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February 11 2008

Case

A 26 year old Hispanic female previously in good health was admitted with one week history of fever, cough productive of green sputum, right sided chest pain and breathlessness on exertion.

On examination she looks very unwell, T 102.3, HR 122/min, BP 84/44, SaO2 91% on room air. CXR showed RLL infiltration. Sputum microscopy shows WBC+++ and Gram positive cocci in chains. Blood culture grew Streptococcus pneumoniae.

• Those with opportunistic infections.
• Those with HIV associated malignancy.
• Those with pneumococcal bacteremia.
• Those with other sexually transmitted diseases like gonorrhea, chlamydia, genital herpes etc.
• Those with signs of immunodeficiency like oral candidiasis, oral hairy leukoplakia.

• Those who report high risk behavior (like IV drug abuse, unprotected sex with multiple partners.
   

•  CD4 cell count
•  Plasma HIV RNA level
•  HIV genotypic resistance testing if HIV RNA load is > 1000 copies/mL
•  CBC, Complete metabolic profile
•  Urinalysis
•  RPR/ VDRL
•  Tuberculin Skin Test (TST)
•   Interferon Gamma Realease Assay (IGRA) for MTB diagnosis.
•   Toxoplasma antibody
•   Hepatitis A, B, C serologies
•   PAP smear in women
•   Chlamydia and neiserria gonorrhea testing to identify high risk behavior
•   CXR only if clinically indicated

 December 10, 2007

 Case
A female in her 40s with a history of Type II Diabetes Mellitus, HTN, and hypothyroidism presented with 5 days of progressive lower extremity weakness causing difficulty walking and shortness of breath following a URI.  On exam patient was orthostatic, had vital capacity of <150mL, decreased bilateral lower extremity weakness and absent deep tendon lower extremity reflexes.  Lumbar puncture revealed CSF fluid elevated protein and <10mm³.  Neurophysiologic testing was consistent with acute polyneuropathy.   The diagnosis of Guillain-Barre syndrome (GBS) was made.

What are the cardinal features of Guillain-Barre syndrome

1. Progressive symmetric muscular weakness
2. Absent reflexes
3. Progression of symptoms over days to four weeks
4. Autonomic dysfunction
5. Mild sensory symptoms
6. No fever at onset
7. Elevated protein in CSF with normal wbc count

What are the GBS variants?

Historically, GBS was considered a single disorder.  It is now recognized as a heterogenous syndrome with several variant forms.

1. Acute inflammatory demyelinating polyradiculopathy (AIDP)- most common form, 85%-90% of cases.  Peripheral nerve myelin is the target of immune attack.
2. Acute motor axonal neuropathy (AMAN)- most cases are preceded by Campylobacter jejuni infection. 
3. Acute motor and sensory axonal neuropathy (AMSAN)- more severe form of AMAN, in which both motor and sensory fibers are affected with marked axonal degeneration, causing delayed and incomplete recovery .

 Pathogenesis of GBS:

Guillain-Barré syndrome is thought to result from an immune response to a preceding infection that cross-reacts with peripheral nerve components because of molecular mimicry. The immune response can be directed towards the myelin or the axon of peripheral nerve, resulting in demyelinating and axonal forms of GBS. 

Campylobacter jejuni infection is the most commonly identified precipitant of GBS. Cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus (HIV) infection have also been associated with GBS.

A small percentage of patients develop GBS after another triggering event such as immunization, surgery, trauma, and bone-marrow transplantation

 
Criteria for ICU admission in patients with respiratory muscle weakness (ie, GBS, MG, etc.):

1. Vital capacity <20mL/kg
2. Maximum inspiratory  pressure <30cmH₂O
3. Maximum expiratory pressure <40 cm H₂0
4. Rapid progression (<7days) weakness
5. Inability to raise the head against gravity
6. Bulbar dysfunction (eg, dysphagia, dysphonia, aspiration)
7. Bilateral facial weakness
8. Significant autonomic dysfunction

 Patients admitted to a non-ICU setting should be observed frequently and reassessed to

assure that muscle weakness is not progressing to the point of respiratory compromise. 

 
Serial measurements of respiratory rate, vital capacity, maximal inspiratory and expiratory pressure are suggested to monitor such patients.

The presence of normal arterial oxygen and carbon dioxide levels in weak tachypneic patients should not be relied upon to determine the need for mechanical intubation. 

How do you distinguish muscle weakness from asthenia?

Many patients who complain of weakness are not objectively weak when muscle strength is formally tested.  A careful history and physical will permit distinction between asthenia, motor impairment due to pain or joint dysfunction, and true weakness.

Patients with true muscle weakness typically complain that they are unable to perform specific tasks, such as climbing stairs, combing hair, or that they have a feeling of “heaviness” or “stiffness” in their limbs.

What are the paraneoplastic syndromes affecting peripheral nerves:? 

Subacute sensory neuronopathy- Characterized by subacute, progressive, painless, and often asymmetric lower motor neuron weakness.

Chronic sensorimotor neuropathy- Common in cancer patients. Approximately 10 to 15 percent of patients with solid tumors develop a clinically apparent paraneoplastic sensorimotor neuropathy.  Approximately 10 percent of patients with chronic sensorimotor neuropathy of unknown origin have a monoclonal gammopathy, including monoclonal gammopathy of undetermined significance (MGUS), primary amyloidosis (amyloid AL), multiple myeloma, Waldenstrom's macroglobulinemia, or the POEMS syndrome

Acute sensorimotor neuropathy (GBS)- Hodgkin's lymphoma is the cancer most often associated with GBS.

