Fatigue / “Weakness”

A very common complaint, frustrating for patients & clinicians alike.  In terms of the latter (i.e. me & you), a systematic approach is always helpful.

STEP 1 — Define Fatigue, distinguishing it from the following:

  • Dyspnea.  This always gets worse on exertion.  Of course, Fatigue can too.  So I ask, “When you walk upstairs, or a few blocks, do you ‘Huff & Puff’ or just feel ‘All Worn Out’?”  When I say “Huff & Puff,” I breathe fast in imitation.  For “All Worn Out,” I droop my arms & legs in weariness.  In Spanish, “cansado(a)” may mean “tired,” “weary,” “sleepy,” or ominously “short of breath.”
  • Somnolence.  Daytime nodding-off suggests sleep apnea or narcolepsy, completely different from Fatigue.
  • Weakness.  Identifiable by the Motor Strength component of the Neuro exam.  Symptoms may include falls, or “dropping things.”  Differential includes entities such as Polymyositis, Myasthenia Gravis, Cord lesions, & Guillain-Barré (I’ve seen the latter walk in, & get intubated within 2 hours).  True Motor Weakness is bad — always test motor strength when patients complain of Fatigue.  But weakness is rare; fatigue common.
  • Generalized pain syndromes such as Fibromyalgia.

From now on, we’re talking about Fatigue.  Even if the patient insists, “I’m weak all over,” I chart “Fatigue, no Weakness” if motor strength is 5/5.  We’re also not addressing generalized Pain syndromes now.

STEP 2  —  Delineate chronology.

  • Acute Fatigue — Under 1 month
  • Chronic Fatigue — over 6 months

Acute fatigue is the most concerning, since the differential includes lethal conditions.  Once 6 months have rolled around, you’ve probably ruled out serious stuff like endocarditis and malignancy.

What about 2-6 months?  If symptoms are progressively getting worse, lump it with “Acute.”  If symptoms remain on a steady level, they’re heading for chronic.  The work-up is the same for all time periods.

“Chronic Fatigue” is not the same as “Chronic Fatigue Syndrome” (CFS).  The latter has specific diagnostic criteria, including “>6 months duration.”  This is for research purposes; many patients who don’t meet the case definition may still have true CFS.  Of course, nobody yet knows what causes “true” CFS, so don’t quibble.  Work-up & management are all the same.



  • Endocarditis
  • Occult Bacteria
  • Mononucleosis
  • HIV
  • Hepatitis
  • TB


  • Chronic Fatigue Syndrome (CFS case-definition or not)


  • Hypo- / Hyper- Na+, K+, Ca++
  • Renal Failure
  • Hepatic Failure


  • Diabetes
  • Hypothyroidism
  • Hyperthyroidism
  • Adrenal Insufficiency
  • Pituitary Insufficiency


  • Malignancy
  • Depression
  • Anxiety
  • Drugs / EtOH / Meds
  • Drug Withdrawal
  • Anemia (severe!)
  • Malnutrition
  • Rheumatologic disorders
  • Chronic GERD or Allergic Rhinitis

Note that there are no links to click on in the above table [sorry].  That’s because there are no particular clinical clues, other than what you most likely already know (e.g. endocarditis gives fevers).  You’re more likely to find, say, hyponatremia by a chemistry panel than by any special symptom complex.

STEP 3 — Take a history to rule out serious disease — seek Red Flags:

  • Fevers
  • Night Sweats
  • Weight Loss

“Night sweats” only count if they’re drenching.  Moist pillows or collars don’t count.  I ask if sweat actually drips from pajamas or sheets upon wringing.  In terms of weight loss, it needs to be documented, but I’m convinced if they say their clothes are significantly looser.  Examine the belt, to see if it’s now being tightened from prior worn notches.

History may offer other diagnostic clues, like substance use, cough, chronic allergy or GER symptoms, etc.  Do a brief physical exam, looking for subtle suggestions of undiagnosed HIV, heart murmurs, hepatosplenomegaly, true neurological weakness (motor strength of proximal & distal extremities), and suspicious lymph nodes suggestive of malignancy [by the way, what’s the most ominous lymph node in the body, & why?  Click here for answer].

In terms of depression or anxiety, statistically the most likely causes of fatigue, I don’t delve too much into them on the first visit.  Exploring this in depth can send a message that “you don’t believe me; it’s all in my head.”  I always mention the possibility, partly to prepare the patient since a psychological diagnosis may ultimately be favored, but mostly as an opening for them to elaborate on their own if they choose.  I’ve seen tears flow at the mere mention of “depression.”

Worst case scenario — patient is acutely suicidal, presents with “fatigue” as a cry for help.  So I bring up “depression,” and “stress,” but if the patient doesn’t endorse the possibility, it’s hard to add, “Well, even if you’re not depressed, have you thought of killing yourself?”

