Pancytopenia

Today we discussed an approach to the patient with pancytopenia

This is an indication for a bone marrow aspirate and biopsy, which usually shows increased or decreased marrow cells:

Hypocellular marrow
-Marrow toxins: May be dose-dependent, predictable as with chemotherapeutic agents, immunomodulators (methotrexate, cyclophosphamide, etc) or idiosyncratic (chloramphenicol, sulfa drugs, phenytoin, many others); radiation, EtOH
-Infection: Parvovirus B12, EBV, HIV, HHV-6, viral hepatitis; severe sepsis
-Immune: SLE, RA (rare), graft-versus-host
-PNH
-Idiopathic stem cell failure

Hypercellular marrow
-MDS, leukemias, lymphomas, myeloma
-Nutritional- severe megaloblastic anemia (B12, folate)
-Marrow replacement/infiltration: myelophthisic anemia , myelofibrosis, granulomatous disease (TB, sarcoid, fungal), solid tumor metastases (prostate and breast are most common)

The topic of the MGUS and multiple myeloma 'spectrum' came up. Here are some helpful criteria based on the NEJM review paper cited below:

MGUS
Marrow plasma cells less than 10% and M-protein (in blood) less than 30g/L
No clinical manifestations

Smouldering MM
Marrow plasma cells at least 10% and/or M-protein at least 30g/L
No clinical manifestations

Multiple myeloma
Marrow plasma cells over 10% and/or M-protein at least 30g/L
Clinical features of hypercalcemia, renal failure, anemia, bone lesions, infections, plasmacytomas

Waldenstrom's macroglobulinemia
Marrow plasma cells over 10% and M-protein over 30 (IgM)
Clinical features of anemia, bleeding, organomegaly, IgM immunoglobulin

Primary amyloidosis (AL)
Marrow plasma cells less than 10% and M-protein less than 30
Clinical fearures of fatigue, wt loss, purpura, nephrotic syndrome, CHF, neuropathy, orthostatic hypotension, massive hepatomegaly

Links:
Click here for a "medical mystery" from NEJM on panyctopenia
Click here for an excellent review paper on MGUS/myeloma differentiation

Eating disorders- medical complications

Today we discussed the medical complications of eating disorders, which can be devastating and affect any system, with mortality as high as 10% in anorexia and 2% in bulemia. A few points:

Electrolyte/renal abnormalities
-Hypokalemia (may be from vomiting, diuretic abuse, laxative abuse)
-Metabolic alkalosis (volume depletion, diuretics)
-Hyponatremia (diuretics, polydipsia prior to weighings)
-Hypophosphatemia
-Hypomagnesemia
-Chronic kidney disease (may be contributed to by nephrocalcinosis, tubular dysfunction)

Cardiovascular
-Bradycardia (may or may not be secondary to electrolyte abnormalities)
-Cardiomyopathy (potentially reversible)
-Long QT
-Mitral valve prolapse

GI
-Parotic hypertrophy
-Decreased contractility
-Mallory-Weiss teats
-SMA syndrome
-Gallstones

Endocrine
-Amenorrhea
-'Sick euthyroid' syndrome
-Growth retardation
-Hypoglycemia

Skeletal
-Osteopenia/osteoporosis

Hematologic
-Marrow suppression

Neurologic
-Seizures
-Peripheral neuropathy

Dermatologic
-Lanugo hair
-Hair loss
-Yellow/orange skin- hypercarotenema
-Russell sign (callus over knuckles)
-Edema

Refeeding syndrome: When pts become rapidly "anabolic" after prolonged periods of starvation, severe electolyte abnormalities can develop and must be aggressively replaced.
-Hypophosphatemia
-Hypokalemia
-Hypoglycemia
-Edema

Link:

Click here for a NEJM review of anorexia

Click here for a case report of reversible severe cardiomyopathy from anorexia

Status Epilepticus

Today we discussed an approach to status epilepticus and seizures in general.

Defined as continuous or repeated seizures without return to baseline for 20-30min (brain activity; may not have convulsions).
NB- there is a movement to make the time part of this definition much shorter (to 5 minutes)

Most seizures last 1-2 min. You need to intervene if beyond this point. At 20 min, the seizure per se damages the brain (scarring, self-perpetuating as sz focus). Also treat if series of short sz with incomplete recovery in between.

Approach is to treat the seizure AND look for the underlying cause

Acute causes: bleed, stroke, trauma, metabolic (e.g. hypoglycemia, hyponatremia, hypocalcemia, others), infections (esp. CNS), hypoxia, intoxication/drugs (or withdrawal), major organ faiure (uremia, hepatic failure)
Chronic: mass, non-compliance with meds

Complications of sz: aspiration, orthopedic complications, lactic acidosis, rhabdomyolysis

Practical approach:

ABC- clear the airway (do NOT put anything in the pt's mouth to prevent 'tongue biting, etc), roll on side, ensure breathing (apply O2)
Get monitors- Vitals, O2 sat,
IV access
CHECK THE GLUCOSE!, If low, amp of D50, glucagon 1mg IM if no IV
Thiamine 100mg IV (esp. if EtOH, pregnant, cancer pts)
Blood: CBC, lytes, renal, Ca profile, glucose, transaminases, drug levels, tox screen

If no immediately reversible cause (e.g. hypoglycemia), drugs to use acutely:

Benzos- lorazepam IV 12-24h anti-sz effect. Loraz 0.1mg/kg at 1-2mg/min (usually 1-2mg aIV at a time, repeated to max) This will stop 80% of sz.
May give diazepam PR if no IV access. 0.2mg/kg PR x 1 or midazolam 5mg IM x1