Paraneoplastic autonomic neuropathy- Frequently accompanies other paraneoplastic symptoms, including encephalomyelitis and sensory neuronopathy, but it can be the only manifestation of an underlying malignancy. Autonomic dysfunction is associated with a variety of symptoms, including hypothermia, hypoventilation, sleep apnea, intestinal pseudo-obstruction, and cardiac arrhythmias that can lead to sudden death.

The tumor most frequently involved is SCLC; these patients usually have anti-Hu antibodies. Other tumors include carcinoma of the pancreas, thyroid, rectum, Hodgkin's lymphoma, and carcinoid tumors of the lung.

Paraneoplastic peripheral nerve vasculitis- ypically presents with painful, asymmetrical sensorimotor deficits resembling a mononeuritis multiplex and, in some patients, proximal motor weakness. Diagnosis of the vasculitis usually precedes the discovery of a cancer. The tumors most frequently involved are cancer of the lung (usually SCLC), prostate, endometrium, and both Hodgkin's and non-Hodgkin's lymphomas.   

What are the paraneoplastic syndromes affecting muscles?

Myasthenia gravis- characterized by the development of autoantibodies directed against the acetylcholine receptor (AChR). Approximately 75 percent of patients have thymic disease, most of whom have thymic hyperplasia, but about 10 percent have a thymic epithelial tumor

Lambert-Eaton myasthenic syndrome- (LEMS) shares the same site of involvement (ie, the neuromuscular junction) with myasthenia gravis, and it is associated with similar pathophysiology (ie, an autoimmune disease usually associated with malignancy). Antibodies directed against the voltage-gated calcium channel play a central role in the pathophysiology of LEMS

Dermatomyositis and polymyositis- Approximately 9 percent of patients with polymyositis develop a neoplasm. However, since the diagnosis of a tumor is sometimes made many years before or after the diagnosis of polymyositis, the association may represent a coincidental occurrence rather than a tumor-induced disease

In comparison, there is probably a real association between dermatomyositis and malignancy. Some studies indicate that by the time the neuromuscular symptoms develop, cancer is identified in about 15 percent of patients

Paraneoplastic neuromyotonia- Neuromyotonia (Isaac's syndrome) is characterized by muscle stiffness caused by continuous muscle fiber activity. The cause of neuromyotonia is thought to be related to antibodies directed against voltage-gated potassium channels (VGKC), either in isolation or as a paraneoplastic process.

Symptoms include undulating muscle twitching during rest (myokymia), cramps, pseudomyotonia (delayed relaxation), increased sweating, and sometimes motor weakness. Intestinal pseudoobstruction occurs rarely. The serum creatine kinase concentration may be elevated.

Patients with neuromyotonia may develop symptoms of CNS dysfunction, including confusion, memory loss, insomnia, hallucinations, or seizures. The association of neuromyotonia and CNS symptoms is called Morvan's syndrome; it also occurs in association with VGKC antibodies and, in some patients, is a paraneoplastic manifestation of cancer.

Acute necrotizing myopathy- Paraneoplastic necrotizing myopathy is a rare disorder characterized by symmetric, painful, predominantly proximal weakness leading to severe disability over one to three months.

 
Compiled by Rodina Vatanparast

 Monday December 3, 2007
Case
A 36 year old female of ethnic descent with a known diagnosis of Sarcoidosis presents with a weeks history of cough and hemoptysis. On the day of admission say coughed up 150mL of bright red blood. Further history revealed progressive breathlessness over the past month with associated malaise. She denies fevers, rash, joint pains, joint swellings, PND, orthopnea and ankle swelling. She has no pets and has not traveled out of the USA in the past 10 years. She had a PPD placed for work related reasons this was non reactive. 

She is a non smoker and works as a clinical nursing assistant. Examination revealed a comfortable afebrile well female. RR 18/min SaO2 94% on 2LPM Oxygen. Pulmonary auscultation revealed bilateral upper lobe wheezes, there were no rhonci or crackles audible. CT of the thorax revealed a LUL cavity with a density occupying the cavity. There was also associated pneumonia. BAL revealed a lot of WBC cultures grew Aspergillus species. She was diagnosed with an Aspergilloma.

[1] What is Sarcoidosis?
This term was coined by a Norwegian dermatologist called Caesar Boeck. He described skin nodules characterized by foci of "epitheloid cells with large pale nuclei and giant cells". Now we know it is a multisystem disease with unknown etiology. There are polygenic influences and environmental triggers. It is characterized by the formation of non caseating granulomas.

[2] What is a Granuloma?
This is a lesion characterized by epitheloid macrophages and giant cells. Think of it as one of the ways the body’s immune system lockdowns and contains foreign protein/antigens. Interferon gamma and TNF – alpha are important cytokines in the formation of granulomas.

[3] What is Lofgren’s Syndrome?
This is acute Sarcoidosis. It consists of arthritis, bilateral hilar adenopathy and erythema nodosum. The inclusion of anterior uveitis in this syndrome is controversial. It has a good prognosis.

[4] What is the differential diagnosis of hemoptysis?

Airway causes
Lung Cancer
Kaposi’s sarcoma
Bronchitis
Bronchiectasis
Airway trauma

Parenchymal causes
Lung abscess
Pneumonia
Tuberculosis
Mycetoma (fungal ball)
Goodpastures
Idiopathic pulmonary hemosiderosis
Lupus pneumonitis
Lung contusionVascular causes
AVMs
PE
Mitral stenosis

Miscellaneous causes
Pulmonary endometriosis
Coagulopathy

[5] What is massive hemoptysis?
Massive hemoptysis is variably described as the expectoration of > 100mL to 600mL over a 24 hour period.

[6] How do you differentiate true hemoptysis from blood from the GI tract?
Hemoptysis is – alkaline and bright red
Hematemesis is – acidic and dark red.

