You are working at a family medicine clinic with Dr. Hill. She tells you, “The next patient, Mr. Smith, is a 53-year-old male with a chief concern of swelling and pain in his left lower extremity.”
Before you go to see Mr. Smith, a quick review of the chart reveals that he has type 2 diabetes, obesity, hypertension, and hyperlipidemia. You note that he has not been to the office in the past six months, and it appears that he should be out of all of his medications.
When you enter the examination room, Mr. Smith, a middle-aged male, greets you from where he is sitting. You introduce yourself and ask him what brings him to the office today.
He replies, “It’s my left leg. The past four days it has been red, swollen, and painful—and it seems to be getting worse.”
You ask him to tell you more about this problem.
He says, “It began several days ago, and the swelling seems to be getting worse. It hurts all the time; it doesn’t even get better when I rest it. It seems to get a little worse when I move around. It hurts to walk as soon as I try to stand on it.”
Now that you have a general sense of Mr. Smith’s issue, you ask more focused questions.
“Did you do anything to injure your foot?”
He replies, “I do not remember any injury, but there has been this sore on the bottom of my foot for several months. There’s nothing draining out of the sore and it doesn’t hurt, although my foot doesn’t have much feeling in it.”
“Before this happened, were you sitting down for a long time without getting up and using your legs, such as taking a long airplane trip; or have you been on bed rest?”
“I wish I could go somewhere on an airplane and get a good vacation, but I can’t afford anything like that. I haven’t been on bed rest. I’ve been pretty busy lately.”
“When was the last time you were in the office?”
“It has been a long time now because my daughter and new baby recently moved in with me and I have been trying to take care of the baby as well as keep my job as a bus driver,” he explains.
“Have you been taking your medication?”
He replies, “I have been out of my medication for several weeks now.”
After talking with Mr. Smith more, you discover:
Social History: Does not drink alcohol, but does smoke 1.5 packs of cigarettes daily, he is unmarried, and lives in public housing with his three children and one grandchild.
Review of Systems: No fever or chills, no chest pain, no shortness of breath, and no swelling of the right leg.
You examine Mr. Smith and find:
Vital Signs: T 36.5 °C (97.8 °F), BP 140/90, HR 85, RR 12, O2 98%
Cardiovascular and lung exam: Unremarkable
Lower extremity exam:
Mr. Smith’s entire left leg is swollen, warm and erythematous. The measurement of the circumference of the largest left calf section is 3.5 cm larger than his right calf at the same location.
There is pitting edema. The leg is tender to the touch, especially along the distribution of the deep venous system.
Dorsalis pedis and posterior tibialis pulses are palpable on both feet. Digital capillary refill time is two seconds. Deep tendon reflexes are present (2+).
He has decreased sensation and is unable to determine the location of a monofilament test on either foot up to the ankle in a stocking distribution.
You note a 2 cm ulceration on the plantar surface of Mr. Smith’s left foot.
At this point, you excuse yourself to discuss your findings with Dr. Hill, assuring Mr. Smith you will return in a few moments.
Dr. Hill asks you to consider a differential diagnosis.
Choose five of the following that are at the top of your differential given what you know of Mr. Smith so far.
The best options are indicated below. Your selections are indicated by the shaded boxes.
A. Cellulitis
B. Deep venous thrombosis
C. Lymphedema
D. Muscle strain
E. Peripheral artery disease
F. Popliteal cyst
G. Venous insufficiency
SUBMIT
Answer Comment
The correct answers are A, B, C, E, G.
Most Likely Diagnoses
Mr. Smith’s concern of swelling that is unilateral is an important finding to support the diagnosis of cellulitis, lymphedema, or deep vein thrombosis (DVT). In contrast, for venous insufficiency one would expect bilateral leg swelling. Peripheral artery disease (PAD) is not particularly associated with edema.
Cellulitis and DVT are acute processes. Lymphedema, PAD, and venous insufficiency are less likely, given the acute nature of Mr. Smith’s symptoms.