Phenytoin (Dilantin) 20mg/kg IV load at 50mg/min (e.g. 1400mg over 30 min in 70kg)
If needed, give further 5-10mg/kg.
A couple of points about phenytoin for status:
Do not mix phenytoin and D5; it crystallizes, which is not very helpful in status epilepticus.
Never give dilantin and dopamine together; can cause profound hypotension for unclear reason

Phenobarbital: Strongly consider intubation here
20mg/kg IV @50-75mg/min. This pt should be in ICU

Others: Propofol infusion, midazolam infusion

Look for underlying- bloodwork, CT, LP if fever.
Mimics of status: myoclonus, rigors, movement disorders, herniation (early)

Link:

Click here for an excellent review of status epilepticus from Chest (yes, a weird place for it to be)

Endocarditis

Today we discussed endocarditis. This is a very important topic to have knowledge of regardless of what area one practices in, both in terms of suspecting and confirming the diagnosis, and proper management. The natural history of untreated endocarditis is 100% mortality. A few points:

Traditional breakdown is by time course; perhaps less relevant today than previously.

Subacute classically presents as a chronic, wasting illness, with fever, wt loss and progressive heart failure and complications as the heart is progressively damaged over weeks to months. Typical organisms are (in order) viridans group streptococci, enterococcus, st. aureus

Acute presents with rapidly progressive valvular destruction over days, often with catastrophic hemodynamic and other complications. Typical organisms are st. aureus, enterococci, viridans group streptococci, HACEK organisms.

Other useful classifications that help with predicting microbiology and complications are native vs. prosthetic valve and R-sided vs. L-sided.

Some physical findings (not exhaustive!)

Signs of valvular involvement or local complications:
-murmurs (esp. AI, MR, TR)
-signs of L or R-sided heart failure
-bradycardia (heart block can occur from paravalvular abscess)

Signs of embolic complications/phenomena and vasculitis
-any focal neurological deficit-peripheral cutaneous signs: Splinter hemorrhages, Osler nodes, Janeway lesions, Roth spots, clubbing, subconjuntival and other mucosal petechiae. Remember to look for these on the feet too
-splenomegaly

Signs of underlying causes
-track marks for IDU
-oral exam for dental hygiene

Diagnosis:
-multiple blood cultures from different sites off antibiotics are KEY to the diagnosis and management

Modified Duke's criteria can be helpful (see link for full details):

Major

-multiple blood cultures consistent or Q-fever serology +ve
-echo consistent (oscillating mass, abscess, dehiscence of prosthesis)
-new murmur

Minor
-predisposing heart condition or IVDU
-fever
-vascular phenomena (emboli, etc as above)
-immunologic phenomena (as above)
-blood cultures not meeting criteria for "major"

Definite: (2 major) or (1 major+3 minor) or (5 minor)
Possible: (1 major and 1 minor) or (3 minor)

ECG- check for new blocks (esp. 1st degree AVB; suggests abscess)

Therapy
General principles- need cidal antibiotic. Generally need minimum 4-6 wks of IV therapy

Indications for valve replacement (NB- surgery is probably under-utilized)
-CHF as a direct consequence
-Severe valvular insufficiency
-Paravalvular abscess
-Embolic phenomena post-initiation of therapy
-Persistently positive cultures or fever despite adequate medical therapy
-Size of vegetation (relative)

Links:

Click here for the complete modified Duke's criteria

Click here for a review article from NEJM

Paroxysmal Nocturnal Hemoglobinuria

Today we discussed a very rare cause of anemia and thrombosis, PNH.

This disease results from an acquired mutation in DNA encoding components of complement system, which leads to several clinical manifestations:

1) Hemolysis, which is episodic ("paroxysmal"). The degree of hemolysis depends on how many RBCs are abnormal. Unclear why it is sometimes nocturnal, as shown above. Chronic hemolysis can cause severe anemia, and renal failure from myoglobin-induced tubular damage

2) Thrombosis. It is unclear why patients with PNH are hypercoagulable; it may have to do with platelet abnormalities in PNH (all hematopoietic stem cells can be involved). Thrombosis is usually venous, but can be arterial. The hallmark is thromboses in relatively unusual places, most commonly portal vein or other intra-abdominal veins and cerebral venous sinus thrombosis.

3) Diminished hematopoiesis. Because marrow stem cells are involved, pancytopenia can be ther presenting manifestation.

Diagnosis: "PNH assay", which is flow cytometry for the clone of cells with abnormal complement-related proteins.

Therapy:

1) For hemolysis:
-supportive measures include transfusion, iron supplementation, folic acid supplementation.
-specific therapy is Eculizumab, a monoclonal antibody that inhibits complement activation, and significantly reduces hemolysis. Limiting factor is cost, estimated at $400,000 / year

2) For thrombosis:
-anticoagulation with heparin then warfarin as secondary prevention
-there may be lower risks of thrombosis on Eculizumab
-there is retrospective evidence supporting prophylactic anticoagulation with warfarin in selected patients

Stem cell transplant is also an option reserved as a last resort

Links:

Click here for the paper showing the effect of Eculizumab in PNH

Cocaine- medical complications

Today we discussed cocaine intoxication. Some points:

Acute intoxication:
Cocaine is a sympathomimetic, and acute intoxication presents with this toxidrome:
Hypertension, tachycardia, fever, flushing, diaphoresis, mydriasis, altered mental status, possibly seizures

The anticholinergic toxidrome presents very similarly. The 2 can be distinguished by:
-diaphoresis in sympathomimetic (vs. 'dry as a bone' in anticholinergic)
-more prominent hypertension in sympathomimetic

Management:
Besides the specific organ issues discussed below, general managment consists of
-benzodiazepines (mainstay!)
-if BP control is required, DO NOT USE PURE BETA BLOCKERS; this causes unopposed alpha agonism and makes hypertension/vascular effects worse; labetalol is safe in this situation (because it is both alpha and beta-blocker), and phentolamine or phenoxybenzamine are alpha-blockers that can be used.

