Images in Historical Pediatrics: 

Albrecht Durer (1471-1528) was one of the great painters of the German Renaissance and helped bring the Italian principles of perspective an classicism into northern Europe. As with all great artists he had a keen eye for human anatomy, and perhaps even neuromuscular pathology. What physical finding does the child in this painting have?

 

Madonna and Child, 1498

 Answer (highlight to see): Erb's Palsy aka "waiter's tip"

Case Records of the Historical Grand Rounds:
Case 7: Felix Mendelssohn 

Felix Mendelssohn-Bartholdy, 1809-1847

Felix Mendelssohn was one of the great yet under appreciated composers of the German-romantic movement. Born into a wealthy Jewish family, he was the grandson of the famous rabbinic philosopher Moses Mendelssohn, though abandoned Judaism to live as an assimilated protestant. He was known as one of the great virtuoso pianists of his age and his compositions are now appreciated for their melancholic, restrained romanticism that never quite abandons the classical age.

Despite being a product of the romantic era, Mendelssohn was staunchly conservative in his musical tastes. His enthusiasm for baroque music, J.S. Bach in particular, revived the public’s interest in these works an elevated Bach from a largely forgotten church organist to a composer of historical importance. He clashed with many of his colleagues, but his sensibilities found a welcome home in England, where he premiered most of his works. The British Royal family even used a piece from his opera A Midsummer Night’s Dream for Princess Victoria’s wedding in 1858. The tradition endures to this day. 

The Mendelssohn family had a history of premature deaths that was unfortunately passed on to Felix. His grandfather, father, and two sisters all died of what appeared to be a series of strokes separated by years with seizure-like symptoms in between. Felix's first stroke occurred at the age of 30 and presented as tingling and temporary loss of function in his hands. A similar event took place seven years later, around the time his sister Fanny died from “apoplexy”. This rendered him speechless for some time. In the following days he had two more strokes that made him immobile and caused him severe headaches described as “a foreign body wanting to impress itself forcefully into his head”. He became delirious and died after a few fruitless attempts by his doctors to revive him with leeches and vinegar massages. Considering his strong family history, it is possible he suffered from an autosomal dominant syndrome that often presents with multiple strokes before age 50. What is it?

Spring Song:

Wedding March: https://www.youtube.com/watch?v=z0wmzoHd6yo

Answer: CADASIL syndrome (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

Images in Historical Medicine: 
 A mummy from the 21st dynasty of Egypt (~1000 BC)
 

Hint: the photo on the right shows evidence of a psoas abscess

 
Answer (highlight to see): Pott's disease

Case Records of the Historical Grand Rounds:
Case 6: Walter Payton

Walter Payton (1953-1999) playing for the Chicago Bears

One of the greatest players in the history of American football, Walter Payton was known for his exceptional skill and toughness, missing only a single game during his record-setting thirteen seasons in the NFL. He was also known as a very kind and generous man off the field, earning him the nickname “Sweetness” among his fans and teammates. Twelve years after his retirement, he held a press conference announcing that he was suffering from a rare disease and would need a liver transplant to survive. His doctors commented that the condition had caused Walter to lose a lot of weight, and “wasn’t related to alcohol, steroids, hepatitis, or immune deficiency.” It also went unnoticed for years before he presented with weight loss, fatigue, and most likely pruritus. As the disease progressed he became increasingly incapacitated and needed stents placed in his common bile duct.

In his last few months, Payton become a strong advocate for organ transplantation and began several campaigns to raise awareness and encourage people to register as donors. While awaiting an organ at the Mayo Clinic, Walter was further diagnosed with a malignancy that is a known complication of his condition. After he passed away later that year, the issue of organ donation became a major headline nationwide, and there was a surge in the number of people trying to register as donors. A foundation created during his lifetime continues to fight for this cause today. What condition did he have and what was the malignancy he died from?

Answer (highlight to see):
Primary sclerosing cholangitis, complicated by cholangiocarcinoma.

Case Records of the Historical Grand Rounds:
Case 5: Ernest Hemingway

Ernest Hemingway, 1899-1961

In 1960, after a 40 year career as an inspired author and war reporter, Ernest Hemingway arrived at the Mayo Clinic seeking treatment for his severe depression. Treatments were limited at the time, though his case was so severe that his doctors decided to try several rounds of electric shock therapy. Unfortunately their attempts did more harm than good, and only served to worsen his already declining memory, ending his writing career for good. They also happened to discover that Hemingway had a whole host of other medical problems that demanded attention. For many years he suffered from severe arthritis that was particularly advanced for a man of his age. He also had a long history of diabetes and had clear signs of cirrhosis. At the time his doctors thought years of alcoholism were likely responsible, though no unifying diagnosis was made. During his two month stay at the Mayo Clinic, he was also diagnosed with a heart condition that today would likely be labeled "congestive heart failure with preserved ejection fraction".

In 1961, Hemingway returned for another round of electric shock therapy which was again ineffective. Later that year he committed suicide as a result of his longstanding depression, chronic pain, and declining mental capabilities. While none of his individual problems are particularly rare, medical records released 30 years later reveal a single unifying diagnosis made shortly before his death. It is something surprisingly common among those of Northern European heritage, and may even have contributed to his depression and cognitive decline. What is it? Also, which characteristic type of arthritis may he have had?

Answer:
Hemochromatosis (diabetes, cirrhosis, restrictive cardiomyopathy, iron deposits in the brain). These patients are particularly prone to pseudogout.

Case Records of the Historical Grand Rounds:
Case 4: Eleanor Roosevelt

 

Eleanor Roosevelt (1884-1962) serving as UN ambassador

Undoubtedly one of the most prominent and influential women in American history, Eleanor Roosevelt became known as the "First Lady of the World" for her human rights work and extensive social activism. She also helped form the foundation of FDR's career, and was instrumental in his reentry into politics following his paralysis from poliomyelitis. The disease that ultimately lead to her death is somewhat complicated and controversial, so for the sake of objectivity I will present it from the perspective of a physician seeing her during a hospital stay in July, 1962. All details are public record of course.

