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December 3 2007
A 34 year old white male presented to the ER with pancytopenia and persistent headaches. A peripheral smear was unremarkable but a bone marrow biopsy revealed a uniform mononuclear cell infiltrate 85%. The cells had large nuclei with visible nucleoli and deep blue cytoplasm. Immunophenotyping revealed  the cell to be CD34+/CD33+/CD13+/CD14+/CD64+/CD56+

[1] What is the diagnosis?
[2] Is the physical examination likely to reveal hepatosplenomegaly and/or gum hyperplasia?
[3] Does this patient need a lumbar puncture? If so why?

 WINNER: Joseph Vadakara

ANSWER
This patient has ATLL - Adult T Cell Leukemia Lymphoma caused by HTLV - 1.

The clues that indicate this condition are the history of stay in Japan, where the virus is endemic and the presence of the so called clover leaf cells or flower cells.

HTLV- 1 is a single stranded positive sense RNA virus, belonging to the family Retroviridae, genus Deltavirus. The association between HTLV-1 and ATLL was first established in 1970’s. This virus has a worldwide distribution, but the world’s highest  prevalence is seen in southern Japan, other places with high prevalence include the Melanesian islands in the Pacific, the Caribbean islands, Middle East, South America and Central Africa.[2] The mode of transmission of the virus is through breast feeding, sexual intercourse, blood transfusion, injection drug use and tissue donation.

Manifestations of HTLV-1 can be divided into three categories.

Inflammatory Conditions

·         HTLV associated Myelopathy/ Tropical Spastic Paraparesis

·         Uveitis

·         Arthropathy

·         Sojgren’s Syndrome

·         Polymyositis

·         Thyroiditis

·         Pneumopathy

·         T  Lymphocytic  alveolitis

Hematological Malignancy

·         Adult T cell Leukemia

·         Cutananeous T cell Lymphoma

Infectious Associations

Stongyloides stercoralis hyperinfection.

·         TB

·         Leprosy

·         Crusted scabies

·         Infective dermatitis

Adult T cell leukemia has different variants[3]

Acute Variant:  This is the most common variant. It manifests with, bone marrow and peripheral blood involvement and the presence of circulating lymphocytes that have the flower shaped or the clover shaped nucleus.  Other features include hypercalcemia, hepatosplenomegaly , cutaneous lesions resebling mycosis fungoides, interstitial pulmonary infiltrates and CNS involvement.
 
Eosinophilia andmonocytosis seen in ATLL is secondary to the Tax protein of the virus causing increased transcription of IL3. IL5 and GMCSF in infected T cells. These cytokines stimulate eosinophil and monocytes proliferation. See http://mcb.asm.org/cgi/reprint/17/8/4272 for further explanation.

Lymphomatous Variant: Lymphadenopathy only , no peripheral blood involvement

Chronic  Variant: Skin lesions, lymphocytosis and no hypercalcemia

Smouldering Variant: No lymphocytosis and <5% circulating neoplastic cells

ATLL  - Malignant T Cells with abnormal nuclear morphology "FLOWER CELL"

 References
 1.  Dahmoush, L., et al., Adult T-cell leukemia/lymphoma: a cytopathologic, immunocytochemical, and flow cytometric study. Cancer, 2002. 96(2): p. 110-6.

2.  Verdonck, K., et al., Human T-lymphotropic virus 1: recent knowledge about an ancient infection. The Lancet Infectious Diseases, 2007. 7(4): p. 266-81.

3.   Freedman AS,  Clinical and pathologic features of adult T cell lymphoma/leukemia Uptodate.com  2007  [cited 2007].

 Answer by Joseph Vadakara, Edited by Omotayo Fasan.

September 3 2007
A 35 year old man went to visit his relatives in North Carolina early in summer. He enjoys many activities including outdoor events. Two weeks after returning he presents to you with a fever, malaise and fatigue, and a rash which resembles erythema migrans. You ask him if he suffered any tick bites and he says yes. 

You suspect he has Lyme disease so you start him on antibiotics and send him to see your local ID physician. The following week you receive a phone call from the ID physician who thanks you for the referral but says he does not think your patient has Lyme disease. He advises you to continue the antibiotic anyway. What is the likely alternative diagnosis? What causes it? What species of tick bit him?