Common specific organ effects (besides acute intoxication):
CNS- cerebral vasoconstriction, including stroke; movement disorders
CV- coronary vasospasm, which may cause MI; tachyarrhythmias, hypertensive urgency/emergency
Resp- perforated septum, smoking cocaine causes SOB, wheezing, chest pain hemoptysis in a large proportion of users. Acute fever, dyspnea, hypoxia, infiltrates soon after smoking has been called "crack lung"; is from alveolar damage. Interstitial lung disease is possible.

Recently recognized complication:
In the past year or so, there have been many recognized cases (including at this hospital) of patients presenting with agranulocytosis from cocaine "contaminated" with levamisole, an anti-helminth drug used in animals.

Click here for a summary of this complication

Click here for a paper from the Annals of Internal Medicine describing this. CMAJ has a similar report.

Dilated cardiomyopathy

Today we discussed causes of dilated cardiomyopathy,

Some etiologies of DCM:

1) Ischemia
This is the most common cause of cardiomyopathy in the developed world. Within the category of "initially unexplained" DCM, ischemia is less common, since this is usually the first etiology excluded.

2) Valvular heart disease
Some valvular lesions are compensated chronically by LV dilation- mitral regurgitation and aortic insufficiency are the most common (although NB- MR can follow DCM from dilation itself; this is often termed "functional MR"). End-stage aortic stenosis can also cause DCM

3) Infections
-Viral infections can cause myocarditis, which can lead to DCM. Coxsackie, adeno, echo are the most common. HIV is a recognized as a cause of DCM
-Chagas' disease (a protozoan infection) is most common cause of DCM in Central and South America.
-Lyme disease is associated with cardiac muscle dysfunction, although heart blocks are more common.

4) Toxins
-Alcohol; amount and duration correlate with risk
-Cocaine; may be independent of ischemia
-Anthracycline-based chemotherapy (usually takes a dose of 450mg/M2; each cycle has about 50)

-Trace elements. Rare cause; cobalt, arsenic, mercury... Click here for an interesting "outbreak" of cobalt-induced DCM in Quebec

5) Genetic

6) Peripartum CM- unclear cause; occurs in late pregnancy and early post-partum. Carries relatively good prognosis, but high risk of recurrence in subsequent pregnancies

7) Infiltrative CM's- hemochromatosis, sarcoidosis, amyloidosis

8) Tachycardia-induced cardiomyopathy. Prolonged tachycardia can cause reversible, sometimes severe, LV dysfunction

9) "Stress cardiomyopathy" AKA "Takotsubo" cardiomyopathy:
Rare, but increasingly recognized cause of LV dysfunction, with characteristic apical ballooning on 2D echo. May be associated with ECG changes including ST elevation. Sometimes associated with a stressful event (physiological or psychological); self-resolving. Click here for the origin of this term, the Japanese octopus trap...

In a significant proportion of cases, the cause remains idiopathic.

Links:

Click here for a recent NEJM review of DCM that goes over the evidence base for various pharmacologic and device therapies

Click here for a study looking at underlying causes and prognosis for initially idiopathic dilated cardiomyopathy.

Hyperthyroidism- physical exam

Today we discussed some of the physical exam findings of hyperthyroidism and how to diagnose a goiter

Hyperthyroidism
A general approach to the examination for hyperthyroidsm with some possible findings
General appearance: restless, anxious, thin
Vitals- tachycardia, atrial fibrillation, wide pulse pressure, fever
Eyes-
lid lag (superior sclera visible as patient looks down),
lid retraction, widened palpebral fissure
Graves' orbitopathy (see below)
CNS- fine tremor with hands outstretched, increased reflexes, proximal muscle weakness
CV- flow murmur
Abdo- increased bowel sounds
Extremities- warm, moist skin, velvety skin, pretibial myxedema (in Graves)
Associations: other autoimmune- e.g. vitiligo, adrenal insufficiency

A word about eye findings in hyperthyroidism
Some eye findings are general to all causes of hyperthyroidism (from increased sympathetic activity), and some are specific to Graves' disease.

Sympathetic
-lid lag
-lid retraction
-stare
-conjunctival injection

Graves orbitopathy
-EOM involvement
-lid edema
-exophthalmos
-loss of visual acuity

Evidence for how to diagnose a goiter:
Inspect and palpate
-look for lateral prominence = distance from imaginary line between cricoid and suprasternal notch to surface of thyroid gland
-Categorize as normal or goiter
-Subcategorize as small (1-2x) or large (over 2x) goiter

Ruling out a goiter:
Normal size by palpation (negative R 0.15)
No lateral prominence (NLR 0.41)
“Goiter ruled out” = normal thyroid size or gland not visible with neck fully extended

Ruling in a goiter:
Estimated size by inspection;/palpation
1-2x normal (positive LR 1.9)
over 2x normal (PLR 25)
Lateral prominence 0-2mm (PLR 3.4)
Lateral prominence > 2mm (PLR infinity)
“Goiter ruled in” = large goiter or lateral prominence over 2mm

Link:

Click here for link to JAMA Rational Clinical Examination for goiter (unfortunately, a special JAMA subscription is required)

Scleroderma

Today we discussed scleroderma (AKA systemic sclerosis)

This is a multisystem disesase of small vessels and skin/organ fibrosis

Epidemiology: Age 35-65, Female more common than male (7-12:1).