Since PAD, venous insufficiency, and lymphedema are not infectious processes, the lack of fever in Mr. Smith’s case keeps these diagnoses on the differential.
In Mr. Smith’s case, the acute unilateral swelling, erythema, and warmth in a diabetic patient, make cellulitis (A) likely. The presence of a fever would support the diagnosis of an infectious process like cellulitis. But the fact that Mr. Smith does not have a fever doesn’t rule out a diagnosis of cellulitis as it is certainly possible to have localized cellulitis without fever.
In Mr. Smith’s case, you feel that the acute nature of his symptoms—the unilateral swelling, and the presence of risk factors such as obesity, smoking, and diabetes—make DVT (B) a very likely diagnosis. Mr. Smith does not have a fever, but the inflammatory process due to a thrombus in his vein could explain his unilateral lower extremity edema.
Lymphedema (C) can be present unilaterally, however this is usually a more chronically developing problem, making this diagnosis less likely.
While venous insufficiency (G) could contribute to the development of a DVT, the acute and unilateral nature of Mr. Smith’s symptoms make you think a diagnosis of venous insufficiency alone is less likely.
In Mr. Smith’s case, a diagnosis of PAD (E) seems unlikely given the lack of claudication and normal pulses on examination. Although PAD may not be the primary cause of Mr. Smith’s leg swelling and pain, it could potentially be contributing to it by increasing his risk for a foot ulcer. Mr. Smith’s history of smoking and diabetes increases the likelihood that he has PAD.
Less Likely Diagnoses
Muscle strain (D)—Although this can be a cause of swelling and pain, in a patient with intact mental status, a history of trauma should be present to consider this.
Popliteal cyst (F)—This should be palpable behind the knee and rarely would cause the extensive swelling and pain seen in Mr. Smith.
TEACHING POINT
Differential of Unilateral Lower Extremity Edema
Most Likely Diagnoses
Lymphedema
Lymphedema is generally painless, but patients may experience a chronic dull, heavy sensation in the leg. In the early stages of lymphedema, the edema is soft and pits easily with pressure. In the chronic stages, the limb has a woody texture and the tissues become indurated and fibrotic.
Lymphedema initially involves the foot and gradually progresses up the leg so that the entire limb becomes edematous.
Cellulitis
Cellulitis is an acute inflammatory condition of the skin characterized by localized pain, erythema, swelling, and heat.
Small breaks of skin are associated with streptococcal infection, whereas staphylococcal cellulitis is commonly associated with larger wounds, ulcers, or abscesses.
Patients with diabetes are more susceptible to infections like cellulitis. Diabetic neuropathy causes an unawareness of abnormal pressure distribution. Ill-fitting shoes, cuts, or punctures can then lead to the development of ulcers.
Vascular disease with diminished blood supply contributes to the development of the lesion, and infection is common.
DVT
Classic symptoms of DVT include swelling, pain, and discoloration in the affected extremity.
Physical examination may reveal the palpable cord of a thrombosed vein, unilateral edema, warmth, and superficial venous dilation.
Classic signs of DVT include Homan’s sign (pain on passive dorsiflexion of the foot), edema, tenderness, and warmth. While difficult to ignore, they are of low predictive value and can occur in other conditions such as musculoskeletal injury, cellulitis, and venous insufficiency.
Chronic venous insufficiency may result from DVT and/or valvular incompetence. Following DVT, the valve leaflets become thickened and contracted so that they are incapable of preventing retrograde flow of blood; the vein becomes rigid and thick-walled. Although most veins recanalize after an episode of thrombosis, some may remain occluded. Secondary incompetence develops in distal valves because high pressures distend the vein and separate the leaflets.
Primary deep venous thrombosis can also occur without previous thrombosis. Patients with venous thrombosis often complain of a dull ache in the leg that worsens with prolonged standing and resolves with leg elevation. Examination reveals increased leg circumference, edema, and superficial varicose veins.