STEP 4 — Assuming the H&P are unrevealing, with no Red Flags, order tests.  Use your differential as a guide, but don’t go overboard.  Some simple starters that cover just about everything on our list:

  • CBC
  • Chemistry Panel
  • TSH
  • Urinalysis
  • Erythrocyte Sedimentation Rate (ESR)
  • HIV Antibody
  • ? Monospot (only for younger patient with <1 month of symptoms)
  • If muscle aches are a component of symptoms, add a CPK

Have the patient return in 2-3 weeks, long enough to reveal any possible weight loss.  Be sure you have a valid telephone number, lest an emergent result require immediate intervention.

STEP 5  —  Any abnormal lab tests will point the direction for further testing.  A few comments:

** An elevated Sed Rate is non-specific.  One lecturer I heard commented, “An elevated ESR proves for sure that the lab was open.”  I find it useful only if very high:

  • ESR >100 suggests metastatic cancer, multiple myeloma, disseminated TB, endocarditis, deep visceral abscess, HIV, or giant cell (temporal) arteritis.
  • Values <40 aren’t useful, unless they progressively rise.
  • Intermediate elevations are tough.  Seek rheumatologic symptoms like early morning stiffness and diffuse myalgias or arthralgias.  Follow weights and hematocrit.

**  BEWARE small abnormalities, like a TSH of 6.0 (normal <4.5), or ALT only twice normal.  Remember that “abnormal” merely means >2 standard deviations from the mean.  By definition, 2.5% of results should be high, & 2.5% low.  These patients have a higher likelihood of having the associated disease, but don’t necessarily have any illness.

  • Statistically, if you perform a test on 20 patients, the odds are that one will be abnormal by pure chance alone.  Likewise if you perform a given test 20 times on one person.  And also, if you draw 20 lab tests at once (a.k.a. “Chemistry Panel”).

**  Don’t miss a statin-induced myopathy.  Seek some component of muscle aching.  The CPK is usually normal (benign myopathy is much more common than rhabdomyalysis, when the CPK is extremely elevated, in the 1000’s).  A trial of discontinuing and rechallenging the statin should be diagnostic.

So the patient returns for follow-up and results.  If anything is markedly abnormal, deal with it.

IF ALL RESULTS ARE NORMAL, and there’s no weight loss  —  Well, we’ve pretty much covered everything except for the quite-uncommon adrenal insufficiency, which I’d only consider in the event of new generalized “suntan” (hyperpigmentation) or orthostatic hypotension.

If you haven’t already, define the extent to which “fatigue” interferes with daily function.  How disabling is it?  This provides less of a clue to diagnosis, and more an indication of how necessary treatment intervention may be.

Now’s the time to explore mood disorders.  Inquire about “stress,” specifically “depression” (sadness, urge to cry) and “anxiety.”  Seek less obvious symptoms such as low energy, sleep & appetite disturbances, poor concentration, lack of interests, anhedonia, low libido, palpitations, tremors, etc.  Most patients are not resistant to the possibility that fatigue may be due to “stress.”

  • “Stress,” of course, may range from economic problems [hard to treat] to suicidal or homicidal ideation.  If the patient endorses symptoms of depression or anxiety, rule out these worst-case extremes.  Also don’t forget to inquire about Domestic Violence, another potentially lethal situation for either patient or possible target.

If the above inventory of mood symptoms is positive, go for a trial of therapy, either pharmacologic or talk.  For the occasional patient who refuses to accept it, I suggest that “even if ‘stress’ isn’t causing fatigue, it’s common for any disabling symptom to cause stress.”

Whether or not you institute treatment, be sure to reassure the patient regarding all the diseases they don’t have.  This, in and of itself, is often therapeutic.  If patients are functioning adequately, no treatment is necessarily indicated.

Whether or not you institute treatment, be sure to reassure the patient regarding all the diseases they don’t have.  This, in and of itself, is often therapeutic.  If patients are functioning adequately, no treatment is necessarily indicated.

And if the entire work-up is negative, the patient seems straight-forward and denies any mood symptoms — then you’re left with the diagnosis of exclusion, “Chronic Fatigue Syndrome.”  Especially if the fatigue persists 6 months and nothing changes.  It’s a diagnosis unsatisfactory to [& often derided by] many clinicians, quite possibly due to an as-yet-unidentified virus.

Explain it, and treat it, as best you can.  Refer if there’s a nearby specialist in it.  And be sure to schedule regular follow-up visits, to monitor for new symptoms, weight loss, and overall life.


  • DON’T order a “gropogram” (e.g. pan-CT)
  • DON’T order tests for “chronic” Epstein-Barr, CMV, or Lyme Disease
  • Other tests that are not useful, in the absence of suggestive symptoms, include the ANA / rheumatologic serologies, Immunoglobins, Celiac Disease antibodies, CPK.

That’s it for “Fatigue;” hope this wasn’t too fatiguing.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s