A 78 year-old woman with a history of aplastic anemia (diagnosed in 1960) presents with a chief complaint of fever. For the past four days she has recorded fevers up to 104F along with chills and night sweats. The fever has been persistent and began two days after a routine blood transfusion. She has noticed low-grade fevers after transfusions in the past but nothing this severe. She also endorses a non-productive cough that has been worsening over the past 2-3 weeks, as well as weakness, fatigue, and easy bruisability that have been worsening over the past four months. Review of systems is otherwise negative. She has been receiving regular blood transfusions for the past year to treat chronic macrocytic anemia and thrombocytopenia. She was started on 20mg prednisone three months ago to help with her increased symptom burden and "stimulate the growth of red blood cells and bone marrow." Her most recent hemoglobin was 7.9 and a bone marrow biopsy from last year showed hypocellularity with 5% myeloblasts. She has no known sick contacts or recent travel, but has been to the middle-east and sub-Saharan Africa several times over the past decade.

On exam the patient is febrile (104.5F) and appeared fatigued with scattered ecchymoses and conjunctival pallor. Examination of the heart, lung, and abdomen revealed no abnormal findings. There was no photophobia or neck stiffness. Laboratory findings included pancytopenia and an ESR of 128. Chest x-ray done shortly after admission showed scarred lungs but no signs of acute infection. Blood cultures were drawn and the patient was placed on empiric penicillin and streptomycin, though they were discontinued on day 4 as cultures showed no growth. Repeat bone marrow aspiration showed no changes from her previous study. Six days after admission the patient's fever went down to 99F and an extensive conversation was held regarding goals of care. The patient said she would never want to die in a hospital and expressed an interest in returning home. She was subsequently discharged with a diagnosis of "Fever of Unknown Origin".

While there is a wide differential for Eleanor's acute presentation, which single diagnosis explains her entire medical history? What test would you have sent (in 1962) to confirm it?

Answer (highlight to see): 
Diagnosis: Miliary tuberculosis with bone marrow infiltration 
Test: acid fast smear and culture from a bone marrow biopsy

Rheumatology (2nd Edition)

1. Nobel laureate Dorothy Hodgkin was one of the great British scientists of the 20th century. Her discovery of protein crystallography gave her the tools to describe the structure of many key biomolecules for the first time, including insulin and vitamin B12. The picture below illustrates a classic physical finding of her rheumatic disease, the extent of which is rarely seen in our age of disease-modifying drugs.

Dorothy Hodgkin, 1910-1994

2. Once again we visit the medical records of King George the VI. As mentioned in a previous post, one of the ways he dealt with his famous speech impediment was chronic cigarette smoking. This eventually lead to severe COPD, lung cancer, and a total left lung resection. In his last years he also suffered from episodes of pain, rash, and signs of decreased perfusion in his feet. During one episode in 1949, the arterial occlusion was so severe that his doctors severed his lumbar sympathetic nerves to avoid having to amputate his leg. The procedure was a relative success, and the king retained the use of his limbs until his death from coronary artery disease in 1953. Apart from atherosclerosis, what possible disease was the king suffering from?

3. In 1665, Rembrandt painted a portrait of fellow Dutch artist Gerard de Lairesse. Little is known about the medical history of this man, but the painting shows a very unique physical finding. What are two rheumatic diseases that could lead to this deformity, and what did he most likely have?

Gerard de Lairesse, 1641-1711

4. The annals of ancient medical history do not offer a wealth of rheumatology cases. However, one passage from Hippocrates gives a very clear description of a specific autoimmune disease. It wasn't until 1937 that the modern medical community fully described the condition.

"There were other fevers also, which I shall describe in due course. Many had aphthae and sores in the mouth. Fluxes about the genitals were copious; sores, tumours external and internal; the swellings which appear in the groin. Watery inflammations of the eyes, chronic and painful. Growths on the eyelids, external and internal, in many cases destroying the sight, which are called "figs". There were also often growths on other sores, particularly in the genitals. Many carbuncles in the summer, and other affections called "rot". Large pustules. Many had large tetters (herpetes)."

Hippocrates refusing the gifts of artaxerxes, 1792. by Anne Louis Girodet

5. In the later years of his acting career, Sir Laurence Olivier's poor health forced him to take smaller roles in "undistinguished films" due to his extreme weakness and fatigue. In 1974, he spent over three months in the hospital due to proximal muscle weakness and pain. After he recovered, he resumed his acting career, and a still from his 1976 movie Marathon Man shows the remnants of a subtle skin finding that may point to his diagnosis. What is it?

Take a close look at the hands.

6. Opera singer Maria Callas also had her career interrupted by this autoimmune disease. It began in 1958 during a performance for the Italian President. She was forced to leave during intermission because of weakness in her vocal chords and a sudden inability to control fluctuations in her voice. She was initially diagnosed with acute tracheitis, but as this became a chronic problem her personal doctor also noted her chronic generalized hypotonia, somnolence, and red discolorations around the base of her neck. She began symptomatic cortisone injections, but many critics commented on her gradual vocal decline and unsteadiness. She ultimately succumbed to cardiovascular complications of the disease (or possibly treatment) at the age of 53.