[7] What is Aspergillus species?
Aspergillus is a mold with septate and branching hyphae 2 to 4 microns is diameter. The species include A. flavus, A. niger, A nidulans, A. terreus. They are ubiquitous in the environment growing on dead leaves, stored grain, compost piles, hay and decaying vegetation.

[8] How does Aspergillus cause human disease?
The spores of this mold are inhaled commonly by all. However in immunocompetent individuals disease is very rare. Invasion of the lung occurs when at least 2 of this 3 factors occur together (i) Granulocyte count < 500, (ii) supraphysiological doses of steroids (the physiological dose of hydrocortisone is 15 to 20mg/day), (iii) other immunosuppressive drugs like calcineurin inhibitors.

Alveolar macrophages from the first line of defense against inhaled aspergillus conidia. If the macrophages are depleted ( e/g due to chemotherapy) the conidia germinate and form hyphae. The next line of defense is the neutrophil. 

However if this is depleted as well then the hyphae proliferate. Normally the neutrophils will attach to hyphae and destroy the, the aspergillus hyphae secretes "virulence factors" like complement inhibitors, proteases and mycotoxins like aflatoxin and gliotoxin. Gliotoxin inhibits T cell function, neutrophil oxidative burst and macrophage phagocytosis all key defense mechanisms against aspergillus.

[9] How does Aspergillus infection manifest?
Allergic bronchopulmonary aspergillosis (ABPA).
This occurs in patients with pre-existing glucocorticoid dependent asthma. Causes intermittent episodes of wheezing, pulmonary infiltrated (from transient focal plugging), eosinophilia, low grade fever and brownish flecks in the sputum. The flecks contain aspergillus hyphae.

Invasive pulmonary aspergillosis.
This occurs in immunosupressed individuals or when a high inoculum of fungal conidia is inhaled. The pathological hallmark of invasive pulmonary aspergillosis is infection across tissue planes. The hyphae invade blood vessels causing infarction and tissue necrosis.

Aspergilloma: 
This is also called ‘mycetoma" fungal ball. It occurs in patients with pre-existing cavities due to diseases like TB, Sarcoid, histoplasmosis and bronchiectasis. It can also occur in other organs like the kidney and the brain. Patients with aspergillomas can be asymptomatic, present with hemoptysis (75%), cough, sob, fever, malaise and chest pain. Some of these symptoms are due to bacterial superinfection. Aspergillomas can also co-exist with invasive pulmonary aspergillosis.

[10] What is the treatment of choice for......

[a] Allergic bronchopulmonary aspergillosis?  - Corticosteroids.
[b] Invasive pulmonary aspergillosis?  - Antifungals like voriconazole, amphotericin B, caspofungin and surgery for localised lesions.
[c] Aspergilloma?  - Surgical resection

 Compiled by Omotayo Fasan.

Monday October 22 2007
Case
A 30 year old African American female with a past medical history of SLE, HTN and ESRD on hemodialysis presents with non healing Rt pre-tibial ulcer and chronic abdominal pain. Examination revealed an obese lady with uncontrolled BP 210/104 and left upper quadrant tenderness. Skin examination revealed right lower extremity ulceration 3X4 cm with satellite bullous lesions. Biopsy of the skin ulcer revealed medium vessel vasculitis.

Chief Resident Questions 

[1] Classification criteria for SLE

Malar rash

Discoid rash

Photosensitivity

Oral ulcers (observed by physician)

Arthritis – non erosive arthritis of 2 or more peripheral joints

Serositis – pleuritis or pericarditis

Renal disorder – proteinuria > 0.5g/day or >3 cellular casts

Neurologic disorder – seizures, psychosis

Hematologic disorder – anemia, leucopenia, thrombocytopenia

Immunologic disorder – antidsDNA, anti Sm and antiphospholipid

Antinuclear antibodies

[2] How does vasculitis present?

Fever

Skin rash (palpable purpura)

Painful skin ulcers

Pulmonary infiltrate

Microscopic hematuria

Chronic inflammatory sinusitis

Joint pain

Abdominal pain

Renal failure

Stroke

Neuropathy

[3] What are the different vasculitides?

PRIMARY VASCULITIS SUNDROMES

Wegner’s granulomatosis

Churg Strauss syndrome

Polyarteritis nodosa

Microscopic polyangitis

Gian cell arteritis

Takayasu’s arteritis

Henoch –Schonlein purpura

Idiopathic cutaneous vasculitis

Essential mixed cryoglobulinemia

Behcets syndrome

Isolated vasculitis of the CNS

Cogan's syndrome (interstitial keratitis and vestibuloauditory symptoms)

Kawasaki’s disease

SECONDARY VASCULITIS SYNDROMES

Drug induced vasculitis

Associated with  malignancy, infection, rheumatic disease.

[4] Pathogenesis of vasculitis.

This is not fully understood but is thought to be related to:

(a) Circulating immune complexes 
(b) Anti neutrophil cytoplasmic antibodies 
(c) Pathogenic T lymphocyte responses and granuloma formation.

[5] Differential diagnosis of bullous lesions.

 Pemphigus Vulgaris (PV) – this is a blistering skin disease seen predominantly in elderly patients. It is associated with HLA DR4 and DRw6. Pathologically there is loss of cohesion between the epidermal cells – acantholysis. There is formation of blisters which rupture easily leaving denuded areas.