The presence of a thrombus in a vein may be accompanied by an inflammatory response in the vessel which may be minimal or may be characterized by granulocyte infiltration, loss of endothelium, and edema. This inflammatory process may also result in a low-grade fever.
Smoking and obesity are the most robust risk factors in the development of DVT. Diabetes, sedentary lifestyle, hypertension, hyperlipidemia, increasing age, prolonged immobility, surgery, trauma, malignancy, pregnancy, estrogenic medications (e.g., oral contraceptive pills, hormone therapy, tamoxifen (Nolvadex)), congestive heart failure, hyperhomocysteinemia, diseases that alter blood viscosity (e.g., polycythemia, sickle cell disease, multiple myeloma), and inherited thrombophilias are other potential risk factors in the development of DVT.
Venous insufficiency
The edema of venous insufficiency can be differentiated from chronic lymphedema as venous insufficiency edema is softer, and there is often erythema, dermatitis, and hyperpigmentation along the distal aspect of the leg. Skin ulceration may occur near the medial and lateral malleoli.
Obesity is commonly associated with venous insufficiency.
Peripheral artery disease
Peripheral artery disease (PAD) is the presence of systemic atherosclerosis in arteries distal to the arch of the aorta. As a result of the atherosclerotic process, patients with PAD develop narrowing of these arteries.
Patients with PAD have a history of claudication, which manifests as cramp-like muscle pain occurring with exercise and subsiding rapidly with rest. In addition, later in the course of the disease, patients may present with night pain, nonhealing ulcers, and skin color changes.
An ankle-brachial index (ABI) can be done to determine the presence of PVD. An ABI of < 0.9 is consistent with the disease.
Classic risk factors for PAD are smoking, diabetes mellitus, hypertension, and hyperlipidemia. Obesity (body mass index (BMI) > 30) increases risk for PAD as well.
Recent trials have added chronic renal insufficiency, elevated C-reactive protein levels, and hyperhomocysteinemia to the list of risk factors.
The greatest modifiable risk factor for the development and progression of PAD is cigarette smoking. Cigarette smoking increases the odds for PAD by 1.4 for every ten cigarettes smoked per day.
Arterial insufficiency is four times more prevalent in patients with diabetes than in those without diabetes. Nearly half of patients who’ve had diabetes for 20 years or more have PAD, usually below the knees.
alue of Diagnostic Tests
Sensitivity is the proportion of patients with disease who test positive.
Sensitivity = True Positives/True Positives PLUS False Negatives
Specificity is the proportion of patients without disease who test negative.
Specificity = True Negatives/True negatives Plus False Positives
Positive Predictive Value is the probability the person with a positive test result actually has the disease being tested for.
PPV = True Positives/True Positives +False Positives
Negative Predictive Value is the probability the person with a negative test result does not have the disease being tested for.
NPV = True Negative/False Negative +True Negative
Sample 2X2 table. Test sensitivity is 98%. Test specificity is 95%. Prevalence of disease is 1 in 100. 10,000 people are screened with the test.
disease
no disease
test +
98
492
test –
2
9408
The positive predictive value (PPV) is 98/(98+492) = 16.6%. Even though the screening test has a sensitivity of 98%, a patient with a positive test result in this low prevalence population has only a 16.6% chance of having the disease.
Some commonly used screening tests have poorer test characteristics than this example. For example, PSA for prostate cancer screening has the following test characteristics, depending upon the cutoff for a positive test:
Cut-off 3.1 ng/mL; sensitivity 32.2% and specificity 86.7%
Cut-off 1.1 ng/mL; sensitivity 83.4% and specificity 38.9%
It is important to understand the characteristics of studies you order to better interpret what the results really mean.
Dr. Hill asks:
“What test do you think we should order?”
You tell Dr. Hill, “I guess we should have a Doppler ultrasound done because it has the best predictive value for a DVT.”