There are 2 types of systemic sclerosis- limited and diffuse

Limited SSc: sclerosis, thickening of distal limbs without truncal involvement. CREST fits into this category. Associated with anti-centromere AB. Calcinosis refers to localized hand masses on fingers/forearms. Telangiectasias are seen in face/mucosa/hands. Most serious manifestations of limited are pulm HTN, digital ischemia.

Diffuse SSc: thickening over distal and proximal limbs and trunk with significant organ involvement. Criteria are thickening of extremities proximal to MCPs or digital ischemia, pulmonary fibrosis. Edematous skin, painful joints, tendon friction rub, rapidly progressive skin fibrosis. Associated with SCL70 antibody.

Clinical:
Initially nonspecific; Raynaud's, fatigue, MSK complaints followed in variable time period by further sx (soon in diffuse, later in limited).
First specific manifestations are skin thickening, starting as swelling/puffiness over fingers/hands.
Subsequently variable; skin, pulmonary, cardiac, renal, GI involvement.

90% of SSc pts have Raynaud's and fibrosis of fingers, with loss of digital pads (sclerodactyly) and digital ulceration.

Skin: edema, tightness, decreased flexibility, contractures, then fibrosis.

MSK: arthralgias, arthritis, calcinosis, tendon involvement. Late: weakness/atrophy, possible overlap myosits

Pulm: Pulmonary fibrosis, PFTs show decreased volumes, diffusion impairment.

GI: small mouth, dysphagia, GERD/esophagitis. Loss of peristalsis

Cardiac: Myocardial fibrosis, myocarditis, diastolic dysfunction

Renal: Pathological change in most (small vessel vasculopathy); extreme is scleroderma renal crisis (acute kidney injury, with microangiopathic hemolytic anemia)

Therapy: No proven disease modifying agents; treatment is by organ system involved. In severe cases, immunosuppression may be used (e.g. steroids, methotrexate, cyclophosphamide)

Skin- key is moisturize, treat pruritus
Raynaud's- CCB, prazosin in severe
GI- treat GERD, prokinetics for paresis
Renal- ACE-I
Pulmonary- measures for pulm HTN

Links:
Click here for a recent NEJM review of scleroderma
Click here for a review from Rheumatology on scleroderma

Alcoholic hepatitis

Today we discussed alcoholic hepatitis.

This is distinct from chronic alcohol-induced liver disease, which causes steatosis and predisposes to fibrosis, then cirrhosis.

Alcoholic hepatitis is a clinical syndrome of jaundice and liver failure (usually after decades of over 100g/d intake). Patients have often stopped drinking for several weeks before onset. Female sex is a risk factor for this specific condition (with equal intake to men), but more men have the typical intake required.

Rapid onset of jaundice is the cardinal sign. Others include fever and ascites. Liver is typically enlarged and tender. Signs of chronic liver disease are often present.

Alcoholic hepatitis is a poor prognostic indicator; 40% of patients with severe alcoholic hepatitis die within 6 months

Diagnosis:
Lab: AST usually above 2x ULN, but rarely over 1000. ALT is lower. WBC count (esp. neutrophils), and INR are usually high. Renal failure (if it is hepatorenal syndrome) carries a poor prognosis.
Biopsy shows swollen hepatocytes with Mallory bodies. Cholestasis may be present.

Ddx includes NASH, viral hepatitis, drug-induced, fulminant Wilson's, autoimmune liver disaese, alpha-1, pyogenic abscess, cholangitis, HCC.

Severity indices:
Maddrey's discriminant function: [4.6 x (pt's PTT - control PTT)] + bili (mg/dL)
Value over 32 indicates severe alcoholic hepatitis; this is threshold for starting steroids.
MELD over 21- severe

Therapy:
General
salt restriction, diuretics, lactulose, thiamine, withdrawal tx as indicated. Tap for SBP
EtOH abstinence
Specific
Steroids: prednisolone 40mg/d x 4 weeks, then taper (or equivalent)
Pentoxyfylline- 400mg PO TID increases in-hospital survival; little head-to head data comparing to steroids; should be considered where there are contraindications to steroids.

Link:
Click here for a 2009 review from NEJM on alcoholic hepatitis that goes over the evidence for various therapies.

Syphilis

Today we discussed syphilis. Some points about this infection that has made a resurgence:

Treponema pallidum (spirochete), is spread through contact with infectious lesions or fluids. 50-75% of exposed sex partners get infected.

Clinical manifestations (NB- syphilis is the "great imitator"; these are the more common presentation, but keep a high index of suspicion in the right epidemiological setting)

Primary:
-skin lesion (chancre) at site of innoculaion ~21d after exposure. Often goes unnoticed. Classically non-tender, indurated, non-purulent. Heals spontaneously.

Secondary:
-4-10 weeks after chancre appearance. Rash in 90%; pink, red, or purpule macules on flanks, shoulders, arms, chest, back. May become maculosquamous/papular and affect hands/soles in 50-80%.
-other signs/symptoms include sore throat, malaise, h/a, lymphadenopathy. Can cause neurologic, renal, ophthalmologic, GI, hepatic disease. Resolves without treatment, may recur.

Tertiary:
Years later- aortitis, gumma (mass), iritis.

A word about neurosyphilis:
Neurosyphillis can occur early or late. May coexist with primary, secondary, or tertiary. May see meningitis, cranial nerve involvement, eye involvement, meningoencephalitis, meningovascular (presents as stroke). Late findings are rare; occur decades later: paresis, dementia with psychosis (rapidly progressive), tabes dorsalis (posterior column involvement, bowel, bladder dysfunction).

