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Uncommon Manifestations of Common Diseases (with some Parisian segues) M. LaCombe MDFMR/UNECOM April 8, 2009
Uncommon manifestations of common diseases are more common than common manifestations of uncommon diseases.
First Case: The patient, a 30-year-old bisexual man, was seen in January because of fatigue, weakness, pharyngitis, nonproductive cough and mild gastrointestinal upset for three weeks. One month before being seen, he noted a flare of psoriasis and one week before, an acneiform rash on his chest. Ten days before presentation, a draining anal fistula occurred. His physician treated him with doxycycline hyclate given by mouth for five days; the fistula began healing. Two days later bilateral lower leg swelling and generalized myalgias developed. He had no urinary frequency, dysuria, oliguria or dark urine, but had noted urgency and excessively foamy urine. A 7-kg (15-lb) weight gain and increasing abdominal girth led to difficulty buttoning his trousers.
A hepatitis B infection two years previously had resolved without sequelae. An erythematous, papular rash a year before, diagnosed as guttate psoriasis, was treated with ultraviolet light and a topical steroid. Gonococcal exposure in the past had been treated with penicillin. He used no medicines and said he did not use intravenous drugs. His last sexual contact had been two months before, at Place Pigalle. On physical examination he was thin but well developed, with a temperature of 37°C, blood pressure 110/70, pulse rate 72 per minute, respirations 16 and weight 69 kg (152 lb), 7 kg more than usual. There were about 20 well-circumscribed, 1-mm blanching, erythematous, papular lesions over the anterior thorax. A few shotty cervical and right axillary nodes were palpable.
Mild left costovertebral angle tenderness and 1 + presacral edema were present. Both hemidiaphragms were elevated, but the lung fields were clear. The abdomen was mildly tender to deep palpation in the right midabdomen and epigastrium, without rebound or guarding. There was 3+ pitting edema to the knees bilaterally. The rest of the examination elicited no abnormalities.
The results of a complete blood count and serum electrolytes were completely normal. Other laboratory studies gave the following values: platelet count 524,000, ESR 113 mm per hour, serum creatinine 1.1 mg per dl, blood urea nitrogen 18 mg per dl, alkaline phosphatase 544 IU per liter, total protein 5.1 mg per dl and albumin 1.7 mg per dl. Urine analysis showed 4+ protein; 1+ heme; 25 to 50 leukocytes; less than 2 erythrocytes; a few granular, rare waxy and many hyaline casts, and oval fat bodies. No erythrocyte or leukocyte casts were identified. Hepatitis B-surface antigen test was negative. Throat culture showed no streptococci. A 24- hour urine collection showed 10.3 grams of protein and a creatinine clearance of 55.3 ml per minute.
A chest film showed bilateral pleural effusions, a pyelogram done following intravenous administration of contrast material showed kidneys of normal size and function and a liver-spleen scan showed moderate hepatosplenomegaly without a focal defect. Urine culture was negative, stool culture showed mixed gastrointestinal flora and examination of three stool specimens for ova and parasites was negative. Serologic studies, including antinuclear antibody, rheumatoid factor, anti-double-stranded DNA antibody, serum complement (CH50), immune complex assay, cytomegalovirus and antistreptolysin 0 titers were unrevealing. Serum protein electrophoresis showed hypoproteinemia (total protein, 4.7 grams per dl), hypoalbuminemia (albumin, 1.5 grams per dl).
A percutaneous renal biopsy was done on the sixth hospital day without complication. The specimen showed mild hypercellularity of the mesangial areas and membranous glomerulonephritis. There was immunofluorescent staining for immunoglobulin (Ig) G, IgM, IgA, C3 and C4 diffusely throughout the peripheral capillary walls of all glomeruli. The patient was treated with a low-salt, high-protein diet and diuretics. What is your diagnosis?
The serologic test for syphilis (rapid plasma reagin [RPR]) done on admission subsequently returned positive at a titer of 1:512. The fluorescent treponemal antibody absorption (FTA-ABS) test was positive. A single intramuscular injection of 2.4 million units of benzathine penicillin G was administered without complication.