“Suppose I told you that this test was relatively expensive and often overused,” Dr. Hill proposes, “Would that change your thinking?”
You respond, “Well you mentioned that the D-dimer test is highly sensitive. Perhaps we could rule out DVT by doing that one.”
“Very good thinking. That is precisely the appropriate role of that study. But, remember that the D-dimer test is best used to rule out a DVT if the pretest probability of having a DVT is relatively low.”
“Is there some way to estimate Mr. Smith’s pretest probability of having DVT?”
“I have read that no singular clinical finding is helpful in that,” you tell her.
“That is true,” Dr. Hill concurs. “But if we use several clinical findings, we may be able to do a better job of predicting pretest probability. I am speaking here of the Wells criteria.”
TEACHING POINT
Wells Criteria for the Diagnosis of DVT
Active cancer (treatment ongoing or within previous six months or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the legs
1
Recently bedridden for more than three days or major surgery within four weeks
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swollen
1
Calf swelling by more than 3 cm compared with the asymptomatic leg (measured 10 cm below the tibial tuberosity)
1
Pitting edema (greater in the symptomatic leg)
1
Collateral superficial veins (non-varicose)
1
Alternative diagnosis as likely or more likely than that of deep vein thrombosis
-2
Low probability 0 or less, moderate probability 1–2, high probability 3 or more.
Which of the following would you order at this point?
Select all that apply.
The best options are indicated below. Your selections are indicated by the shaded boxes.
A. Arterial blood gas
B. Chest x-ray
C. Complete blood count
D. C-reactive protein
E. Electrolytes, glucose, creatinine, and blood urea nitrogen (BUN)
F. Hemoglobin A1C
G. Sedimentation rate
H. Thyroid studies
SUBMIT
Answer Comment
The correct answers are C, E, F.
A CBC (C ) with leukocytosis might make you consider an infectious process. Given you are in clinic and he has not been seen in almost 6 months electrolytes, glucose, BUN & creatinine (E) as well as a Hemoglobin A1c (F) would be important to evaluate diabetic control and renal function.
Arterial blood gas (A) or chest x-ray (B) in a patient without symptoms of respiratory difficulty is unlikely to be useful.
Sedimentation rate (G) and c-reactive protein (D) might be elevated, but would be in both cellulitis and DVT, so it is not particularly useful in determining a diagnosis at this point.
Thyroid studies (H) are unlikely to provide any useful information about the absence of signs and symptoms of thyroid disease.
Several days have gone by and you and Dr. Hill are now rounding on your patients in the hospital. When you get to Mr. Smith, you tell Dr. Hill:
“This is Mr. Smith’s third day in the hospital. He says he is feeling better, the pain and swelling in his leg is improving. His temperature is 36.2 °C (97.2 °F), his pulse is 80 beats per minute, his respiratory rate is 16 breaths per minute, his blood pressure is 128/78 mmHg. On exam, his foot ulcer has some fresh granulation tissue on the wound edges. Labs include his fasting glucose this morning was 128 mg/dL (7.0 mmol/L). His CBC was normal and his platelets are stable from admission.”
Dr. Hill responds, “Good. I just got word from his pharmacy that the enoxaparin has now been approved by his insurance, so if he can inject himself for two more days, he can go home. We will need to arrange a close follow-up with visiting nurses and at our office, so he can continue his treatment for his diabetic foot ulcer.”
You comment, “This all seems so much easier than it would have been if he were taking warfarin. How long would it take to get his INR to the therapeutic range if he were using warfarin?”
Dr. Hill tells you, “It varies a lot from person to person, but it commonly takes at least five days for a patient’s INR to get above 2.0. When starting it, you have to balance speed with the risk of overshooting his INR goal and ending up increasing his risk of bleeding by making him supratherapeutic. It is good to consider warfarin dosing since it is still commonly used. It is a very effective medication, but it can be dangerous as well.”