LP indicated in any of 1) neuro/ocular/otic symptoms/signs. 2) biochemical evidence of late latent syphilis (or unknown duration) in HIV pt. 3) active tertiary- gumma, aortitis, iritis. 4) treatment failure for non-neurosyphilis

Lab testing
The lab testing for syphilis is very complex and confusing. Here are some general comments; click here for detailed interpretation from the Ontario Public Health Lab website

NB- RPR is essentially synonymous with VDRL
1) EIA (enzyme immunoassay), TPPA, FTA-Abs. All of these are durable antibody tests that are very sensitive, and remain positive for life. If negative, syphilis is usually ruled out. If positive, need confirmatory testing (there are false positives)
2) RPR- This is also an antibody test, but more suggestive of active infection. If postive, this confirms diagnosis. If negative, it can mean 1 of several things: a) very early primary- retest in 2 weeks. b) successful treatment. c) late latent d) biologic false positive

Treatment:
NB- latent =seroreactivity without clinical manifestations. Early is infected within previous year by documented conversion. Late is over 1 year from primary infection

Primary, secondary, early latent: Pen G 2.4M U IM single dose
Late latent, unknown, tertiary: Pen G 2.4M U IM qweekly x 3.
Neurosyphilis, ocular, otic: Pen G IV 18-24M units/d divided q4h for 10-14d.

NB- need repeat serology to confirm/document treatment success- see paper below for details

Primary should have RPR negative at 1 year. Secondary at 2 years. Tertiary at 5 years.

Links:
Click here for a JAMA review of syphilis that most of this post is based on
Click here for the Ontario Public Health Lab algorithm for interpreting the MANY permutations and combinations of lab results

Myelopathy causes

Today we discussed myelopathy (i.e. spinal cord pathology)

Features to suggest myelopathy:
-bilateral motor and sensory signs or symptoms not involving the head
-weakness, spasticity, hyperreflexia (although may see hyporeflexia acutely)
-sensory findings with a descrete level
-bowel and bladder involvement

Causes of myelopathy:

1) Compression- herniated disc, tumor (extramedullary or intra-medullary) most common. Epidural abscess (often st. aureus). Also consider in conditions with c-spine instability like Down's and rheumatoid arthrititis

2) Inflammatory- MS; typically incomplete. SLE- usually incomplete, within a vascular territory (i.e. transverse myelitis), CNS vasculitis

3) Metabolic- subacute combined degeneration (i.e. dorsal column and corticospinal tract)- ddx is B12 deficiency and tabes dorsalis (syphilis)

4) Infectious- cord itself: syphilis, HIV, HTLV (esp in Caribbean), VZV. Surrounding structures causing compression: epidural abscess, vertebral osteomyelitis (bacterial, mycobacterial or fungal)

5) Vascular- cord infarction- rare (can be seen in aortic dissection or hypercoagulable state), AVM- very rare.

6) Genetic- Devic's (optic neuritis, myelopathy only- probably variant of MS)

Link:

Click here for a NEJM review paper by UHN physicians on cervical radiculopathy and myelopathy

Dyspnea in a patient with cancer

The general approach to the patient with a malignancy who presents with dyspnea is similar to that in a patient without a malignancy, but some considerations are more prominent in this situation. Some issues to think about:

Infections:
-post-obstructive pneumonia
-opportunistics: PCP, especially if on prednisone 20mg for over 2 months (or equivalent).
-nosocomial pneumonia
-fungal esp. if neutropenia.
-TB reactivation
-tachypnea as compensation for lactic acidosis in sepsis

Vascular/lymphatic:
-pulmonary embolism
-lymphangitic carcinomatosis
-tumor emboli syndrome (seen in lung, prostate, breast- micromets plugging pulmonary capillaries. PFTs may show diffusion abn).
-secondary pulmonary HTN

Airway:
-endobronchial lesion
-COPD- esp smoker with lung ca,

Neuromuscular:
-Lambert-Eaton
-phrenic nerve involvement
-steroid myopathy

Parenchymal/interstitial (in addition to infectious items above):
-drug effect
-radiation effect

Pleural:
-pleural effusion
-pneumothorax
-pleural involvement of malignancy itself

Cardiac:
-pumonary edema seconary to cardiomyopathy- chemotherapy toxicity (esp. anthracyclines) -pericardial effusion

Other:
-anemia

CLL and its complications

Today we discussed CLL and some issues related to hyperleukocytosis

Chronic lymphocytic leukemia:
Briefly, the most common leukemia; commonly an indolent condition for up to decades, but a subset transform to another lymphoproleferative disorder (e.g. lymphoma) or AML.

Most commonly picked up as incidental finding of lymphocytosis >5000, splenomegaly, lymphadenopathy, smudge cells on blood film (shown above). Sometimes B symptoms. Is diagnosed by flow cytometry showing monoclonal B markers (bone marrow bx not always needed).

Complications of CLL:
1) Immunodeficiency as outlined below
2) Autoimmune hemolytic anemia
3) Red cell aplasia
4) Transformation as above

Immunodeficiency in CLL:
This is B-cell disorder, so humoral immunodeficiency.
This type of immunocompromise is seen in congenital hypogammaglobulinemia (common variable immunodeficiency), B cell disorders (inc. myeloma, Waldenstrom's, CLL). Causes susceptibility to encapsulated (s. pneumo, H. flu, meningococcus), as well as Giardia, and C. Diff.
IVIG may be indicated in severe infection or immunoglobulin level <0.5 lower limit of normal (see link below). These pts get recurrent sinopulmonary infections because they do not produce secretory IgA.