One of her most celebrated arias, from the opera Norma

7. One more exercise in physical diagnosis:

Michael Jackson, 1958-2009

 Answers: (highlight to see)
1. Rheumatoid Arthritis
2. Thromboangiitis Obliterans (Buerger's Disease)
3. Relapsing polychondritis, granulomatosis with polyangiitis. Most likely congenital syphilis.
4. Behcet's disease
5. Dermatomyositis - Gottron papules
6. Dermatomyositis
7. Malar rash (Discoid lupus in this case)

Case Records of the Historical Grand Rounds:
Case 3: Georgiana Cavendish, Duchess of Devonshire

Georgiana Cavendish, 1757-1806

Today we will discuss a condition that received prominent mention in our anatomy lectures, despite there being almost no reported cases of it in over 50 years. Georgiana, Duchess of Devonshire became a commanding presence in the realm of politics, fashion, and high society at a time when women were seldom known to do so. At the age of 17 she married the most powerful Duke in England and immediately became a social celebrity. This was all up until the Duke grew tired of their marriage and took her best friend as his mistress, sending Georgiana into a downward spiral that included a string of scandalous affairs, crippling debts, and a whole host of other social embarrassments. This is all addressed quite decently in the movie The Duchess (2008).

These hardships were made worse by an eye problem that struck her at the age of 35. Georgiana often complained of migraine-like headaches and vague eye pain, but one night she went to bed with a headache that developed into excruciating right eye pain and swelling. She also complained of nausea, vomiting, and photosensitivity. Apparently her screams were so loud  her children had to be transferred to a different estate. Three or four days into the episode she lost the ability to move the right eye and was permanently confined to a dark room. It is unclear whether or not she had a fever though there were definite chills and diaphoresis, which worsened with the development of a corneal ulceration. The left eye was also mildly swollen. The most esteemed physicians of the day were called, including the "Senior Surgeon-Extraordinary to the King", who recommended attaching leeches to the eye and partial strangulation to flush the eye of excess blood. These efforts were not terribly successful. Her mother Lady Spencer described her appearance: (read carefully...)

"The inflammation has been so great that the eye, the eyelids and the adjacent parts were swelled to the size of your hand doubled, and projecting forward from the face. Every attempt was made to lower this inflammation so as to prevent any ulceration, but this has been in vain. A small ulcer has formed on top of the cornea and has burst, and as far as that reaches the injury is not to be recovered. If the inflammation should increase, the ulcer form again, and again burst, it would destroy the whole substance of the eye, which would then sink. The eyelids are still much swelled and scarred with the leeches, and the little opening between them is always filled with a thick white matter... The eye itself, to those who see it (for I cannot) is still more horrible."

Lady Spencer to Ms. Sarah Trimmer, August 4th, 1796

Over the course of several weeks the swelling and headaches subsided, but the Duchess could still only make out shapes with the affected eye and needed to be kept in a dark room for months. She became increasingly frail over the next few years and had recurrent bouts of fever and headache. Charles Darwin's grandfather, Erasmus Darwin, even tried treating her with electric shock therapy to help with her vision, unfortunately without much success. Some wrote that she managed to re-enter society with great courage and a new-found confidence, though she never fully regained her vision or former appearance. She died of complications from a liver abcess at the age of 48. 

So what pathological event do you think was the most likely cause of the Duchess's eye problem?

The Duchess famously used her allure for political gain, trading kisses for votes at election rallies

Answer: (highlight to see)
Cavernous sinus thrombosis (orbital cellulitis is a less likely cause of exophthalmos and chemosis)

Case Records of the Historical Grand Rounds:
Case 2: Miles Davis

Regarded as one the most influential musicians of the 20th century, Miles Davis epitomized the style, individuality, and improvisation commonly associated with jazz music. The son of a wealthy dentist, he was sent to study music at Julliard Academy in the 1940s, but left after growing tired of their emphasis on Classical style. He went on to have a successful but turbulent career that was interrupted on several occasions by his numerous medical conditions. In addition to suffering from poorly controlled type II diabetes and several bouts of alcohol and drug abuse, he began having crippling joint pain in his late twenties that forced him to temporarily retire from public performance. By the 1960s he was playing in almost "constant pain" and frequently self-medicated with alcohol and narcotic drugs. His later years were also marked by severe back pain, episodes of abdominal pain leading to a cholecystectomy, and a hip replacement for a "collapsed segment of bone". He died in 1991 after a hospitalization for a stroke lead to a rapidly-progressing episode of pneumonia. Throughout his life he rarely spoke about his illness and only mentions it briefly in his autobiography. Which congenital condition ties all of his symptoms together?

Miles Dewey Davis III (1926-1991)

 

Answer (highlight to see): Sickle-Cell Anemia (Vaso-occlusive crises, avascular necrosis, gallstones, stroke, pneumococcal bacteremia)

Images in Historical Medicine: Edith Piaf

 

The famous French singer suffered from severe Rheumatoid Arthritis in her later years. Note the MCP, PIP, and wrist deformity with spared DIP joints.

Case Records of the Historical Grand Rounds: 
Case 1: A Fever of Unknown Origin

In 1935, a renowned physician named E.H. Derrick was sent to the Australian countryside to investigate a mysterious illness plaguing workers in the meat-packing industry. The patients were all men who were otherwise healthy, and the onset of the illness was similar to that of a common viral illness: fever, malaise, headache, anorexia, and muscle pains. However, over time the fever became more intense, and rose dramatically once every day or two, putting the patients into a stuporous state. In most patients the fevers lasted two to three weeks, then subsided with only supportive care. Other unusual features noted by the doctor included a slow pulse rate, severe headaches with photophobia, and weakness that lasted for months after resolution of the other symptoms. All blood cultures and agglutination tests were negative, as were separate tests for various forms of typhoid fever. Doctors also noticed that a few of the patients who recovered had mysterious episodes of culture-negative endocarditis years later. The medical community referred to the illness as "the query" for two years before the immunologist and future Nobel laureate Sir Frank Burnet discovered the etiology of the disease. What was it?

Australian pathologist Sir Edward Derrick (1898-1976)

 





















Answer: (highlight to see)
 Q fever (Q stands for Query), Pathogen is Coxiella Burnetii, named for the two doctors who discovered it.

Dear Friends,

It saddens me to present the last full edition of the Historical Grand Rounds. We've had a good run, but thankfully the labors of coursework are behind us and there is less of a need for distraction. However, to keep myself occupied I will still post a case now and then during third year, perhaps one per month, so I encourage you to check the website once in a while. As those around us embrace the doldrums and despondency of board examinations, I hope you friends of mine maintain the spirit for learning that sets you apart.