Associated Segue: The French Disease Syphilis was given this term by the Germans and the Italians. In France it was called The Italian Disease.
Treponemes were not identified in the brain of patients with tertiary syphilis until 1913
Case 2: A 40 year old man comes to your clinic at FMI complaining of anorexia and malaise. He has lost ten pounds of body weight in the past month, but has continued to work at his job as a warehouse foreman. He is taking no medications, has not seen a doctor in years, has had no significant past illnesses nor any surgeries. He has been married for 14 years, remains in a monogamous relationship and has three children. He smokes 2 packs of cigarettes per day, having a 40 pack-year history of smoking. His review of systems, other than for some chronic low back pain which he relates to his job, is negative.
On physical exam in your office his vital signs are unremarkable. He weights 176 pounds, is 5’11”. He looks chronically ill but his general physical exam is otherwise normal. What will you do now?
Labs, for a CBC and a CMP, are drawn, and he is scheduled for a chest film and given an appointment for follow-up with you in two weeks.
Four nights later he comes to the ER, and you happen to be on call. The ER physician tells you your patient has a WBC of 17K with 7 bands and a temp of 101.4. He states that your patient has a normal CXR, unchanged from the one you obtained four days earlier, has a normal UA, and that his CMP is normal and unchanged from yours four days ago. His exam, the ER physician states, is unremarkable. The ER physician has obtained blood cultures and has given your patient 2 gms. of IV ceftriaxone.
You confirm the facts as presented to you by the ER physician, i.e. that your patient is febrile, acutely ill, and has a normal physical examination, including a rectal exam which had not been done. His chest film to your review is normal as well. Neither the patient nor his wife offer any further history to elucidate the situation. What will you do now?
He is admitted to A-3, given IV fluids, and his ceftriaxone is continued. Through the night he has nausea and vomiting requiring Zofran. In the morning his temp remains elevated at 101.8, a repeat WBC is 19K, his blood cultures are growing nothing, he continues to have nausea and vomiting, and your surgical consult reports a negative abdominal exam. A transthoracic echo, obtained to r/o endocarditis, is normal, showing no vegetations. The patient has several nonbloody, guaic negative diarrheal stools that day. What now?
An abdominal CT shows a swollen, possibly inflamed pancreas, and an amylase and lipase are markedly elevated. Not all cases of acute pancreatitis, you remind yourself, present with acute onset, abdominal pain radiating to the back, retching, fever, severe vomiting and mild abdominal rigidity on physical examination.
You keep your patient NPO, insert an NG tube because of the protracted vomiting, continue IVF’s and stop the ceftriaxone. Two days later his fever defervesces, his nausea leaves him, and you pull the NG tube, start clear liquids, and continue the IV fluids. That evening the A3 nurses call you at 1AM. Your patient is diaphoretic, tremulous, and has a BP of 80/40. Thoughts?
He does not respond to fluid boluses and you transfer him to the ICU after examining him. (He is indeed in shock, has a negative exam, including abdominal exam, and vows he has not had alcohol for two weeks – despite having neglected to tell you about his heavy drinking history when in your office initially – you hadn’t asked.) In the ICU, you place a central line to monitor his CVP, which averages 12-15, and a foley catheter to monitor his urine output, which is about 20 cc. per hour.
His BP remains at 70-80 systolic with a CVP of 14 and you start pressors (norepinephrine) directing the nurses to titrate it to an MAP of 65. His BP remains unchanged, the surgeon reassures you that his belly is negative, and a repeat abdominal CT shows a decrease in pancreatic size with no evidence of a cyst and with normal sized biliary ductal system. What other common problem are you missing, and what will you do?
His serum phosphorus is 0.3 mg/dl (2.5-4.5) a result of his diarrhea, vomiting, and your nasogastric suctioning.