In patients with CLL who are treated, there can be severe immunodeficiency of other types:
1) Neutropenia from myelotoxic chemotherapy (e.g. chlorambucil)
2) Cell-mediated- from fludarabine (t-cell inhibitor sometimes used); susceptible to PCP, listeriosis, fungal, etc.

This makes a severe, combined immunodeficiency state (like congenital SCID)

Leukostasis:
More important if cells are sticky (esp blasts). Causes leaky endothelium. May cause noncardiogenic pulm edema, retinal hemorrhage, encephalopathy, stroke, renal failure, MI, heart failure.
Not all leukocytosis is the same; risk of hyperviscosity/leukostasis depends on how 'sticky' the involved cell is:
Highest risk is blasts in AML.
If AML, very high risk is WBC over 100
CML- WBC in 200's or blast conversion
CLL-very rare to have leukostasis complications regardless of level.

If acute complications of leukostasis, hematologists/oncologists will sometimes use hydroxyurea, cyclophosphamide, or even leukopheresis

Link:
Click here for the abstract of the RCT showing benefit of IVIG in pts with CLL with hypogammaglobulinemia and recurrent infections

Amyloidosis

Today we discussed amyloidosis. A few points about this rare, but serious and often multi-systemic condition

Amyloidosis refers to deposition of an altered conformation of a protein into amyloid fibrils that deposit systemically, giving various clinical manifestations depending on which system(s) are involved. One way of classifying amyloidosis is by which protein is forming the amyloid:

AL: amyloid is formed by immunoglobulin light chains or fragment produced by clone of plasma cells. Plasma cell burden is usually low (~5-10%). 10% have multiple myeloma.

AA: amyloid is formed by 'amyloid A protein', an acute phase reactant. This form of amyloid is associated with longstanding inflammatory conditions. Classic ones are RA, IBD, FMF

Familial amyloidosis: proteins forming amyloid are transthyreitin, apolipoproteins, lysozyme, etc.

"Senile systemic": transthyreitin amyloid, predominantly in heart.

Others: Alzheimer's disease is associated with amyloid fibril deposition in the brain; the protein is a-beta 40 and 42. It is unclear whether amyloid fibrils are causitive.

Possible clinical manifestations:

1) Neurological- CNS- intracranial hemorrhage (amyloid angiopathy), dementia. PNS- peripheral neuropathy (glove-stocking), compressive neuropathy (e.g. carpal tunnel)

2) Cardiac- infiltrative cardiomyopathy- systolic or diastolic dysfunction, arrhyhtmia (heart blocks or ventricular arrhythmias). Cardiac involvement carries the worst prognosis. Rare in AA amyloidosis.

3) Renal- may cause nephrotic syndrome or asynptomatic proteinuria

4) GI- hepatomegaly with or without splenomegaly, GI bleeding, dysphagia

5) MSK- macroglossia as shown above, arthritis

6) Dermatologic- ecchymoses from friable vessels, periorbital purpura, fat infiltration is common but asymptomatic- may allow for diagnosis

7) Hematologic- Factor X deficiency leading to bleeding diathesis, petechiae (F10 binds to amyloid fibrils)

8) Pulmonary- less common; persistent pleural effusions

Diagnosis is made by organ system involved. Abdominal fat pad bx (stained for Congo red) is positive in 80% of AL, 65% of AA.

Treatment depends on type.
In AA, directed at underlying inflammatory disorder
In AL, directed at underlying plasma cell disorder

For cardiac amyloidosis, implanted defibrillator is sometimes indicated. High dose systemic chemotherapy (e.g. melphalan) is sometimes used.

Link:

Click here for a NEJM case discussion of amyloidosis- nicely summarizes the issues

Hypercalcemia

Today we had some discussion about hypercalcemia. Some points:

Symptoms:
GI- anorexia, n/v, abdo pain, constipation.
Renal: stones, polyuria.
Neuro: weakness.
Cardiac: arrhythmias

Etiology:
Useful first division is by PTH level
1) High PTH- expect high Ca, low PO4.
-primary/secondary/teriary hyperparathydoidism, parathyroid hyperplasia
-lithium
-familial hypercalcemic hypocalciuria

2) Low PTH
-PTHrP from malignancy (esp. SCC- lung, H+N)
-hypervitaminosis D- expect high Ca and high PO4- from granulomatous disease, lymphoma)C) -OAF = IL6 (local paracrine effect; in breast and hematological cancers)
-Direct effect of mets (e.g. prostate, lung, etc.)
-Myeloma
-Medications- HCTZ, Ca, vit. D
-Milk alkali syndrome
-Hyperthyroidism

As inpatient, #1 cause = malignancy
As outpatient, #1 cause = primary hyperparathyrodisim

Tx:
Fluids!
Consider bisphosphonate if malignancy-related or v. high (but takes days to work)
Calcitonin by nasal spray or subq.
If hyper D from sarcoid or lymphoma, possible steroids.
Avoid lasix since most patients are profoundly volume depleted.
Last resort is dialysis

Milk-Alkali syndrome
Triad of hypercalcemia, met alk, renal failure assoc with ingestion of large amts calcium, alkali
Once common because of PUD treatement. Making resurgence b/c of calcium for osteoporosis, and prevention of secondary hyperparathyroidism in CKD
Sequence: hypercalcemia, dec GFR, met alkalosis ("contraction"). Hypercalcemia per se stimulates renal bicarb fomation.
Pts on vit D, thiazides, vol contraction, CKD are at higher risk

Some links:

Click here for NEJM clinical problem solving case on hypercalcemia
Click here for a review of calcium disorders in renal disease

Atrial fibrillation- acute management

Today we discussed issues related to acute management of atrial fibrillation. A few points:

After establishing that the patient's airway and breathing are stable, the first decision point is whether the patient needs emergent synched cardioversion.
Indications as per ACLS algorithm:
1) Hemodynamic instability, 2) Shock (i.e. hypoperfusion), 3) Pulmonary edema, 4) Ischemia
HOWEVER, remember that clinical judgement is absolutely required; this is not risk-free, and many patients have mild pulmonary edema and borderline hypotension with rapid A-fib and do not all need to be cardioverted.