 Manual pressure to the skin of these patients elicits separation of the epidermia – Nikolsky’s sign. This is characteristic but not specific for PV. Lesions typically appear on the oral mucosa, face scalp, neck, axilla and trunk.
 A biopsy will reveal  - intraepidermal blisters within the suprabasal portion of the epidermis. Immunoflurescence will reveal antibodies on the surface of keratinocytes. This IgG antibodies are directed against a glycoprotein called desmoglein (typically Dsg-3). PV can be life threateneing. Prior to glucocorticoids mortality was 60 – 90%. Now with glucocorticoid therapy it is 5%.

Pemphigus Foliaceus (PF) – similar to PV but the antibodies are directed against Dsg – 1. Typically spares mucous membranes. In Brazil it is called Fogo selvagem.

Paraneoplastic Pemphigus – occurs in association with occult or confirmed neoplasm. Palms and soles are typically involved. Immunoflourescence will reveal IgG and complement on the surface of keratinocytes. The antibodies are directed against the Plakin Family of cytoplasmic proteins. Associated with malignancies like NHL, CLL, Castleman’s disease, Thymoma and Spindle Cell Tumor.

Bullous Pemphigoid – also a subepidermal blistering disease. Tense Blisters, oral lesions in up to 40% of cases. Immunoflourescence shows linear deposits of IgG and C3.

Stevens Johnson Syndrome(SJS) and Toxic Epidermal Necrolysis (TEN). These are due to drug reactions. They are charecterised by blisters and epidermal detachment resulting from epidermal necrosis without dermal inflammation.

If < 10% of the skin is involved it is SJS.
If 10 – 30% of the skin is involed it is SJS/TEN.
If >30%of the skin is involvedit is TEN.

SJS/TEN patients typically present with acute symptoms, painful skin lesions, fever > 102 F, sore throat and visual symptoms. Implicated drugs include oxicam NSAIDS, Lamotrigine, Sulfonamides and Aromatic anticonvulsants.

[6] How do glucocorticoids work?  

Hench and colleagues noted over 50 years ago that the symptoms of Rheumatoid Arthritis improved during pregnancy and when a patient had jaundice – both situations associated with an increase in the natural glucocorticoids. Hench surmised that glucocorticoids might have anti-inflammatory properties so he gave small doses of cortisone to patients with RA and their symptoms improved dramatically. He and others won a Nobel prize in physiology and Medicine for his work (along with Kendall and Reichstein).

Glucocorticoids bind to the Glucocorticoid Receptor (GR). GR is located in the cytoplasm, on binding it translocates to the nucleus. It binds to Glucocorticoid Responsive Elements (GRE) of different genes. It positively regulates genes of proteins involved in gluconeogenesis. However genes of inflammatory proteins do not have GREs. 

Glucocorticoid/GR - down regulates inflammatory proteins by transcriptional interference. NFkB (Nuclear Factor kappa B)  and AP-1 (Activator Protein – 1) are key transcription factors for inflammatory proteins. The Glucocorticoid/GR complex interferes with the action of NFkB abd AP-1, reducing their ability to transcribe inflammatory proteins. Glucocorticoid are also known to inhibit signaling via MAPkinase and destabilise the mRNA of COX -2.

http://arthritis-research.com/content/pdf/ar398.pdf

[7] How do RANK, RANKL and OPG regulate bone metabolism?

Bone remodeling in normal persons is a balance of osteoblastic activity (bone formation) and osteoclastic activity (bone resorbtion). Normal healthy bone is in a dynamic flux.

Pathological bone resorbtion such as that seen in prolonged glucocorticoid use, Multiple Myeloma and other metastatic malignancies like breast cancer is a result of the subversion of this normal dynamic process. 

Osteoclastic formation and activation depends on ligand binding to a membrane receptor called RANK. RANK is activated by RANK Ligand.

RANK Ligand is elaborated mainly by bone marrow stromal cells. Malignant cells, inflammatory cytokines, PTH, PTHrp, glucocorticoids and , estrogens all affect the levels of RANK-Ligand. Osteoblast can also secrete RANK Ligand.

RANK Ligand (Receptor Activator of Nuclear Factor kappa-B Ligand/RANKL) also called OPG Ligand or TRANCE is a member of the “TNF super family”. It binds to RANK its receptor found on osteoclasts( or their monocytic precursors). This receptor-ligand interaction results in maturation and activation of osteoclasts. Unopposed this will result in bone resorbtion.

However osteoblastic lineage cells and other marrow stromal cells secrete OPG (osteoprotegerin). This protein is a decoy receptor for RANK Ligand. It interrupts binding of RANKL to RANK. This prevents the formation of activated osteoclasts and hence bone resorbtion. OPG also suppresses osteoclast survival. Hence the presence of OPG in the bone microenvironment has the net effect of suppressing bone resorbtion.

OPG/RANKL ratio is an important concept to grasp. This ratio determines the direction of the dynamic process either to the direction of bone formation or the direction of bone resorbtion. A protean number on cytokines and substances influence the OPG/RANKL ratio. A few of them are Estrogens, Glucocorticoids, PGE2, IL6, IL1, PTHrP and PTH.

Estrogen deficiency, glucocorticoid excess, PGE2 (a product of the inflammatory process) adversely affect the OPG/RANKL ratio resulting in bone resorbtion.

Further reading :

[1] Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/ osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998;95:3597–3602.

[2] Estrogens suppress RANK Ligand induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun. http://www.pnas.org/cgi/reprint/97/14/7829

[3]RANK Ligand and Osteprotegerin in Myeloma Bone Disease.
http://bloodjournal.hematologylibrary.org/cgi/reprint/101/6/2094 .

[4] Biology of Osteoclast Activation in Cancer. http://jco.ascopubs.org/cgi/reprint/19/15/3562.