-Michael


Pulmonology

 

1. Named after the Greek word meaning "unextinguishable," this material has been wreaking havoc on the lungs of mediterranean people for over 4000 years. Its first documented use was making fire-proof tablecloths (The Emperor Charlemagne used his to amaze party guests), and in the mid 1800s it was incorporated into a whole host of other industrial products. One notable epidemic was that of Greek women who would mix the material with white paint for their houses, making them resistant to fire and giving them a nice clean look. Unfortunately, many of these women started getting specific types of pulmonary malignancies in the 1960s and 70s. What histological finding would you expect to see in the most common tumor-type associated with this material?

a. psammoma bodies wrong, mesothelioma less common
b. atypical epithelial cells within the bronchial mucosa correct, bronchogenic carcinoma
c. keratin pearls and intracellular bridges
d. pleomorphic giant cells
e. nests of neuroendocrine cells

(The correct answer will have "correct" written in white font next to it. Highlight to see.)

2. George Orwell's life was a chronicle of pulmonic misfortunes. Born in India in 1903, he spent his early years suffering from numerous bouts of bronchitis and non-descript lung infections. After later episodes of dengue fever, tuberculosis, and years of heavy smoking, he finally retired to Northern Scotland where he would write his greatest work. Some say the torture scenes in 1984 were even inspired by a procedure he went through to collapse the cavitary lesions from his TB. Soon after completing the book, he died of a  condition characterized by copious amounts of purulent sputum, hemoptysis, dilated airways, and recurrent infections. What was the most likely causative factor in his final illness?

a. chronic allergies
b. defective ion transport wrong, no GI symptoms
c. lung scarring and fibrosis
d. poor ciliary motility correct, bronchiectasis as a consequence of smoking
e. viral URI


Eric Arthur Blair (aka George Orwell), 1903-1950


3. Baruch Spinoza was a Portuguese Jew who became one of the greatest philosophical minds of the 17th century. After being excommunicated from the Jewish community for his rationalist thinking, he lived a simple life as a lens grinder, spending hours each day inhaling fine glass dust. He died at the age of 44, allegedly of a serious lung illness purported to be tuberculosis. Which of the following describes the condition that made him more susceptible to this infection?

a. calcification of the hilar lymph nodes correct, silicosis
b. macrophages laden with carbon
c. calcified pleural plaques
d. pneumoconiosis affecting primarily the lower lobes
e. noncaseating granulomas


4. The now famous King George VI, father to Queen Elizabeth II, had a lifelong stammer that he dealt with by smoking (with some additional help from his Australian speech therapist). Somewhat ironically, he later developed lung cancer and was forced to undergo a pneumonectomy of his left lung, leaving him unable to speak more than a couple sentences at a time. His last few broadcast speeches had to be recorded in sections and edited together. What is the best physiological description of his lung function after the surgery?

a. increase V/Q ratio
b. decreased FEV1/FVC ratio   
c. decreased FiO2
d. increased FEV1/FCV ratio
e. decreased V/Q ratio correct, same air volume, twice the blood flow




Albert Windsor (George VI), 1895-1952


5. The story of Patrick Bouvier Kennedy is not well known, since his death was overshadowed a few months later by his father's assassination. Born at 29 weeks gestation to First Lady Jacqueline Kennedy in 1963, he developed infant respiratory distress syndrome soon after birth, and died two days later following treatment in a hyperbaric chamber. At that time no other treatments were in place, but his death sparked a push in research on prematurity that lead to several important innovations. What modern day treatment would have been most likely to help Patrick?

a. inhaled glucocorticoids
b. i.v. glucocorticoids
c. maternal steroids before birth correct
d. albuterol
e. bosentan




Nephrology

Not the most fruitful topic when it comes to Historical cases... However, one clever case appears in the work of Charles Dickens. Tiny Tim, the son of Ebenezer Scrooge's clerk Mr. Cratchit, suffered from a short stature, asymmetric crippling, and episodes of weakness that would have lead to his death had Scrooge not dreamt of his tombstone and decided to pay for his medical treatment. The most plausible explanation for his symptoms is renal tubular acidosis type I, which, left untreated, leads to osteomalacia, paralysis, and death by renal failure. What treatment would have been most effective for Tiny Tim?

a. spironolactone
b. acetazolamide
c. ammonium nitrate plus calcium
d. vitamin supplements
e. sodium bicarbonate plus calcitriol correct, to neutralize the acid in his blood

Board Review Edition

Here is the first ever Board Review Edition of the historical grand rounds. I took a fair bit of poetic license (most of the details are made-up), but everyone featured really had the disease in question. The correct answer will have "correct" written in white font next to it. Highlight to see.

1. One of the world's greatest ever Opera divas spent her last months locked in her Parisian apartment. On a home visit her doctor notice that she had an erythematous periorbital rash, red patches overlying her knuckles, and diffuse muscle pain. He warned her that this condition carries an increased risk of occult malignancy. Which antibody is her condition associated with?

a. anti-dsDNA
b. anti-microsomal
c. anti-Ro/SSA
d. anti-Jo correct, dermatomyositis
e. anti-Smith
f. anti-scl-70
g. pANCA

a. Leontyne Price
b. Renee Fleming
c. Birgit Nilsson
d. Maria Callas  correct

2. In 1911, an Austrian composer presented to Mt. Sinai Hospital complaining of a fever that he had for 2 weeks. He reported no other symptoms but on physical exam they noticed tender raised lesions on his palms, pale mucus membranes, splinter hemorrhages on his nails, and a low frequency murmur heard best at the lower left sternal border. How is the most likely pathogen identified when it's cultured?