If emergent cardioversion is indicated, important steps include
1) Consider pre-treatment with antiarrhythmic (e.g. amiodarone); increases the likelihood of success
2) Analgesia and sedation, requiring the capability to deal with the airway; usually requires the help of anesthesia unless in the ICU
3) Application of the pads- "sandwich"- front and back is more successful than sternal and lateral
4) Synchronized cardioversion with 50-100J
5) Anticoagulation for at least 4 weeks post-cardioversion

Watch for
-bradycardia (pts usually have some AV nodal agent "on board" prior that was dosed to their a-fib; if now in sinus, may be bradycardic
-embolic complications

If elective cardioversion (i.e. not emergent), considerations include
1) Embolic risk
If a-fib is present more than 48h (usually difficult to determine) or the patient was not therapeutically anticoagulated for 2 weeks or more prior, there is a significant (but difficult to quantify) risk of systemic embolization with restoration of sinus rhythm. A trans-esophageal echo that shows no evidence of a thrombus makes the risk very low, and is done in situations where emergent cardioversion is not necessary, and the above criteria are not met.
NB- the risk of embolization exists for pharmacologic cardioversion as well, although may be lower than electrical (think about this when using antiarrhythmics like amiodarone)

2) Procedural risk (sedation, analgesia, arrhythmia, etc)

If cardioversion is not indicated, rate control is the next management choice. Options include:
1) Beta-blockers (e.g. metoprolol 2.5-5mg IV over 5-10min)
2) Non-DHP calcium channel blockers (e.g. diltiazem 15-20mg IV over 5-10 min)
3) Digoxin (e.g. 0.25mg IV load)
4) Amiodarone (but note cardioversion risk as outlined above)

There is little evidence to guide us in the acute setting (but lots of evidence in the chronic setting- e.g. AFFIRM)
Reasons to use beta blockers or CCB: Little toxicity, easy to titrate, often the patient has another indication (for B-blocker), rate control is more reliable than digoxin (see below)
Reasons to think twice before using a beta blocker or CCB: LV dysfunction (esp. CCB), pulmonary edema (both), reactive airways (B-blocker), conduction system disease (both)

Reasons to consider digoxin: Is an inotrope, and carries lower risk of hypotension or worsening pulmonary edema. Works particularly well in decompensated aortic stenosis since allows more filling time without affecting contractility
Reasons to think twice before using digoxin: Patient can override it with sympathetic stimulation (that is usually present) since it does not block this, risk of toxicity if levels supratherapeutic, more difficult to use, debatable long-term benefit (definitely no mortality benefit from DIG trial)

Anticoagulation may be initiated in the ED if clearly indicated, but may also wait until the patient is more stable, and risks/benefits (which usually favour anticoagulation) have been discussed.

Lymphadenopathy

Today we discussed an approach to lymphadenopathy. A few points:

Normally, nodes are smaller than 1cm, mobile, soft, nontender. May be larger in young pts. Palpable inguinal nodes or submandibular can be normal.

Generally subdivide into local (1 grp) vs. general.

Local-

Cervical:
Infection- EBV, CMV, toxo, TB (lymphadenitis if intact, "scrofula" if burst), cat scratch (bartonella), staph, strep infections
Malignancy- lymphoma, metastatic squamous ca (esp. posterior)
Other- Kikuchi's disease (cervical LA and fever in young female)

Supraclavicular:
Malignancy- 24-50% of pts over 40 with supraclavicular adenopathy. R-sided is associated with thoracic (lung, mediastinum, esophagus). L-sided is assocaited with abdominal (virchow's node; especially gastric ca)

Axillary:
Infection- cat scratch, trauma
Malig- BrCa, mets

Epitrochlear:
Infection- local trauma, secondary syphilis, tularemia
Malig- lymphoma
Other- sarcoid

Inguinal:
Infection- lower ext/gu inf
malig- lymphoma

Generalized:

Malignancy- lymphoproliferative, leukemia, mets
Infection- HIV (acute seroconv), EBV (fever, lymphad, pharyngitis; post>ant), typhoid, CMV, histoplasmosis, mycobacterial infection (TB, MAI), others...
SLE
Serum sickness (=tetrad of fever, arthralgias, rash, LA). Drugs often cause: allopurinol, phenytoin, penicillin, hydralazine, carbamazepine, gold, etc)
Others: Sarcoidosis, Castleman's disease

Approach:

H: infection/malig, time course, pain, etc, exposures (bites, uncooked meat, sexual hx, drugs)
P: location, size, tenderness, consistency, mobility, spleen, look for primary

Inv: in generalized, CBC, lytes, ca, LDH, uric acid, PBF, CXR, HIV, ANA, VDRL. Localized: if no suggestion of malig, may observe for 3-4 wks. If persistent, biopsy.

Link:

Click here for an excellent article on lymphadenopathy from American Family Physician

Diplopia and dysconjugate gaze, ptosis

Today we discussed an approach to ptosis, diplopia and dysconjugate gaze. A few points:

An approach to diplopia: A useful first step is to break down between monocular (i.e. present with 1 eye closed) and binocular (far more common). If binocular, run through the potential causes anatomically from the central to peripheral.