 Winners: Robert Clark and Joseph Vadakara.

ANSWER
The patient hasSouthern Tick Associated Rash Illness  STARI  , also called Master’s disease.

This disease was described in the early 1990’s by Dr Edward Masters from Cape Girardeau, Missouri who described an ECM (Erythema Chronicrum Migrans) like rash in a population of patients living in Missouri.

He observed that in these patients, Lyme’s Serology was negative and at the same time they did not have a normal serology as seen in the normal population.[1]

The Postulated organism for this is Borrelia lonestari species novum, which is spread by the Lone Star Tick, Amblyomma americanum.

Although the organism does not fulfill Koch’s postulates, there is a published report where a person developed an ECM like rash and PCR of the skin lesion and the attached tick both yielded DNA material positive for Borrelia lonestari.[2]

The distribution of the tick is from Central Texas and Oklahoma eastward across the southern states and along the Atlantic coast as far north as Maine.[4]

1. Masters, E., et al., Physician-Diagnosed Erythema Migrans and Erythema Migrans-like Rashes Following Lone Star Tick Bites. 1998. p. 955-960.

2. James, A.M., et al., Borrelia lonestari infection after a bite by an Amblyomma americanum tick. Journal of Infectious Diseases, 2001. 183(12): p. 1810-4.

3. Tibbles, C.D., et al., Does this patient have erythema migrans? JAMA, 2007. 297(23): p. 2617-27.

4. CDC. Southern Tick-Associated Rash Illness. http://www.cdc.gov/ncidod/dvbid/stari/index.htm  2006  [cited 2007].

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August 20, 2007
A 20-year-old female in her first trimester of her first pregnancy is referred to you because of progressive dyspnea. She has no history of illness or hospitalization. Physical exam reveals a prominent parasternal lift and a loud pulmonary component of S2. No S3 or S4. No murmur is noted. The electrocardiogram shows tall P waves in leads Limb leads II, III, aVF  and tall R waves in V1, there is also Right axis deviation.. 

1) What is your working diagnosis based on physical exam findings?
2) What other conditions must you rule out?
3) List the long-term complications of the above condition.

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ANSWER
This is one of the periodic fevers TRAPS (TNF receptor associated periodic fever) also called familial Hibernian fever.  Hibernia is derived from Ivernia, which in turn is latinised Ierne. Ierne was the name given to Ireland by Pytheas of Massilia, the Greek merchant and explorer from the 4th Century BC. Hence the name as this common in people of Irish-Scottish descent.
Diagnosis:
First rule out all other causes of fever including infection, malignancy, and connective tissue disease.
The diagnosis of TRAPS is confirmed by genetic testing for mutations in 5 kDa receptor for tumor necrosis factor, TNFR1. It is an Autosomal Dominant disease with incomplete penentrance.
ESR and CRP are usually elevated.
Longterm Complication:
Like with other periodic fevers is Amylodosis
Other Familial fevers:
Familial Mediterranean Fever- as the name implies in those from this area
Familila Hibernian fever- in those of irish/ scottish descent.
Hyper IgD syndrome- In the Dutch and French- charecterized by incresed IgD
PAPA syndrome- Pyogenic arthritis, Pyoderma gangrenosum, Acne syndrome seen in children
Muckle Wells Syndrome- Fever, non pruritic urticaria, amylodosis and sensory neral hearing loss.
NOMID:Neonatal onset multisystem inflamatory syndrome.

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August 6 2007
A 54-year-old male presents to you complaining of joint pain involving his fingers and right knee for several months' duration. On review of systems, he also notes several months of polyuria, polydypsia, and weight loss despite a good appetite. He denies any other systemic symptoms. On exam you find twinges of pain upon flexing the small joints of the hand, particularly the second and third metacarpophalangeal joints; joint inflammation is minimal. There is no swan neck deformity. Upon examining the hip, you find normal range of motion with minimal pain and joint inflammation. You perform an X-ray of the knee and you see chondrocalcinosis. At this point what test would you order and why? What are the other causes of chondrocalcinosis?

 Winner: Vamsee Yaganti

ANSWER
The patient has Hereditary Hemochromatosis complicated by bronze diabetes and CPPD. At this point you would send off a fasting transferrin saturation. A value of > than 45% is suggestive. Confirmatory testing would be by perfoming analysis for a mutation of the HFE gene. 