 Complied by Omotayo Fasan

Monday October 8, 2007
Case
An 84-year-old white female resident in an assisted living facility with a past medical history of AF, OSA, CHF, HTN, Early onset Dementia, Depression and Hypothyroidism presented with 1 week history of URTI symptoms followed by an acute onset SOB with desaturation to 84%. She had an unproductive cough. 

On examination she was afebrile but had coarse crackles audible in both lungs. She did not have any signs of CHF. Lab data showed elevated WBC at 16000/mm3 with 84% PMNs. CXR shoed RLL shadowing, a CT confirmed Multifocal PNA with masses in the RUL and RLL lobe. She responded to antibiotics therapy.
This patient very likely had a community acquired pneumonia which responded appropriately to antibiotic treatment.

[1] Causes of CAP
Streptococcus pneumonia
Hemophilus influenza
Mycoplasma pneumonia
Legionella pneumophilia

[2] When should you admit a patient with CAP?
The 2007 consensus guidelines from the IDSA and ATS recommend using the CURB-65 criteria.
C – Confusion
U – Uremia - BUN > 19mg/dL
R – RR > 30
B – Blood pressure - SBP < 90 or DBP < 60
65 – Age > 65 years

Chief Resident's Questions
[1] What are the risk factors for Aspiration PNA?
Risk Factors for Aspiration Pneumonia
Dementia
Alcoholism
CVA – Pseudobulbar palsy
Neuromuscular Disorders – Bulbar palsy
Elderly patients
Intubated patients
Peri-procedure – bronchoscopy, EGD
NG tube feeding
Upper esophageal disorders
Hospitalized patients
Altered consciousness
Sedative drugs

[2] What are the clinical features for aspiration pneumonia?
Clinical Features
Sudden onset,
Low grade fever
Cyanosis
Diffuse crackles infiltrate on CXR (dependent parts)
Absence of rigors
Putrid sputum

[3] What are the different types of Dementia?
Types of Dementia
Alzheimer (60 – 80% of chronic dementia, 4 million patients, >$40, 000/yr)
Vascular dementia
Dementia with Lewy bodies
Parkinson’s disease with dementia
Frontotemporal Dementia
Reversible Dementia

[4] What is the prognosis of Alzheimer’s Dementia?
Prognosis
The 6 year survival rate for AD was 21% vs. the expected 48.5%.
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=3776457&dopt=Citation
Median survival is 9.3 yrs from symptom onset (range 1.8 to 16 yrs.)
If MMSE is < 18 then median survival is reduced by 3 yrs.
In another study the median survival was 3 adjusted 6 years unadjusted for time bias.
http://content.nejm.org/cgi/content/abstract/344/15/1111

[5] How do you assess the risk for stroke in Atrial Fibrillation?
This can be done by using the CHADS2 index.
CHADS2 Index
C – CHF – 1 point
H – HTN – 1 point
A – Age>75 – 1 point
D – DM – 1 point
S – Stroke/previous embolic phenomena – 2 points

Risk of Stroke in AF
Score 0 - Low Risk for Stroke or Peripheral Embolization - 0.5%/ year. Score 1 or 2 - Intermediate Risk - 1.5 to 2.5%/year.
Score  3 - High Risk for Stroke 5.3 to 6.9%/ year.

Rate of ischemic stroke is related to risk category 
 

The incidence of a stroke in patients with either intermittent or sustained atrial fibrillation (AF) is related to risk category; the patients were treated with aspirin and followed for a mean of two years. Among those with intermittent AF, 24 percent were high risk, 32 percent are moderate risk and 43 percent are low risk; among those with sustained AF, the respective values were 30, 34, and 36 percent. The stroke risk was similar in patients with intermittent and sustained AF.

High risk: any of the following - age >75 and hypertension, age >75 and female, systolic BP >160 mmHg, prior stroke or transient ischemic attack; Moderate risk: either of - hypertension and age  75 or diabetes and no high risk features; Low risk: no moderate or high risk features.
Data from Hart, RG, Pearce, LA, Rothbart, RM, et al, J Am Coll Cardiol 2000; 35:183.

Image reproduced from Up-to-date.

[6] Which is better in preventing Stroke, coumadin or aspirin?

Coumadin vs. Aspirin
Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA): a randomized controlled trial of warfarin versus aspirin for stroke prevention in the management of atrial fibrillation in an elderly primary care population

Compared adjusted dose coumadin INR 2-3 with ASA 75mg daily
Population: 973 patients aged 75 years or greater

Outcome Measure: Primary endpoint was fatal or nonfatal disabling stroke, either ischemic or hemorrhagic, or significant arterial embolism.

Results
Patients on coumadin had a significant reduction in the primary endpoint 24 events (21 strokes, 2 ICH and 1 systemic embolus vs. 48 events in the Aspirin group (44 strokes, 1ICH and 3 systemic emboli)

ARR/ year – 2%
NNT =50

[7] What happens to your lungs after a pulmonary embolus?
 Physiological effects of pulmonary emboli
Increased PVR due to vascular obstruction
Increased PVR due to platelet secretion of neurohormonal agents
Impaired gas exchange due to increased alveolar dead space
Hypoxemia from alveolar hypoventilation relative to perfusion of non obstructed lung
R-L shunting
Increased airway resistance due to constriction of airways distal to bronchi
Decreased pulmonary compliance due to lung edema
Decreased pulmonary compliance due to lung hemorrhage
Decreased pulmonary compliance due to surfactant loss.

 Compiled by Omotayo Fasan.