a. Gram positive, catalase positive, coagulase positive cocci correct, staph aureus 
b. Gram positive, catalase positive, novobiocin resistant cocci
c. Gram positive, catalase negative, optochin resistant cocci
d. Gram positive, catalase negative, optochin sensitive cocci
e. Gram positive, catalase positive, novobiocin sensitive cocci

a. Franz Liszt
b. Gustav Mahler correct
c. Johannes Brahms
d.  Franz Schubert

3. This preeminent physicist, who became famous for his 1905 paper "On the Electrodynamics of Moving Bodies", died suddenly after an episode of intense chest pain. He had multiple cardiac risk factors included hyperlipidemia, hypertension, and smoking. An autopsy was not performed, but months prior his physician noted a large pulsating mass in his abdomen. Which of the following is not a possible cause of this event?

a. medial calcific sclerosis correct
b. Treponema Pallidum infection
c. mutation in the gene coding for collagen type III
d. defect in the fibrillin 1 gene
e. Takayasu's arteritis

a. Robert Oppenheimer
b. Richard Feynman
c. Paul Dirac
d. Albert Einstein correct

4.  The founder of the New York City Ballet and one of the greatest choreographers of the 20th century presented to NYU hospital with ataxia and new-onset dementia. Soon after he was admitted his attending physician performed a physical exam and found the patient delirious with hyperreflexia and startle myoclonus. He died four weeks later and a tissue biopsy was performed, which to the pathologist's surprise, was negative for alpha synuclein. What is the most likely cause/etiology of his disease?

a. tau protein aggregates
b. amyloid precursor protein
c. Infectious cause correct, creutzfeldt-jacob disease
d. Vitamin deficiency
e. Copper accumulation

a. Mikhail Baryshnikov
b. Rudolf Nureyev
c. George Balanchine correct
d. Vaslav Nijinski

5. This monarch of the British Empire underwent an infamous mental decline in their final years due to a series of severe psychological disturbances. However, their personal physicians noticed a constellation of other symptoms including episodes of abdominal pain, polyneuropathy, and dark red urine. There was never any documented photosensitivity or exposure to environmental toxins. This disease is characterized by an accumulation of which of the following subsrates:

a. porphobilinogen correct, acute intermittent porphyria
b. uroporphyrin
c. vWF multimers
d. protoporphyrin
e. glycine

a. King George III correct
b. King Edward VIII
c. Queen Elizabeth II
d. Diana, Princess of Wales

6. This composer, Michael's personal favorite, had a unique talent for presenting intense romanticism through a veil of elaborate civility. He suffered from chronic bronchitis and steatorrhea, and was always a very frail, delicate man. When he died at the age of 39, his autopsy report said he had TB, but the doctor admitted that the enlarged heart and abnormal lung findings pointed to a different pathology that was "unknown to medicine" at the time. He also had a sister who died of unknown causes at a young age, and he never had children despite having a female partner for over 10 years. What is the mechanism of the exotoxin produced by the most likely cause of his recurrent pulmonary infections?

a. protease that cleaves SNARE
b. activates T cells
c. over activates adenylate cyclase
d. Inactivation of 60S ribosome
e. inactivation of elongation factor EF-2 correct, pseudomonas in cystic fibrosis

a. Mozart
b. Bach
c. Chopin correct
d. Schubert 

Endocrinology and Reproductive Medicine
(Ancient Rome Edition)



Roman Mosaic from Centocelle

1. Since the beginning of civilization couples have searched for ways to prevent conception while still being able to enjoy the pleasure of each other's company. One ancient method involved a certain species of plant that grew on the shores of North Africa called silphium. It was first noted by the Egyptians and Phoenicians, who discovered that a small dose of the resin that came from its roots had the power to both prevent and terminate pregnancy. Unfortunately the plant could not be cultivated, so there were only small amounts available to those wealthy enough to obtain it. Roman aristocrats, who were renowned for their debauchery and numerous mistresses, became enamored with the power of this plant, and its value became such that they started minting coins depicting its seeds. It is even mentioned by Pliny the Elder, who attested to its ability to "promote the menstrual discharge". Silphium went extinct sometime around 100AD due to over-harvesting, and the last specimen on record was presented to Emperor Nero "as a curiosity". Based on modern day contraceptives, how do you think the medicine worked?


A coin depicting the silphium seed. Many scholars cite this plant as a possible origin of the heart symbol.
 
More coins, uncovered at Cyrene, 6-5th century BC. Several ancient sources make the connection between silphium, sexuality, and love.


2. By the time Emperor Maximinus I came to power in 235AD, Rome was already crumbling under the pressure of invasions, civil war, plague, economic depression, military revolts, and religious upheaval. It was termed The Crisis of the Third Age, and sowed the seeds for what would inevitably become medieval Europe. However, Emperor Maximinus had his own problems to worry about. Roman historians write about his "colossal" size and "frightening appearance", and it is clear from the statue of him below that he had some abnormal facial features. His hands were said to be so large that he was able to wear his wife's bracelet as a thumb ring. He also suffered from severe bouts of sweating and headaches, as well as a specific type of congestive heart failure. He was assassinated by his own soldiers in 238AD. What disease did he likely have?


Maximinus I, 173-238AD


3. Some of our greatest insight into the Roman world come from polymath-type writers such as Strabo and Pliny the Elder, who sought knowledge from across the empire and compiled it into enormous volumes containing history, geography, philosophy, medicine, botany, etc. One interesting anecdote found in both their writings is an account of several small villages hidden away in the Alps whose inhabitants all suffered from a strange series of physical misfortunes. They were all "short, strangely behaved creatures" who had what they called a "bronchocele" tumor. These towns lasted up until the 1700s, when mountain travelers would still encounter them and sometimes draw their findings (see below). Roman writers had a theory that drinking snow-water was responsible, and they came up with the rather clever treatment of eating burnt seaweed (Galen suggested burnt sponge). What did these villagers have and what was the treatment?

 
A French print depicting villagers in the Swiss Alps.


