Diagnosis and Medical Differential Diagnosis

        The diagnosis of CFIDS can be made by a careful history, physical exam and
observation over time, and with the knowledge that a spectrum of medical disorders can present with fatigue as the presenting symptom[48].  While there are no definitive laboratory tests as yet, though such may soon be announced, (as suggested by Landay[12]) and no unequivocal physical findings; the history, physical findings and laboratory results often fit typical patterns.   Shafran states "As a general rule, the longer the duration of the illness and the greater the number of symptoms, the less extensive an investigation is required"[49].

        Except for the tender point exam, the physical exam may show only subtle signs.  On the physical exam of adults the following may be noted:  frequent low grade fever alternating with subnormal basal body temperature; light sensitivity noted on funduscopic exam with occasional conjuctival inflammation; pharyngeal inflammation with mouth ulcers is common, with occasional thrush in 10% of the cases; palpable or tender (but not enlarged) sub-auricular, cervical, and axillary lymph nodes (occasionally femoral and inguinal); abdominal tenderness and occasional hepatic and splenic tenderness; muscle tenderness (especially digastric muscles) at tender points typical for fibromyalgia (see Figure 2.), though this may vary with the cycle of illness; and mild muscle atrophy in the hands, arms or legs in sicker patients.  A positive Romberg and difficulty with tandem walking may be noted on the neurological exam, as well as new difficulty with serial sevens.  The skin may demonstrate a typical pallor, almost resembling anemia, though a
"rosy cheek" flushing may also be noted; the fine lace-like rash on the neck and chest, if present, is persistent.  The physical exam of children may be similar to that of adults[34,50].

        The differential diagnosis might include: neurologic diseases (including multiple sclerosis), infectious diseases (including mononucleosis, CMV, toxoplasmosis, Lyme disease, AIDS, tropical and parasitic infections), metabolic diseases, connective tissue disorders, lymphoma and other carcinomas, and major primary depression (Table 3).

Table 3.  Differential Diagnosis of CFS

        Neurological
                Multiple Sclerosis
                Traumatic Brain Syndrome
        Infectious Diseases
                Mononucleosis
                Cytomegalo virus infection
                Chronic Epstein-Barr infection (Laboratory proven)
                Coxsackie B virus
                Chronic Hepatitis
                Acquired Immune Deficiency
                        Syndrome
                Tropical and Parasitic Disease
                Lyme Disease
                Toxoplasmosis
        Connective Tissue Disorders
                Rheumatoid Arthritis
                Systemic Lupus Erythematosis
        Metabolic Disease
                Thyroid
                Diabetes
        Lymphoma and other Carcinomas
        Major Primary Depression

Adapted from Holmes, et al[1].

Laboratory Studies

                Routine studies may be normal and are not required to satisfy the definition of CFIDS but must be performed to exclude other illnesses:  CBC, urinalysis, sed. rate (often low)[34], routine chemistries, thyroid, renal and liver function tests.  While Komaroff asserts that no single lab test is definitively abnormal in CFIDS, he does believe certain findings are seen more often with this illness:  lymphocytosis, monocytosis, atypical lymphocytosis, modest elevation in ALT and AS, elevated alkaline phosphatase, elevated IgG and IgM, low levels of ANA and low levels of circulating immune complexes[20,51].  Other tests, such as rheumatoid factor, antinuclear antibody, Lyme disease antibodies, etc. will be indicated by the history and physical exam.  Thyroid abnormalities may appear later in the illness and testing should be repeated in those with a prolonged illness.  Several laboratories have shown immunological abnormalities in a large proportion of patients with CFIDS.  Many patients show high antibody levels to any virus measured.  Approximately one third of patients demonstrate elevated immune complexes and some affected individuals have abnormal appearing or abnormally high levels of cytokines (particularly IL-2).  Natural killer (NK) cell dysfunction has been demonstrated in some patients.  Enzyme activity (e.g. 2',5' oligoadenylate synthetase[17,52]) may be abnormal.  These immunological and enzymatic tests are not yet clinically helpful at this time either because the proportions of CFIDS patients showing these abnormalities have yet to be more clearly established and/or the tests showing promise are not readily available.  Landay et al have recently reported evidence of specific laboratory markers (CD8, CD38, HLA-DR)[12] for CFIDS that look promising.