Manifestations of phosphate deficiency Weakness of skeletal or smooth muscle is the most common clinical manifestation of phosphate deficiency. It can involve any muscle group, alone or in combination, ranging from ophthalmoplegia to proximal myopathy to dysphagia or ileus.Hypophosphatemia also causes rhabdomyolysis via ATP depletion and the consequent inability of muscle cells to maintain membrane integrity. Patients undergoing acute alcohol withdrawal are especially vulnerable to rhabdomyolysis secondary to hypophosphatemia, which is caused by the rapid uptake of phosphate into muscle cells. Rhabdomyolysis occurs more rarely in patients being treated for DKA or being refed after starvation.Respiratory insufficiency may occur in some patients with severe hypophosphatemia, particularly when the underlying cause is malnourishment. Impaired cardiac contractility occurs, leading to generalized signs of myocardial depression. Blood pressure and stroke volume have been shown to improve when serum phosphorus is corrected. The hypophosphatemic myocardium also has a reduced threshold for ventricular arrhythmias. Phosphate deficiency commonly impairs neurologic function, which may be manifested by confusion, seizures, and coma.
Peripheral neuropathy and ascending motor paralysis, similar to Guillain-Barré syndrome, may occur. Extrapontine myelinolysis has also been reported. Hematologic function may be impaired. The hemolytic anemia associated with severe hypophosphatemia has been attributed to the inability of erythrocytes to maintain integrity of cell membranes in the face of ATP depletion, leading to their destruction in the spleen. Phosphate deficiency also compromises oxygen delivery to the tissues due to decreases in erythrocyte 2,3-DPG and the resulting leftward shift in the oxygen-hemoglobin dissociation curve. Diminished oxygen delivery to the brain may be the cause of some of the neurologic manifestations mentioned above. Leukocyte function is affected, which results in impaired chemotaxis and phagocytosis. Manifestations of phosphate deficiency may occur singly or simultaneously.
The disease was first described by Jean Landry fifty years earlier, and should appropriately be termed: Landry-Guillain-Barre Syndrome Landry died in Paris, having contracted cholera from one of his patients.
Third Case: A previously healthy 37-year-old man had a sudden syncopal episode that lasted an estimated 10 seconds. The patient's wife, who witnessed the event, said that his eyes rolled back and that he urinated but had no tonic-clonic activity. On regaining consciousness, he complained of dizziness, shortness of breath, and sweating. An emergency medical service then brought him to the hospital.
On further history, he has had three prior episodes of syncope, all unexplained. His family doctor obtained a holter monitor after the first event, and this test was normal. After the third such episode, the patient was sent to cardiology where he had tilt-table testing, event monitoring, and EP testing, all of which were normal.
In the emergency department, the patient subsequently felt well and denied chest pain, cough, fever, headache, weakness, or previous neurological difficulty other than the prior syncopal episodes. He had no significant past medical history and had been well before losing consciousness. On physical examination, the patient was alert and oriented but anxious. His oral temperature was 99°F; pulse, 115 bpm and regular; blood pressure, 105/70 mm Hg; and respirations, 20 breaths per minute. Cranial nerve function and optic fundi were normal. Neck veins were not distended, and the precordium was quiet, with normal heart sounds and no murmurs. Lungs were clear to auscultation. Abdominal findings were unremarkable, and the extremities had full, equal pulses with no edema.
Results of the following laboratory studies were normal: complete blood count; urinalysis; serum creatinine, calcium, phosphorus, and electrolytes; blood sugar and urea nitrogen; and liver function tests. What are your possible diagnoses, and what will you do now?
The patient remained stable for 5 hours; then suddenly, while awaiting admission for workup of "new-onset seizures," he lost consciousness again. This time he had tonic-clonic activity of both upper extremities. The pulse oximeter showed a saturation of 86%, and a repeat chest radiograph demonstrated no significant change. Shortly thereafter, asystole developed. During vigorous resuscitative efforts, the patient received a 20-mg IV bolus of TPA, followed minutes later by a 60-mg bolus. All measures proved fruitless, and 6 hours after his illness began, the patient died. Any further thoughts before we open the envelope?
At autopsy, the patient had submassive pulmonary emboli, as well as evidence of healed pulmonary infarctions consistant with prior embolic disease. Testing of his blood post-mortem disclosed presence of factor V Leiden.