 September 24, 2007
Case
70yo Puerto Rican female with PMHx of hyperlipidemia and osteoarthritis presents to the ER complaining of fever for the past 5 days. She had been in her usual state of good health until 5 days prior to arrival when she began noticing fever up to 102.6°F. She took Tylenol 650mg q4h around the clock to combat the fevers, despite this she still had fevers up to 99-100°F. There was no pattern to the fevers. Associated symptoms included severe fatigue and malaise, anorexia, nausea, and diffuse myalgias and arthralgias. She had never experienced anything like this before. Review of systems was otherwise negative—she denies headache, photophobia, phonophobia, URI symptoms, sore throat, cough, vomiting, abdominal pain, diarrhea, dysuria, joint swelling, calf tenderness, skin rashes, gingival bleeding, melena, hematuria, easy bruising, or focal weakness. Her social history is unremarkable. 

Her travel history is remarkable for recurrent trips back and forth between Puerto Rico, Texas, Florida, and Pennsylvania. She flew back to the Philadelphia area 1week ago after spending 3-4 weeks in her native Puerto Rico. While in Puerto Rico, she did spend time outdoors at two picnic dinners. She denies any mosquito bites but did not wear any insect repellants. She does report a sick contact—her neighbor in Puerto Rico has also had fevers arthralgia and myalgias recently and had been diagnosed with Dengue Fever.

Past medical history is as mentioned. She has not had any surgeries. She does not use illicit drugs; neither does she use alcohol or tobacco. Her only medications are Premarin 0.3mg daily, Zetia 10mg daily and the Tylenol. She is allergic to Minocycline.

Examination revealed a tired looking Hispanic female who appears younger than stated age. She was not distressed. Temp 101.1, HR 84, BP 112/58, RR12, Sat 98% on room air. There was no icterus or pallor, her oropharynx was clear without lesions or bleeding. Her tympanic membranes were clear bilaterally, neck supple with full range of motion. Auscultation revealed clear lungs bilaterally, normal heart regular S1 and S2 without murmurs, gallops or rubs. Her abdomen was not distended with normal bowel sounds. It was soft to palpation with mild epigastric tenderness. There was no rebound or guarding. Her liver and spleen were not palpable. Skin exam did not reveal any rashes. Lymphatic exam was normal without cervical, axillary or inguinal lymphadenopathy. Her joint all had a normal range of motion and were without swelling or deformity. Neurological examination was normal.

Laboratory data
Blood chemistry was normal, WBC 1.6, neutrophil 59%, bands 19%, lymphocytes 18%, Hb 13.6, Plt 100, AST 776, ALT 430. UA was normal.

Imaging
CXR- normal lung fields, no acute lesions.

Essential core data
70yo Puerto Rican female with recent travel from PR to US 1 week prior to admission, presents to ER with 5days of fever, nausea, anorexia, diffuse myalgias/arthralgias, fatigue—laboratory tests reveal leucopenia, thrombocytopenia, and elevated hepatic transaminases.

HEURISTICS
This case illustrates the cornerstone of diagnosing infectious disease…..a complete and thorough history including travel history. Patients returning form tropical countries or climes other than temperate and then present to the hospital with fever present a diagnostic challenge. Solving the mystery will require not just seasoned heuristics but good old fashion detective work. It requires us to think not only of common diseases in our area, but also in the areas of travel. In this case, the patient actually gives us a clue about her condition by telling us her neighbor in Puerto Rico recently had Dengue Fever. A quick look at the CDC website www.cdc.gov allows physicians to type in the country of interest and find out what diseases are endemic to the area. In this case, you would have learned that Puerto Rico is suffering from an epidemic of Dengue Fever presently and that the diagnostic clues are fever, arthralgias, leucopenia, thrombocytopenia, and elevated transaminases. Malaria is the other arthropod borne illness of concern in travelers to endemic regions. Other conditions to consider are other viral infections such as acute hepatitis, EBC, CMV, Parvovirus B19, and Leptospirosis.

Further Lab Data
The patient had a battery of lab tests done including acute hepatitis panel, EBV titers, ParvoB19 antibodies, Leptospira antibodies, CMV antibodies, and a thick and thin films for malaria parasites - all of which were negative. Her transaminases continued to increase, peaking in the 1500 range, but nearly normalizing by the time of discharge 5 days later. Dengue IgM antibodies sent off came back positive at 9.44 (with <0.9 considered negative and >1.1 considered positive). Her WBC and platelet count improved over the hospital stay and at discharge her WBC was 5.0 and Plt count 107.

Conclusion
A diagnosis of presumed Dengue Fever was made.

Further Reading
Infections Caused By Arthropod and Rodent Borne Viruses, Harrison's principles of Internal Medicine, 16th Edition, Chapter 180, Page 1161.

Written by Allison Ferris, edited by Omotayo Fasan.

HOW IT OCCURS
Dengue Fever, also known as "break bone fever" is the most important arbovirus infection worldwide. There are 50-100million cases per year of Dengue Fever and 200,000-500,000 cases of Dengue Hemorrhagic Fever per year.

Dengue Virus is transmitted via the mosquito vector Aedes, predominantly Aedes aegypti, which is also the vector for yellow fever. There are 4 serotypes of Dengue virus, (DENV-1, 2, 3, 4). It is a member of the Flaviviridae family and is a single-stranded RNA virus surrounded by an icosahedral scaffold and lipid envelope. 

There is a 2-8day incubation period followed by a 1 week illness consisting of fever, severe headache with retro-orbital pain, anorexia, myalgias, and often severe arthralgias, hence the name "break bone fever". Other symptoms include a maculopapular rash and minor hemorrhagic episodes such as gingival bleeding, epistaxis, and petichiae. Laboratory abnormalities include leucopenia, thrombocytopenia, and elevation of transaminases.

Dengue Hemorrhagic Fever (DHF) is defined by WHO as meeting four criteria: fever of 2-7days, tendency for hemorrhage as demonstrated by positive tourniquet test or spontaneous bleeding, thrombocytopenia of <100,000, and evidence of plasma leakage. Plasma leakage leads to hemoconcetration. Hence the patients typically have leucopenia, thrombocytopenia but a preserved or elevated Hb concentration.