4. Julia Domna was the daughter of a Syrian high-priest who rose up to become one the most powerful women in history. As the wife of Emperor Severus, she became the de facto ruler of the Roman empire through her intelligence and shrewd political scheming, and her husband was so reliant on her wisdom that she was frequently brought along on military campaigns and political dealings. She also gave birth to and influenced future emperor Caracalla, famous for building one hell of a bath house (See Baths of Caracalla). When her son was assassinated by a rival in 217AD, she reportedly struck herself on the breast hard enough to inflame a "dormant cancer", which from that point on remained as an irregular mass until her death soon after. Historians are uncertain whether she died of breast cancer or self-inflicted starvation because of the loss of her son, but luckily we may be able to settle this debate. What is one likely breast pathology that Roman doctors may have mistaken for cancer?

 
Julia Domna, 170-217AD


5. A celebration of the classics would not be complete without a little archaeology. In 2010, the skeletal remains of a 30-40 year old woman were uncovered in the ruins of a Roman town in Catalonia. Overall she seemed pretty healthy, apart from a few ordinary bone spurs in her spine and arthritic lesions in her joints. However, there was a peculiar large calcified mass found in her pelvis. Researchers weren't able to identify it so they sent it off for some fancy scans and chemical analysis. All this was quite unnecessary because once they broke open the mass it became clear what it was. From the picture below can you identify it? This is the only example of this pathology ever found among ancient remains.

 
Contents of the archaeological specimen


6. CHALLENGE CASE!

While not himself a Roman, the British historian and member of parliament Edward Gibbon is perhaps the man most responsible for our current understanding of Ancient Rome. Born in 1737 in a small town in Surrey, Gibbon was "a puny child, neglected by his Mother, starved by his nurse". As was customary he was sent away to boarding school at the age of 9, and underwent a semi-religious education that was interrupted by his poor health, which included episodes of severe muscle and joint pain, fever, and flailing arm movements all consistent with Rheumatic fever. Further, at the age of 24 he began noticing some scrotal swelling that would one day lead to his death, and unfortunately prevent any exploits with the opposite sex.

Though perhaps Gibbon's amorous misfortunes were necessary for his success, for no man caught up in petty romantic pursuits could ever find the time to produce such a work as The History of the Decline and Fall of the Roman Empire. This six-volume series is among the best and most stylistically inspiring works of history ever written, and it gives a complete account of the years between the rule of the Caesars and the middle-ages. However, soon after its completion Gibbon's bothersome scrotal mass suddenly swelled to "the size of a small child", and in 1793 his physicians began tapping the fluid, collected upwards of 6 quarts of clear liquid each time. His death soon followed, likely from peritonitis, and on his autopsy doctors found his scrotum hanging below his knees and filled with fluid as well as large portions of his large and small bowel, to the point that it was dragging his stomach down to the pubic bone. Apart from his childhood maladies his past medical history also included lifelong obesity, gout, and frequent alcohol consumption (he'd have several glasses of madeira every night after writing), as well as increasingly severe leg edema, poor skin, and a non-existent libido. Given this description, see if you can explain the source of the massive swelling, as well as the anatomic anomaly that must have been present from a young age.


“The ascent to greatness, however steep and dangerous, may entertain an active spirit with the consciousness and exercise of its own power: but the possession of a throne could never yet afford a lasting satisfaction to an ambitious mind.”   -Edward Gibbon, The History of the Decline and Fall of the Roman Empire


ANSWERS: (highlight to see)
1. High dose of estrogen prevents ovulation. Even emergency contraception works via this mechanism.
2. Gigantism, Acromegaly
3. Congenital hypothyroidism, treated with iodine
4. Fat necrosis following trauma
5. Teratoma
6. The swelling likely started as an indirect inguinal hernia, and began filling with fluid as a result of ascites secondary to alcoholic liver disease. For the scrotum to fill with fluid he would need to have had a patent processus vaginalis.

GI/Liver 


Napoleon abdicating in Fontainebleau, by Paul Delaroche 

1. Napoleon's death on the Island of St. Helena has been the subject of many medical debates. Elaborate theories about arsenic poisoning and potential foul play by his British captors have been around for centuries, though few fully consider the circumstances of his death. Let's walk through the available evidence and see if we can't put this matter to rest. During the first two years of his captivity his health was relatively stable, but in January 1819 he started complaining of severe epigastric pain radiating towards his right shoulder blade. The physician's log book reported emesis, diarrhea alternating with constipation, recurrent fevers, chills, and headaches. A note from December 1820 stated "The illness of the Emperor has definitively worsened. His pulse is weak, his gums, lips and nails are colorless." In the following months he began losing weight and experiencing such severe night sweats that he had to change his clothing several times each night.

In April 1821 there was noted hematemesis, melena, and tachycardia (112 bpm). The emperor died about a month later. According to the autopsy report filed by an esteemed Italian anatomist, his stomach was filled with dark "coffee ground" like material, and there was an ulcerated lesion with raised, hardened, and irregular borders extending from the cardia to the pyloric region. There were also hardened and enlarged lymph nodes around the stomach and mediastinum. In addition to all of this, he spent his life eating a large amount salt-preserved foods and smoked meats during military campaigns. There is even speculation that an episode of GI bleeding interrupted his command duties at the battle of Waterloo, and contributed to the infamous French defeat. Seems like a classic case, what did he die of? What are two other pathologies present in this description?

 
Some say this famous pose originated from Napoleon's chronic epigastric pain.

2. Theodor Billroth was one of the greatest surgeons of the 19th century, and is best known today for developing procedures that treat refractory peptic ulcer disease. However, he was also an avid violinist, and was a dear friend to the composer Johannes Brahms. Together they were at the center of the Viennese music scene. Brahms frequently used Billroth's opinion to influence his compositions, and Brahms helped Billroth with his research on cognition and musical perception, the first of its kind. Unfortunately, Billroth died in 1894, two years before Brahms developed an illness that he potentially could have helped with (as the father of modern abdominal surgery). Less than a year before Brahms' his death an observer wrote, "He looked terribly miserable. The thin white beard, the withered face, the yellow eyes, the flabby thin body, his clothes hanging like on a hanger." His doctor also noted "considerable swelling of the liver with complete obstruction of the biliary ducts," perhaps related to his lifelong alcohol consumption or heavy smoking. Before jumping to any conclusions, it is important to note that his health was very good up until his illness began at age 73, and his decline was very rapid. Of the several possible causes of his death, which is the most likely?