Only 13% of patients with pulmonary emboli present with syncope. Of the many other different neurological manifestations of PTE, the most frequent are restlessness, anxiety, focal or generalized seizures, altered mental state (including stupor and coma), and weakness or paralysis of limbs (eg, monoparesis, hemiparesis, and hemiplegia). Other occasional manifestations are ocular palsies, transient cortical blindness, dysarthria, aphasia, ataxia, hiccups, fecal or urinary incontinence, and an overpowering urge to defecate.
Hypoxia of the brain undoubtedly plays a major role. Neurological manifestations of PTE generally appear in elderly, bedridden, and cardiac patients. They usually are abrupt in onset and often are transient and recurrent (how many TIAs are, in fact, PTE?). And they can be the first, the most prominent, or as in this case, the only manifestation of pulmonary embolism.
Why is it called Factor V Leiden? Who was Leiden?
Leiden is a what, not a who. A city in The Netherlands, where the mutation was first described in 1994
Case # Four: A Quickie A 44-year-old woman presents to your clinic with resting tremor, rigidity and bradykinesia in the left limbs. She has recently returned from Paris, where she shopped and ate at the Marché rue Cler. She has an extensive history for illicit drug use, including the use of ecstasy (MPTP).
A computed tomography scan demonstrated a huge high-density mass in the right frontal lobe and marked surrounding edema causing compression of the basal ganglia. Cerebral angiography showed a typical sunburst tumor stain and three feeding vessels from the bilateral middle meningeal arteries and the right callosomarginal artery. The pathologic diagnosis was transitional type meningioma. Before surgery, treatment with levodopa and bromocriptine was significantly effective in controlling hemiparkinsonism, which completely disappeared after surgical removal of the tumor. This outcome supports the notion that local compression due to edema may cause a functional disorder in the basal ganglia producing reversible contralateral parkinsonism.
Case # Five: Another Quickie, and perhaps an easy one… A 14-year-old right-handed girl had a history of recurrent attacks of severe abdominal pain over 6 months. She was born after an uncomplicated pregnancy and delivery and had a normal development and schooling. There was no history of prior significant illness. She reported two or three attacks per month. She experienced intense colicky periumbilical pain accompanied by pallor and dizziness.
These episodes lasted for seconds to several minutes and ended abruptly. There was no alteration of consciousness. Nausea, vomiting, or diarrhea was not associated with these events. Physical and neurologic examination were normal. Laboratory tests including gastrointestinal investigations were unremarkable.
Abdominal CT scan was normal. The patient was diagnosed as having “abdominal migraine” and treated with naproxen. As the symptoms remained unchanged after 2 months of treatment, an MRI of the brain was done and this too was normal. Thoughts?
During hyperventilation in the course of an EEG, the patient suddenly complained of severe periumbilical pain, clasping her hands to the epigastrium. She appeared pale and dizzy. However, she was conscious and able to describe her symptoms and answer the technician’s questions. The event persisted for 2 minutes. No postictal confusion was observed, and memory for the episode was preserved. She described this incident as one of her habitual attacks. The ictal EEG showed a unilateral discharge of rhythmic repetitive spikes, sharp waves, and high-voltage slow waves over the left inferior frontal and temporal electrodes.
Review of the MRI by a pediatric neuroradiologist disclosed asymmetric bilateral abnormalities consisting of cortical thickening with irregular boundaries in the posterior wall of both sylvian fissures, in keeping with polymicrogyria, more pronounced in the left hemisphere. The diagnosis of abdominal epilepsy was made, and antiepileptic treatment with valproate instituted. This was followed by a significant clinical improvement, and she has experienced only two attacks during a 1-year follow-up.
Le Log––– was a florist’s delivery man in Paris. One evening, in October 1885, he was wheeling his barrow home through busy streets when it was hit from the side by a carriage which was being driven at great speed. Le Log–––, who had been holding the handles of his barrow tightly, was spun through the air and landed on the ground. He was picked up completely unconscious. He was then taken to the nearby Beaujon hospital where he remained unconscious for five or six days. Six months later he was transferred to La Salpêtrière. By this time the lower extremities of his body were almost completely paralysed, there was a twitching or tremor in the corner of his mouth, he had a permanent headache and there were ‘blank spaces in the tablet of his memory’. In particular he could not remember the accident itself. But, because there had never been any signs of external injury, Charcot decided that Le Log––– was a victim of traumatic hysteria and that his symptoms had arisen as a result of the psychological trauma he had suffered. Charcot came to this conclusion knowing full well that some weeks after his accident Le Log––– had suffered heavy nose-bleeds and a series of violent seizures – seizures which Charcot deemed hysterical.