        Please note that while some particular additional procedures may be necessary to rule out other illnesses, these should be limited to what is clinically reasonable.  Many procedures, particularly ones only remotely pertinent, can be expensive, exhausting, alarming, and discouraging.  Management of the diagnostic studies and follow-up treatment should be carried out by a primary care physician with referral to specialists, and limited to only those that are absolutely necessary.

        CFIDS is not just an illness diagnosed by exclusion.  It has a recognizable profile as described above and below.

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Psychiatric Differential Diagnosis

        CFIDS can and should be differentiated from primary psychiatric diagnoses of anxiety, major affective, and somatoform disorders (Appendix: Tables 2-5).  The depression commonly seen with CFIDS may resemble a major depression with atypical features.  However, there are many differences.

        Both may include a sleep disorder but in CFIDS, the sleep disorder involves non-REM sleep instead of the REM sleep disturbances seen in major depression[41]. Although fatigue is present in both conditions, the fatigue in CFIDS is profound and accompanied by intense frustration from not being able to do what one still wants to do; ie: patients do not usually lose motivation and interest.  In contrast, apathy or anhedonia generally accompany the fatigue in primary depression.  Furthermore, persons suffering from a severe primary depression may "forget" that they have ever felt any other way and may have given up hope that their bleak state can improve.  Patients with CFIDS, on the other hand, are exquisitely aware of not feeling as well as they used to or as well as they hope to.

        Patients with depression and anxiety often complain of difficulty with thinking and concentration, as do patients with CFIDS; however, the manifestations of cognitive abnormalities noted on neuropsychological testing typically reveal different patterns.  CFIDS patients tend to present a characteristic profile of apparently multi-focal deficits including short term memory, figure-ground, and aphasic difficulties[13,19].  Furthermore, unlike patients with major depression, CFIDS sufferers may benefit from very low doses of antidepressant medication
and may be unable to tolerate the usual therapeutic dose.  And finally, a concurrent major depression in CFIDS may respond to antidepressant medication, but the systemic complaints and cognitive impairments persist even when mood improves, thus differentiating CFIDS from an atypical depression or "depressive equivalent".

        As in anxiety disorders, CFIDS patients may report symptoms of autonomic
hyperactivity, motor tension worry and/or dread, dizziness, loss of balance,
lightheadedness, or hypersensitivity.  Panic attacks or feeling overwhelmed may even be a patient's presenting complaint, but a careful history will reveal other characteristic multisystemic symptoms of the illness.

        It is important to differentiate CFIDS from phobic avoidance disorders.  Unlike
agoraphobia, staying home does not significantly alleviate the patient's symptoms. In children, school phobia must also be considered but can usually be ruled out by the persistence of the symptoms on weekends and holidays and by a lack of a premorbid history suggestive of the common patterns for school avoidance (These children want to go to school if they could!).

        Interestingly, Straus, in writing about the history of chronic fatigue syndrome, has noted the similarity to early descriptions of nervous exhaustion and neurasthenia, the latter term only much later falling into disfavor as the meaning changed to imply an affective disorder only[5].

        A history of polysystemic symptoms, acute flu-like onset and prominent experiences of muscle pain and muscle fatigue etc. simply are not typical of primary psychiatric disorders.  Somatization disorder or hypochondriasis does involve somatic as well as neuropsychiatric complaints, but fatigue is not usually the predominant symptom.  Hypochondriasis typically presents with physical symptoms but no actual loss or distortion of body function.  Recurrent and multiple somatic complaints involving several organ systems characterize somatization disorder (Briquet's Syndrome) and may include conversion symptoms which are inconsistent with any known physical disorder.  Unlike CFIDS, which may afflict patients of any age and sex, somatization disorder begins before age thirty and is rarely diagnosed in males.  "The onset of multiple physical symptoms later in life is almost always due to physical disease[53]."

        Finally, it is important to consider other specific and identifiable causes of an organic brain syndrome or mild dementia.

        There have been classic guidelines in medicine to distinguish organically caused neuropsychological reactions from primary psychiatric disorders:

        1) The signs and symptoms do not fit an established psychiatric diagnostic
            category.
        2) There is no prior psychiatric history or symptoms in the patient.
        3) The patient demonstrates an abrupt change in behavior or personality.
        4) The signs and symptoms fluctuate in correspondence with the organic
            illness.
        5) The condition does not respond to solely psychiatric treatment[34].

        In our view these guidelines very much apply to the neuropsychological
characteristics of CFIDS.