 
Theodor Billroth Operating, A.G. Seligmann

3. Hollywood icon Audrey Hepburn was born in Belgium in 1929 to semi-aristocratic parents, both of whom were members of the British Union of Fascists. Luckily her father, who was a real nazi sympathizer, left the family when Audrey was six years old, and didn't have any lasting impact on her sensibilities. Though what she experienced during the war in Holland impacted her for life, and by all accounts she conducted herself quite nobly. Despite suffering from malnutrition, anemia, respiratory problems and edema, she insisted on helping with the war effort. She gave secret dance recitals to collect money for the Dutch resistance, acted as one of their underground couriers, and baked cakes out of tulip bulbs during the Dutch famine of 1944. Later in her life she became heavily involved with UNICEF, and was very dedicate to fighting child hunger around the world.

Like many who survived the war, Audrey was left with lifelong psychiatric problems, and struggled with depression and an eating disorder throughout her career. She said the one thing that helped most was gardening, which she was very passionate about. In 1993 she made an emmy-winning program called "Gardens of the World," which aimed to transmit the serenity and catharsis she found in them. However, soon after she finished filming she began having sudden, terrible abdominal pain. She checked herself into Cedars Sinai in Los Angeles and the doctors performed laparoscopic surgery. Surgeons found a tumor of the appendix that had metastasized to the small intestine, and they removed a large portion of ilium. After that she received 5-Fluorouracil and leucovorin therapy, which was largely ineffective. She died several months later at the age of 63. What she had was an extremely rare cancer of the appendix called pseudomyxoma peritonei. Based on gut physiology, can you think of what made her tumor present with sharp pain so suddenly without preceding symptoms? The answer is not appendicitis. 

 
Audrey Hepburn, 1929-1993

A clip from her excellent documentary on gardens: http://www.youtube.com/watch?v=t6ArElsvCUA

4. Dr. Frederick Treves was a British physician who had one of the most extraordinary careers in the history of medicine. He became famous for his relationship with Joseph Merrick, aka "The Elephant Man", which turned both of them into Victorian celebrities. He was also a renowned surgeon and was named honorary surgeon to the royal family. In 1902, Prince Albert of Wales (Soon to be King Edward the VII), who had waited 62 for his mother Queen Victoria to die, was finally going to assume the throne in a lavish coronation ceremony. Unfortunately, days before the event he fell ill with sharp lower right quadrant pain. Treves was called and explained that the king likely had an appendicitis, and would probably die if he did not operate. Appendectomies were not well received at the time, but Treves was adamant and finally convinced him. With the personal assistance of Lord Joseph Lister his operation was a success, the monarchy was saved, and from that point on surgery became the standard treatment for appendicitis. Dr. Treves retired having completed over 1000 appendectomies, and spent his final years traveling the world. He wound up in a Swiss nursing home, and in 1923 died from an abdominal infection. There was no autopsy, but it was noted that he suffered from peritonitis during his last few days. I searched and searched but there are no more details on this great doctor's illness. Had his pain started in the lower right it is likely he succumbed to an appendicitis of his own, but what would be the most likely diagnosis had it started on the left?

 
Dr. Frederick Treves, played by Sir Anthony Hopkins in The Elephant Man

 
A British newspaper clipping from 1902

5. There's not much history here, but I want to finish with another music clip. Pavarotti, despite his dalliances with the pop music world, was one of the most beloved singers of the 20th century. His powerful, golden voice was recognized the world over, and his death in 2007 sparked national mourning in his native Italy. A year earlier, he came to New York to have an tumor removed that appeared very suddenly and probably had something to do with his lifelong obesity. Despite complete resection and five rounds of chemotherapy, he was never able to recover. He will be missed.

  
Luciano Pavarotti, 1935-2007

 
My favorite aria, from Puccini's Tosca

 

ANSWERS (highlight to see):
1. Gastric adenocarcinoma, likely from an H. pylori infection. Cholecystitis (right shoulder blade pain), Iron deficiency anemia.
2. Pancreatic cancer (at the head of the pancreas)
3. Bowel obstruction. Ilius and intussesception often occur near the ileocecal valve and as a result of neoplasms in adults.
4. Diverticulitis
5. Pancreatic cancer

Finally, I would like to dispel a malicious rumor that our well-meaning but grossly misinformed lecturers propagated throughout the course. As brilliant as the ancient Greeks were, there is in fact no evidence that they knew about the regenerative capacities of the liver. Prometheus's liver did indeed grow back each day after being devoured by an eagle, but then, there are a whole host of other mythologies whose anatomic claims did not pan out with the coming of modern medicine. Manipulating history to reinforce our current beliefs is a slippery slope, and should not be indulged regardless of the stakes!

 
Tityus, by Titian. A lecturer used this painting to tell the story of Prometheus, unfortunately it portrays an entirely different legend concerning the god Tityus who had his liver eaten by two vultures. It's been a carnival of errors this year in terms of historical accuracy.

Hematology

 
The Latona Fountain in the gardens of Versailles

1. We will begin by revisiting a criminal investigation that took place in France in 1668. Jean-Baptiste Denis was the son of the chief hydraulics engineer to Louis the XIV, and was famous for creating an elaborate system of pumps that transported water from the Seine to the great fountains of Versailles. Rather than become an engineer himself, Jean-Baptiste decided to combine the family craft with the field of medicine. During his time as a lecturer in physics, mathematics, and medicine, he came across the work of William Harvey, and became fascinated with the possibility of blood transfusions. On June 15th 1667, he conducted the first ever animal to human transfusion using 13 ounces of lamb's blood and a series of goose quills as an I.V. line. His work made him a Parisian celebrity, but also earned him a fair number of enemies within the French Medical Academy. They were vehemently against the procedure and jealous of his position as personal physician to the king.