Case # Six: A thirty-four year-old Indian physician and resident in family medicine consults you for paresthesias. She is right-handed, and has noted diminished sensation in digits 3-5 of the right hand, as well as a sensation of “fuzziness” in the palm of that hand. She denies any diplopia, urinary incontinence, or foot drop. She is on no medications, has enjoyed prior excellent health without any surgeries or hospitalizations, although she did have rheumatic fever as a child. There is no family history of any neuromuscular disease. She is from Chingleput in Tamil Nadu, South India and attended the medical school there. It is affiliated with the University of Madras, just to the north.
Here she is as a young pre-med student involved in outreach clinics in her home province.
Following medical school, she spent four years in infectious disease basic research in the San Francisco area before coming east for a family medicine residency. She is married, monogamous, and has two children. Her husband has a PhD. in electrical engineering and teaches at the local university.
On review of systems, she tells you she has had long-standing asthma since childhood, controlled with an MDI which she uses on a prn basis. Six months ago she had an episode of erythema nodosum. She is on BCP’s. You ask her to undress for the physical exam and leave the room while she does so.
On exam, she is healthy appearing, of normal body weight, with normal vital signs There is something wrong with this picture. What is it?
She has hypesthesia in the ulnar distribution of the right hand, and a suggestion of motor weakness there as well. What will you do now?
Both brain CT and brain MRI are normal. There is no evidence of demyelinating disease. Now what?
Now, with her back in your office, you do what you should have done at the first encounter. You ask her to get completely undressed and use the gown, tying it in the back.
And on complete physical exam, there is this additional finding: What is your diagnosis, and what will you do now?
Skin and nerve biopsies show: Acid-fast bacilli diagnostic of leprosy
Some corollary points about physical diagnosis: <ul><li>The more attractive the patient the less thorough the exam. </li></ul><ul><li>The younger the doctor the less thorough the exam. </li></ul><ul><li>The younger the patient the less thorough the exam. </li></ul><ul><li>Male physicians do poor breast exams because they do not take their time and are not thorough. </li></ul><ul><li>Never listen to the heart through any layer of clothing, not even the gown. </li></ul><ul><li>Examine all of the skin. </li></ul><ul><li>Patients do not like to undress for their doctors. In fact, be wary of the patient of the opposite gender who is eager to undress. </li></ul><ul><li>Completely undressed means gown only. </li></ul>
A brief history of leprosy The earliest possible account of a disease that many scholars believe is leprosy appears in an Egyptian Papyrus document written around 1550 B.C. Around 600 B.C. Indian writings describe a disease that resembles leprosy. In Europe, leprosy first appeared in the records of ancient Greece after the army of Alexander the Great came back from India and then in Rome in 62 B.C. coinciding with the return of Pompeii's troops from Asia Minor.
Throughout its history, leprosy has been feared and misunderstood. For a long time leprosy was thought to be a hereditary disease, a curse, or a punishment from God. Before and even after the discovery of its biological cause, leprosy patients were stigmatized and shunned. For example, in Europe during the Middle Ages, leprosy sufferers had to wear special clothing, ring bells to warn others that they were close, and even walk on a particular side of the road, depending on the direction of the wind. Even in modern times, leprosy treatment has often occurred in separate hospitals and live-in colonies called leprosariums because of the stigma of the disease.
The leper colony at Molokai Surrounded on three sides by the Pacific ocean and cut off from the rest of Molokai by 1600-foot (488m) sea cliffs, Kalaupapa provided the environment. In early 1866, the first leprosy victims were shipped to Kalaupapa and existed for 7 years before Father Damien arrived. The area was void of all amenities. No buildings, shelters nor potable water were available. These first arrivals dwelled in rock enclosures, caves, and in the most rudimentary shacks, built of sticks and dried leaves.