Dengue Shock Syndrome is simply DHF with signs and symptoms of shock or circulatory collapse.

Each infection with a Dengue virus serotype confers lifelong immunity to that serotype but not to the others. Although it is possible to get DHF with the first Dengue infection, more commonly DHF occurs with repeated infections with Dengue. Also, older patients tend to suffer the more severe diseases.

Diagnosis of Dengue Fever can occur in several ways, isolation of the virus in serum or pathology specimens, detection of virus by PCR, demonstration of a rise in IgG titers, or demonstration of IgM in the serum. The latter, Dengue IgM antibody, is typically considered "probable" Dengue infection, not confirmed.

Treatment of Dengue Fever, DHF, and DSS is supportive care with intravenous fluid resuscitation and acetaminophen for anti-pyretic effects. NSAIDs should be avoided because of the risk of bleeding. Dengue is mostly a self-limiting infection with most people fully recovering in 7-10days. Prevention efforts are aimed at surveillance and vector control by means of limiting standing water and usage of insecticides. A live-attenuated vaccine is in development.

 References
[1] Ligon BL. Dengue Fever and Dengue Hemorrhagic Fever: a Review of the History, Transmission, Treatment, and Prevention. Seminars in Pediatric Infectious Diseases. 2004. 60-65.
[2] Wichmann O and Jelinek T. Dengue in Travelers: a Review. Journal of Travel Medicine. 2004; 11:161-170.
[3] Harrison’s Principles of Internal Medicine, 16^{th ed.} Page 1164.
^{[4] Duane J Gubler, Dengue and Dengue hemorrhagic Fever . Clinical Microbiology Reviews, July 1998, page 480-496. http://cmr.asm.org/cgi/reprint/11/3/480 .
[5] CDC website: www.cdc.gov}

Compiled by Omotayo Fasan 

September 10, 2007
CASE
A 72 year old Caucasian female was presented to the emergency room with complaints of recurrent episodes of loss of consciousness (LOC) over 4 weeks.  Patient remembered having four episodes of loss of consciousness over 4 weeks, two of which were witnessed.  All four episodes occurred at rest and started with a feeling of light-headedness, followed by a limp, loss of consciousness and urinary incontinence.  No reported vertigo, blurring of vision, focal weakness, sensory deficit or involuntary movements.

The LOC lasted approximately 2 minutes with spontaneous arousal and minutes of residual lethargy.  No post-ictal state.  Patient saw a neurologist at another hospital after the second episode.  She had an MRI and EEG both of which were reportedly normal, however she was started on Keppra by the neurologist. 

Her past medical history was significant for the following:
1983-> Right cervical adenopathy-> Non-Hodgkin’s Lymphoma Rx with XRT
1994-> Recurrence of NHL Rx with CHOP followed by autologous transplant-> has remained in remission
2006-> Dysphagia-> Stage IVa SCC of left tongue base Rx with XRT and Erbitux,s/p PEG tube placement
2007-> underwent cholecystectomy for cholecystitis

Her current medications include Prevacid and Keppra. She has penicillin/cephalosporin allergy with reaction of hives.  She denies smoking, alcohol or IVDA. ROS was significant for one episode of nausea and vomiting.

Examination:
T 98.6 F  HR 28/min  BP 60/40  RR 18/min SpO2 98% RA.  With a 500cc bolus of normal saline her blood pressure increased to 103/68 and HR 60.   

She was alert oriented to person, time, and place.  She had no pallor and was anicteric.  She had mildly dry mucous membranes, clear oropharynx.  She had large 2-3cm hard, non tender, immobile left submandibular mass.  She had normal JVD. No thyroid nodules.  She had symmetric chest expansion with normal respiratory effort, clear to auscultation bilaterally.  She had a normal breast exam. Cardiovascular exam revealed bradycardia at a regular rate and rhythm.  There were no audible murmurs, rubs, or gallops. Abdominal exam revealed a right upper quadrant well healed scar and an intact PEG tube.  Her rectal exam was heme-negative with brown stool.  She had no lower extremity edema, clubbing or cyanosis. Neurological exam revealed no focal abnormality.

Laboratory Data
Na 141  K 3.6  Cl 110  CO2 22  BUN 24  Cr 0.7 Glu 90  AST 28  ALT 30  AP 131 TBIL 0.47 Ca 8.0 Alb 3.6  T prot 6.8 WBC 6.1  Hb 12.3  Plt 134  INR 0.96   

Essential Core Data
A 72 year old female presenting with recurrent episodes of syncope, bradycardia, hypotension and a new large left submandibular mass with the background of stage IV head & neck CA and NHL.

HEURISTICS
Syncope is the abrupt loss of consciousness associated with the absence of postural tone; it is followed by a rapid and usually complete recovery.  

A careful history is the most important diagnostic tool.  The nature of the events and their time course immediately prior to, during, and after the episode often provide valuable etiologic clues.

First, think of reflex mechanisms such as vasovagal, vasodepressor (neurocardiogenic syncope), carotid sinus hypersensitivity, cough, micturation, and valsalva.  

There are also orthostatic hypotension, dysautonomias (high vagal or decreased sympathetic tone), fluid depletion, antidepressants or sympathetic blockers.  

Finally, cardiovascular causes can be broken down into arrhythmic vs. non-arrhythmic causes.  Arrhythmic causes commonly are AV block with bradycardia, sinus pauses/bradycardia (vagal, sick sinus syndrome, or negative chronotropic drugs), ventricular tachycardias due to structural heart disease.  

