orderly. I was inclined toward medical school at that point as an intellectual exercise, but needed to know whether I could handle the trenches, the blood and guts. The training classes started in early summer and mine was the only white face in the crowd of about a dozen. Many of the others were older men who would need to support families on the same pittance.

We learned how to give a bed bath, how to change the sheets with the patient still in the bed, how to take vital signs and much more. The nurses proved exacting instructors. They assigned me to the surgery ward, full time during the summer and part time during the school year, mostly weekends.

One of my tasks that summer was to apply Witch Hazel compresses three times a shift to a man’s massive hemorrhoids. I had only a vague idea what a hemorrhoid was so gulped with shock on first looking at these slimy, gray-pink lumps the size of lemons bulging from the man’s rectum. Here was a wealthy, high-powered Atlanta businessman laid low by the most mundane of ailments. All his money and influence could not protect him from the veins in his rectum deciding to go on strike.

I had probably not yet run across the word cachexia when assigned another patient that summer, a middle-aged man with terminal cancer. Sparse, brown hair clung to his always sweaty forehead. His sunken eyes, small orbs peering out from deep in a gaunt face, seemed to reflect despair and resignation. His joints stuck out from his stick-like extremities like a pig freshly swallowed by a python. When I would turn him or move him during bed baths, he weighed about as much as a garden hoe.

He never seemed inclined to talk much, made few demands. After several weeks of this, I came in one day to find him gone. The nurses hardly mentioned it. Just shrugged.

Working on the surgery ward, dealing with surgeons, naturally led to the idea of becoming a surgeon. I asked one of the vascular surgeons to let me go to the OR. The case he allowed me to watch was a woman undergoing an aortobifemoral bypass graft for occlusive vascular disease, obstructed arteries to the legs. The kindly nurses told me what to do to stay out of trouble—stand over there, don’t touch anything. I couldn’t see much but one scene riveted itself into my memory banks.

The aorta lies in the retroperitoneum, a space behind the abdominal cavity. In order to access the aorta and graft it to the occluded iliofemoral arteries that supply the legs, the surgeon had to move the abdominal contents, mostly the intestines, out of the way. So, he took the woman’s intestines, mainly her small bowel—coiled, wet, slippery, pink tubing many feet long—and struggled to put the bowel into a transparent plastic bag, about the size of a small, kitchen garbage bag.

When he finished, a plastic bag of guts hung over the side of the table, fastened securely in place with sterile clips, as he went about dissecting the retroperitoneum and preparing the aorta for grafting. I can still see that bag of guts hanging over the side of the table.

The summer before senior year I requested a transfer to the Emergency Room. I thought the job might prove more interesting. And it was. My primary function was to help the general surgery residents who covered the ER. I would room the patient and take their vital signs, retrieve any x-rays and assist with any procedures.

In those days, the mid-1960’s, all the men working at Emory Hospital wore the same uniform: white trousers and a short sleeve white shirt, supplied crisply starched by the hospital laundry, with a hospital logo over the left breast pocket. The only way to know who was who was that the residents were all white and the orderlies were all Black, except for me. The ER residents of course knew I was just a college student and an orderly.

That summer a new orthopedist, Dr. Hunter, a recently retired Army Colonel, joined the faculty and began to visit the ER periodically when on call. Dr. Hunter, a friendly, jolly man, had a salt-and-pepper crew cut and a middle that was getting out of regulation.

In the course of my orderly responsibilities, I would frequently retrieve the films on someone with a suspected fracture, and, in the treatment room, snap a film into the x-ray view box for him to review. Sometimes, he would ask me a question about it. The film might look fairly normal and he would say, “What do you see?”

I would stare at the x-ray, knowing it was a film of the radius and ulna but not much else, seeing nothing obvious amiss.

“Looks OK to me.”

“Don’t you see the fracture?”

“No, Sir.”

“Look at the medial aspect of the radius.”

Medial/lateral—these are concepts from week one of medical school, but I had no idea what he was talking about.

“Run your finger along the medial aspect of the radius.”

I would invariably put my finger in the wrong spot.

“Jesus, Son.”

Or, sometimes, a grossly obvious fracture might stare out at me, and he would say, “What kind of fracture is that?”

“I don’t know, Sir.”

“That’s a Colles fracture. You’ve heard of a Colles fracture, haven’t you?”

“No, Sir.”

“Jesus, Son.”

One day an ambulance delivered us an auto accident victim with a broken leg. Dr. Hunter came in to help. After things settled down, I joined a group gathered in the large, main treatment room finally applying the cast. Helping Dr. Hunter were two surgery residents who frequently covered the ER and knew me well. Dr. Hunter kept up a running patter, cracking jokes but also teaching and asking the residents questions. Then at one point he turned and asked me a question, an orthopedic question.