After a couple more "successful" trials, he performed his fourth animal-human transfusion on a madman named Antoine Mauroy, who died soon after the procedure. However, the case was wrought with suspicious behavior, especially from the man's wife who buried her husband herself to avoid the inevitable autopsy. At Denis' trial there was a witness who described Mauroy's death. Apparently he became very pale and started having seizures and may have shown evidence of GI irritation and discoloration of his nails (leukonychia striata). There was no jaundice, splenomegaly, hematuria, or fever. The judge was smart enough to know that these were the signs of overdose from a type of syphilis treatment common in those days. Denis was set free, and the wife was convicted of murder. Unfortunately the case left such a stain on Denis' reputation that he quit medicine, and the idea of transfusing blood disappeared for 150 years. Can you name the substance that killed Mauroy? What would be the cause of death from xenotransfusions?


A diagram of Denis' method

2. Most people know Pythagoras of Samos for his work on the triangle, but he was also one of the first documented polymaths. He was said to have studied medicine in Egypt, he wrote music, made extensive contributions to philosophy, and even started a kind of mystic mathematical cult called Pythagoreanism. In 529 BC he established a school near the southern Italian town of Crotone with a small group of his followers. They lived an aesthetic lifestyle, spent their free time practicing music and math, and ate an exclusively plant-based diet (interestingly, before the 1800s vegetarianism was known as The Pythagorean Diet). There was however a very strict rule against eating beans, which was likely the result of Pythagoras witnessing episodes of severe hemolytic anemia among some of his male followers. Today, the same area around Crotone is known to have the highest incidence of a certain Mediterranean genetic defect linked to this phenomenon. What is it? What is the genetic term we use to describe what happened with the Pythagoreans?


Pythagoreans celebrate sunrise by Fyodor Bronnikov


We've been here before. Pythagoras teaching music in Raphael's School of Athens

3. In 1932 two men excavated a temple in England from the 4th century AD. The temple was dedicated to the god Mars and it was written that any of his followers suffering from weakness could come drink from the temple waters and acquire some of the god's strength. Also of note was that the temple waters were frequently discolored on account of the high mineral content of the nearby soil. They even appeared red at times (hence the Mars-red connection). The two archeologists uncovered an interesting statue at the site, displaying one of the typical symptoms one might find among these weak followers. What did people come to the temple to treat? What is name of the symptom shown below?


Hand uncovered at Lydney, Gloucestershire

4. Now time for some political intrigue. In 1974 the Shah of Iran noticed a swollen lymph node in his neck, and was secretly treated by two French physicians for the next five years. He kept it a secret even from his wife until 1979, when he became severely ill at his villa in Mexico. He suddenly developed jaundice, nausea, chills, and a fever. Local doctors confused his symptoms with malaria, so an American doctor was brought in from Cornell to consult. Unfortunately he also made an incorrect diagnosis, thinking it was gallstones. But when the Shah began rapidly deteriorating his French doctors finally spoke up, and President Jimmy Carter made the very controversial decision to allow the Shah into the U.S. for treatment at Sloan-Kettering. In the hospital he received a full workup, and they discovered that he had a very unusual type of cancer characterized by an increased blood viscosity without lytic bone lesions, as well as other features typical of lymphoma. When news got out that the Shah was in the U.S. for treatment, the Ayatolla Khomeni became furious, and pro-revolutionary student groups began protesting outside of the U.S. embassy in Tehran. A quite well-known hostage crisis ensued, decades of political strife followed, and an overrated movie was made. What was the specific disease that set all of this off?


The Pahlavi Family

5. One of the greatest pianists of the 20th century is also one of the least well known. Dinu Lipatti was praised in his own lifetime by some of the most famous musicians of his age. Francis Poulenc called him "an artist of divine spirituality", and Herbert von Karajan described his playing as "no longer the sound of the piano, but music in its purest form." Though sadly, at the age of 29 he began suffering from a mysterious illness that started as a persistent fever and weight loss. After a number of incorrect diagnoses and random treatments, his doctors began administering x-ray therapy, which he said helped immensely. He also went through a trial of mustard gas injections, which caused swelling and disfigurement in his left arm. At 31 he began requiring weekly blood transfusions, and stopped chemotherapy after it destroyed one of his lungs. He remained positive and calm throughout, saying his swollen left arm gave "such formidable sonorities in the bass," and he continued touring, captivating audiences with "a different kind of expression." Based on his age and treatment, which disease was he suffering from?

 
Dinu Lipatti, Romanian classical pianist and composer (1917-1950)

In the midst of his final decline, and against the advice of his doctors, Lipatti decided to give one last recital in the French city of Besançon. Barely able to walk onstage, he gave a performance that has entered into legend, displaying an artistry that epitomized his musical purity. Towards the end of the concert, he found himself too weak to finish a series of Chopin waltzes, and ended with a simple Bach Chorale instead. The audience knew this was a final prayer from a man at the end of his life, and were moved to tears by the performance. Lipatti died ten weeks later at his home in Geneva, at the age of 33.

Listen to Dinu Lipatti's performance of J.S. Bach's Chorale, Jesu Joy of Man's Desiring:

ANSWERS (highlight to see):
1. Arsenic, autoimmune hemolytic anemia. Rumor has it members of the Paris Faculty of Medicine supplied the wife with arsenic in an attempt to frame Denis.
2. Glucose-6-phosphate dehydrogenase deficiency (G6PD), founder effect
3. Iron deficiency anemia, koilonychia. Mythology states that Iron was a gift from Mars to mankind.
4. Waldenstrom's macroglobulinemia
5. Hodgkin's Lymphoma