CAUSES OF CHONDROCALCINOSIS
Hypothyroidism
Hypophosphatemia
Hyperparathyroidism
Hypomagnesemia
Hemochromatosis

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 Winner: Mini Mathew

ANSWER
All Trans-retinoic Acid syndrome (ATRA Syndrome). Frankel et al gave the first description of this syndrome in nine of 35 (25%) newly diagnosed APL patients they treated with ATRA. Signs occurred after 2 to 21 days of treatment and were generally associated with increasing white blood cell (WBC) count and combined fever, weight gain, dyspnea, pleural effusion, and pulmonary infiltrates on chest radiograph and, in some patients, renal failure, hypotension, and pericardial effusion. Five of the nine patients required transfer to an intensive care unit and mechanical ventilation, and three patients died. The postulated mechanism is two fold. The elaboration of cytokines like IL6, IL8, and TNF by differentiating APL cells and ATRA driven upregulation of high affinity adhesion molecules like ß2 Integrin (CD11b/18), LFA1 and ICAM-2. It is treated with glucocorticoids like Dexamethasone.

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July 23 2007
You are called by the ER to see a patient who apparently is complaining of double vision. As part of your complete neurological examination you assess the patient's extraocular eye movements. You notice that the patient has a divergent squint, normal abduction in both eyes but abnormal adduction; i.e., the eye movements are dissociated. However, on covering the abducting eye, adduction in the other eye is normal. Finally you note nystagmus which is more prominent in the abducting eye. What is this called and where is the lesion?

Winner: Chileshe Nkonde

ANSWER
This gaze abnormality is known as Internuclear Opthalmoplegia and the lesion is at the Medial Longitudinal Fasciculus (MLF). An internuclear ophthalmoplegia (INO) results from injury to the MLF within the dorsomedial pontine or midbrain tegmentum. The side of the INO is named by the side of the adduction deficit, which is ipsilateral to the medial longitudinal fasciculus (MLF) lesion. In essence, this clinical phenonmenon is opthalmoplegia arising from damage to the fibres critical in delivering information to achieve lateral conjugate gaze. (The muscles themselves are intact, as are the 3rd, 4th and 6th cranial nerves). 

These critical nerve fibres connect the  ipsilateral 6th nerve nucleus (Lateral Rectus) to the contralateral 3rd nerve nucleus (Medial Rectus)- hence the term "internuclear" and are known as the Medial Longitudinal Fasciculus (MLF). Although classically associated with Multiple Sclerosis- it is more accurate to say that these fibres can be damaged by  MS plaques (most common), small vessel infarction, any other form of space occupying lesion (such as  tumour (brainstem and 4th ventricle), subdural hematoma, hydrocephalus and the Arnold Chiari Malformation. Systemic disorders affecting the cerebrum can damage the MLF,such as drug intoxication,metabolic and nutritional disorders. Anatomically, the right and left MLFs run very close to each other it is not uncommon to see bilateral INOs.

Reference
Uptodate and Pathologic Basis of Disease.

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JULY 9 2007
A 73-year-old white male presents to you with diplopia and ataxia following a febrile illness. After investigation you diagnose him with a Brain Stem Encephalitis. On the 4th day of admission his respiratory function deteriorates, you draw an ABG which reveals a PCO2 of 90 and PAO2 of 65. You are considering intubation but a relative who happens to be nearby reminds you that her uncle had indicated “DNI/DNR” to her the previous night. She is his power of attorney. However she says if his condition is reversible you should go ahead. What laboratory test result would be invaluable when making your decision?

Winner: Missale Solomon.

ANSWER
The patient described had Bickerstaff's Brainstem Encephalitis (BBE). BBE is a post infectious syndrome of ophthalmoplegia, ataxia and hyperreflexia accompanied by disturbance of consciousness. It is believed to be an autoimmune phenomenon as evidenced by the presence of antiganglioside anti GQ1b antibodies which are positive in two thirds of cases. Patients may respond to plamapheresis or IVIG. It has a good prognosis. An excellent review (free) was published in Brain in 2003, see link below. http://brain.oxfordjournals.org/cgi/reprint/126/10/2279 . 

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