One of the residents looked at him and said, “Dr. Hunter, he doesn’t know the answer to that, he’s just an orderly. He’s a college student.”

At that, Dr. Hunter threw back his head and laughed, and laughed and laughed. When he at last regained control of himself, he looked at me, flashed his endearing smile and said, “Jesus, Son, you have no idea how glad I am to hear that. All this time I’ve been thinking you were an intern. In fact, I’ve been thinking you were the dumbest, damn intern I’d ever seen.”

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.”

References

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2. Kasarskis EJ, Winslow M. When did Lou Gehrig's personal illness begin? Neurology. 1989 Sep;39(9):1243-5.

3. Traynor BJ, Codd MB, Corr B, Forde C, et al. Amyotrophic lateral sclerosis mimic yndromes: a population-based study. Arch Neurol. 2000 Jan;57(1):109-13.

4. Patten BM, Pages M. Severe neurological disease associated with hyperparathyroidism. Ann Neurol. 1984 May;15(5):453-6.

5. Patten BM, Engel WK. Phosphate and parathyroid disorders associated with the syndrome of amyotrophic lateral sclerosis. Adv Neurol. 1982;36:181-200.

6. Patten BM, Bilezikian JP, Mallette LE, Prince A, et al. Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med. 1974 Feb;80(2):182-93.

7. Patten BM, Mallette LE. Motor neuron disease: retrospective study of associated abnormalities. Dis Nerv Syst. 1976 Jun;37(6):318-21.

8. Vicale CT. The diagnostic features of a muscular syndrome resulting from hyperparathyroidism, osteomalacia owing to renal tubular acidosis, and perhaps to related disorders of calcium metabolism. Trans. Am. Neurol. Assoc. 1949:74;143-147.

9. Aran FA. Recherches sur une maladie non encore decrite du systeme musculaire (atrophie musculaire progressive). Arch Gen Med 1850;24:5-35,172-214.

10. Livesley B, Sissons CE. Chronic lead intoxication mimicking motor neurone disease. Br Med J. 1968 Nov 9;4(5627):387-8.

11. Campbell AM, Williams ER, Barltrop D. Motor neurone disease and exposure to lead. J Neurol Neurosurg Psychiatry. 1970 Dec;33(6):877-85.

12. Currier RD, Haerer AF. Amyotrophic lateral sclerosis and metallic toxins. Arch Environ Health. 1968 Nov;17(5):712-9.

13. Boothby JA, DeJesus PV, Rowland LP. Reversible forms of motor neuron disease. Lead "neuritis". Arch Neurol. 1974 Jul;31(1):18-23.

14. Morgan BW, Barnes L, Parramore CS, Kaufmann RB. Elevated blood lead levels associated with the consumption of moonshine among emergency department patients in Atlanta, Georgia. Ann Emerg Med. 2003 Sep;42(3):351-8.

15. Kathuria P. Lead Toxicity. https://emedicine.medscape.com/article/1174752-overview. Accessed December 16, 2024.

16. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. New Engl J Med 2001;344:1688-700.

17. Pestronk A, Cornblath DR, Ilyas AA, Baba H, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol. 1988 Jul;24(1):73-8.

18. Lewis RA, Sumner AJ, Brown MJ, Asbury AK. Multifocal demyelinating neuropathy with persistent conduction block. Neurology. 1982 Sep;32(9):958-64.

19. Lewis RA. Multifocal motor neuropathy and Lewis Sumner syndrome: two distinct entities. Muscle Nerve. 1999 Dec;22(12):1738-9.

20. Parry GJ, Clarke S. Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve. 1988 Feb;11(2):103-7.

21. Di Bella P, Logullo F, Dionisi L, Danni M, et al. Chronic multifocal demyelinating neuropathy simulating motor neuron disease. Ital J Neurol Sci. 1991 Feb;12(1):113-8.

22. Bentes C, de Carvalho M, Evangelista T, Sales-Luís ML. Multifocal motor neuropathy mimicking motor neuron disease: nine cases. J Neurol Sci. 1999 Oct 31;169(1-2):76-9.

23. Evangelista T, Carvalho M, Conceição I, Pinto A, et al. Motor neuropathies mimicking amyotrophic lateral sclerosis/motor neuron disease. J Neurol Sci. 1996 Aug;139 Suppl:95-8.

24. American Association of Electrodiagnostic Medicine, Olney RK. Guidelines in electrodiagnostic medicine. Consensus criteria for the diagnosis of partial conduction block. Muscle Nerve Suppl. 1999;8:S225-9.

25. Olney RK, Lomen-Hoerth C. Exit strategies in ALS: an influence of depression or despair? Neurology. 2005 Jul 12;65(1):9-10.

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.