Monocular: Consider ophthalmological causes

Binocular:
If changes through the day, consider myasthenia gravis
If thyroid disease present, consider Graves ophthalmopathy
If facial trauma, consider orbital fracture (most likey to cause inferior oblique palsy because of orbital floor fracture) other orbital diseases (e.g. tumor, infiltration, etc)

Once neurological:
1) Cerebral hemisphheres- gaze palsy/preference from frontal lesion (e.g. stroke), progressive supranuclear palsy (vertical then horizontal palsy with dementia, parkinsonism)
2) Brainstem- III, IV, or VI nuclei, internuclear ophthalmoplegia (can't adduct eye)- ipsilateral median longitudinal fasciculus (MLF)- leaves convergence intact. Brainstem causes include ischemic stroke, tumor, bleed, infection, demyelination
3) Nerves exiting the brainstem- compression (tumor, aneurysm), infarction or inflammation(e.g. DM2, vasculitis). REMEMBER WERNICKE'S! (thiamine deficiency), Miller-Fisher variant of Guillan-Barre (would have areflexia, ataxia),
4) Meninges- meningitis, neurosarcoid, leptomeningeal spread of cancer
5) Cavernous sinus thrombosis- III, IV, V1, V2, VI pass through; often associated with facial infections
6) NMJ- myasthenia as above

In someone with diplopia, how do you figure out which eye is the problem (if it's not obvious)?
A couple of pearls:
1) If someone complains of diplopia on looking in one diagonal direction, it is either the same-sided and oriented rectus muscle or the other-sided oppositely-oriented oblique muscle (e.g. diplopia on looking up and right, it is either R superior rectus or L inferior oblique. Diplopia on looking down and L is either L inferior rectus or R superior oblique)
2) If you cover up an eye when the patient is having diplopia, the eye that, when covered, takes away the most peripheral image is the problem

Ptosis:
Some considerations:
CN III palsy- should have ocular movement abnormalities, may have pupillary involvement (would be mydriasis from loss of parasympathetics)
Horner's syndrome- miosis (from loss of sympathetics), anhydrosis
Neuromuscular junction disorders- myasthenia gravis, botulism

Links:

Click here for a review from Neurology on evaluation of diplopia (need subscription to get)

Click here for a review of the link between migraine and stroke (a controversial, hot topic)

Pleural effusions

Today we discussed pleural effusions

Most common causes of effusion in North America are CHF, pneumonia and cancer.

Indication for thoracentesis: Clinically significant effusion (i.e. over 10mm thick on u/s or lateral decubitus) with no clearly known cause.
If CHF with bilateral effusions, trial of diuresis first. 80% of CHF effusions are bilateral. If unilateral, should be tapped. 75% of CHF effusions resolve within 48h of diuresis.
If over 3d, thoracentesis is indicated.
If pt has SOB at rest, therapeutic in addition to diagnostic tap should be done (i.e. up to 1-1.5L).

No need to do routine CXR post except if air is obtained, c/p, cough, dyspnea.

Bloody effusion narrows Ddx somewhat to cancer, PE, trauma, infection (inc. pneumonia, TB)

Transudative: leading causes are CHF, cirrhosis, PE.
Exudative: leading causes are pneumonia, cancer, PE.


Light's criteria for exudative effusion:
Any of
protein level pleural:serum over 0.5
LDH pleural:serum of over 0.6
pleural LDH over 2/3 upper limit of normal for serum

Light's criteria are sensitive for exudate; may have transudates falsely called exudates. If clinical appearance suggests transudate but Light's criteria says exudate, measure albumin in serum vs. pleural fluid. If serum albumin is over 12 greater than pleural fluid almost all have transudative. This criterion is more specific for transudate, because it calls some exudates transudates.

If transudative effusion, determine which of CHF, cirrhosis, PE exists.
If exudative, further workup is needed, including cell counts, culture, glucose, cytology, TB studies.

Cell count:
Predominence of PMNs (over 50%) suggests acute process (parapneumonic, PE, pancreatitis). Only ~15% of malignant, and almost no tuberculous effusions have PMN over 50%.
Mononuclear predominance (lymphocytic) suggests chronic process; cancer, tuberculous, post-CABG.
Eosinophils (over 10%) is usually blood or air in pleural space. Unusual causes are Churg-Strauss, drugs (dantrolene, bromocripine, nitrofurantoin), asbestosis, parasitic infections.
Basophils: leukemic infiltration

Culture: yield is higher if also blood C+S.

Glucose: low glucose suggests empyema or malignant. Less commonly, hemothorax, TB, parasitic (e.g. paragonimiasis), primary inflammatory (e.g. RA, SLE, Churg-Strauss)

Cancer: cytology yield is highest for adenoca. Less useful for mesothelioma, squamous, lymphoma, sarcoma. VATS is choice if suspected ca but negative cytology. If lymphoma suspected, flow cytometry can show pleural fluid clonal population.

TB: tuberculous pleuritis effusions resolve, but pulmonary or extrapulm TB develop in >50%. Investigate for TB if lymphocytosis. Less than 40% have positive pleural cultures.

pH: indicated if parapneumonic or malignant suspected.

PE: Suspect if dyspnea out of keeping with size of effusion, pleuritic c/p, hemoptysis.

"Complicated pleural effusion"- i.e. an indication for drainage (pigtail or surgical chest tube) Any of
1) cloudy fluid
2) pH less than 7.2
3) Glucose less than 2.2
4) Pleural to serum glucose ratio less than 0.5
5) LDH over 1000
6) Neutrophils over 25000
7) effusion occupying 50% of hemithorax (relative indication)

Links
Click here for NEJM review of pleural effusions by Dr. Light himself
Click here for an excellent review from Clinical Infectious Diseases on empyema and parapneumonic effusions