Non-arrhythmic causes would include hypertrophic cardiomyopathy causing dynamic outflow obstruction precipitated by hypovolemia and postural changes and aortic stenosis causing fixed outflow obstruction associated with exertion secondary to inability to produce a compensatory increase in cardiac output.

Another differential important to consider although not a cause of true syncope is undiagnosed seizure especially with the background of malignancy with possible cerebral metastases. Usually these patients present with abrupt onset of symptoms followed by a post-ictal state.  It is important to note that seizure could complicate syncope i.e convulsive syncope due to persistent global hypoperfusion of the cerebrum. 

Further results
In this patient EKG revealed sinus bradycardia of 40 bpm with normal PR interval.  She had an initial non-contrast CT of head which showed no bleed.  2D-echo which revealed normal valves and LVEF 50%.  She had an MRI/MRA of the brain consistent with mild periventricular white matter changes. Tilt Table Test which was positive, patient became bradycardic, hypotensive and lost consciousness hence was diagnosed with neurocardiogenic syncope. Contrast CT of the neck was performed to evaluate the left neck mass which revealed a left parapharyngeal mass displacing the L internal carotid artery.  She had a CT guided biopsy of the mass which was consitent with squamous cell carcinoma. 

Conclusion
Hence, it was concluded that the patient had a recurrence of her squamous cell carcinoma of head and neck compressing the Lt internal Carotid Artery leading to Carotid Sinus Hypersensitivity.

FURTHER READING
Harrison’s Principles of Internal Medicne 16th Edicition; page 126-133.

INFORMATION COMPILED BY RODINA VATANPARAST

HOW IT OCCURS:
CAROTID SINUS HYPERSENSITIVITY — Hypersensitivity of the carotid sinus results in vagal activation which in turn leads to similar physiologic manifestations to those seen with neurocardiogenic syncope; this is also called the carotid sinus syndrome.   It is precipitated by pressure on the carotid sinus baroreceptors, which are located cephalad to the bifurcation of the common carotid artery.  It typically occurs with turning of the head to one side.  Activation of the carotid sinus baroreceptors  gives rise to impulses carried via the nerve of Hering, a branch of the glossopharyngeal nerve, to the medulla oblangat.  The afferent impulses activate the efferent sympathetic nerve fibers to the heart and blood vessels, cardiac vagal efferent nerve fibers, or both.  In patients with carotid sinus hypersensitivity , these responses may cause sinus arrest or AV block, vasodilation, or both.   In two large series of patients with syncope, carotid sinus hypersensitivity accounted for 6 to 14 percent of patients.

CLINICAL EVIDENCE
How should we intereprete a positve Carotid sinus massage?
A finding of asymptomatic CSH on carotid sinus massage is only an initial step in evaluation. The most common cause of syncope and falls in elders is carotid sinus hypersensitivity (CSH). To determine CSH prevalence in an unselected population of elders, researchers invited 1000 general practice patients aged 65 or older to undergo carotid sinus massage (CSM). Ultimately, 272 patients (median age, 71; 57% men) underwent CSM. 

The protocol was 5 seconds of massage over the point of maximal carotid pulsation on the left and right sides, both while the patient was supine and while tilted to 70 degrees. Cardioinhibitory CSH was defined as asystole of  3 seconds with an SBP drop of <50 mm Hg; vasodepressor CSH as an SBP drop of  50 mm Hg; and mixed CSH as a combination of the two.

One hundred seven patients (39%) exhibited CSH (6 cardioinhibitory, 42 vasodepressor, and 59 mixed); 43 of the 107 (40%) had associated symptoms, and 24 had asystole  3 seconds. Older age and male sex were the only significant predictors of CSH in a multivariable analysis. Of a subgroup of 80 patients without histories of syncope or falls, 28 (35%) had CSH, 10 of whom had associated symptoms. CSM response values above the 95th percentile were asystole lasting >7.3 seconds and an SBP drop >77 mm Hg.

Comment: This study is a sobering reminder of how many asymptomatic elderly people have abnormal responses to carotid sinus massage. Clinicians should not rush to implant pacemakers simply based on a positive response to CSM. An editorialist reminds us of the importance of determining whether symptoms accompany abnormal hemodynamic and electrocardiographic abnormalities during CSM and of being alert to other potential causes of syncope and falls. The potential clinical value of the authors’ proposal to redefine cutoff levels for carotid sinus hypersensitivity (based on their data) must be addressed in further studies.

Reference
Kerr SRJ et al. Carotid sinus hypersensitivity in asymptomatic older persons: Implications for diagnosis of syncope and falls. Arch Intern Med 2006 Mar 13; 166:515-20.

Published in Journal Watch Cardiology April 13, 2006. Hugh Calkins, M.D.

WHAT ’S NEW
New Agent for Atrial Fibrillation?
Dronedarone, an agent similar to — but potentially less toxic than amiodarone, showed some promise in a placebo-controlled trial.
 
Atrial fibrillation is the most common arrhythmia in most countries and is expected to grow in prevalence as longevity increases. Treatment of AF is targeted at reducing fatigue and increasing exercise tolerance, which require maintenance of sinus rhythm, and at reducing the risk for stroke. However, amiodarone, the antiarrhythmic agent most efficacious in AF, is associated with potentially serious adverse events. In two identically designed, manufacturer-funded, international, prospective trials (one in Europe; the other in the U.S., Canada, Australia, South Africa, and Argentina), investigators compared dronedarone, an agent derived from amiodarone but believed to have fewer adverse effects, with placebo in individuals with AF and without heart failure.

A total of 828 patients received dronedarone, and 409 received placebo. The median time to first recurrence of AF was significantly reduced