Friday, July 18, 2014

The Diagnosis of Chronic Fatigue Syndrome: An Assertive Approach by Dr. Paul R. Cheney and Dr. Charles Lapp

This paper (below) by Dr. Paul Cheney and Dr. Charles Lapp was written more than two decades ago. It contains detailed descriptions of numerous test abnormalities found in ME/CFS patients, all which can be used for diagnosis.

In spite of the fact that these (and other) objective findings have been noted by specialists for decades, the CDC has not made any of these criteria available to the broader medical community. It is equally as incomprehensible that in spite of these findings - described in great detail in the Cheney/Lapp paper - we now have two federal initiatives involving the diagnosis of ME/CFS, neither of which has taken into account the numerous objective markers for the disease. 

Thirty years after the Incline Village outbreak, the myth still persists that ME/CFS cannot be diagnosed using objective measurements (which are still considered "controversial").  ME/CFS is still described as "mysterious." And it is still a waste-basket diagnosis.

Dr. Cheney and Dr. Lapp were not ahead of their time. The problem is that all of our institutions lag far behind.

The Diagnosis of Chronic Fatigue Syndrome: An Assertive Approach by Paul R. Cheney, MD, PhD and W. Charles Lapp, MD, FAAP

Introduction: The Case for Diagnosis by Objective Criteria

Over the past ten years, a considerable and diverse medical literature has arisen concerning the chronic fatigue syndrome (CFS). Like all medical literature written on an emerging disorder, these published findings include a range of views and some discrepancies.

Systematic errors exist among the tools used to discern differences between CFS cases and "healthy" controls. The central problem, however, is case selection. Many patients with CFS are excluded from studies because they seem "too sick" to have CFS and are perceived as having something else. CFS cases are mixed in with non-cases. Inappropriate controls are sometimes used. Some investigators, aware or unaware of a bias, attract or include in their studies the very patients who best fit their view of CFS. This so-called selection bias can markedly affect the observations of a study. Despite these discrepancies, a more or less consistent pattern of observable abnormalities has emerged and we believe a case definition using objective abnormalities can now be defended.

Having stated the inherent problems with CFS research, we will attempt to defend an assertive approach (i.e.,diagnosis by inclusion) to the diagnosis of CFS using the available medical literature to support it. This is a different approach from just applying the Centers for Disease Control (CDC) case definition, which in essence defines a sign-symptom complex in the absence of a "known medical illness" (i.e., diagnosis by exclusion). The medical evidence cited for CFS asserts that the following are present more or less in every patient during the course of his or her disease: T-cell activation, discrete immune defects, viral activation or re-activation, exercise-related dysfunction, and evidence of brain dysfunction or injury. While none of these tests can stand alone to "diagnose" the illness, an array of these tests can be used to support this diagnosis, given the proper clinical context derived through the application of the CDC case definition. The use of non-specific tests to defend or support a diagnosis is a time-honored tradition in medicine, and the concept is used to diagnose such disorders as multiple sclerosis, lupus erythematosus, acute infectious mononucleosis, and even AIDS.

There are a number of criticisms given for using nonspecific tests in the diagnosis of CFS. They include the following:

(1) We lack a gold standard for determining this disorder and therefore lack a means to test the relative value of certain tests (i.e., false positive and false negative rates).

This is certainly a valid point in confirming a diagnostic test, but it is not a valid criticism in using a non-specific test to support a clinical impression. If a test abnormality has been shown in the medical literature to be associated with a certain disease, such as a positive ANA in lupus, then it is valid test to be used in supporting a clinical diagnosis. Furthermore, as in the "diagnostic" tests for the hepatitis C virus and the Lyme agent, poor test performance may be ignored in the case where benefits, however defined, outweigh poor performance.

(2) Even if there are test abnormalities which can be associated with CFS there is no need to make a more definitive diagnosis because there is no treatment for the disease.

If this were a valid argument, then it would also apply to multiple sclerosis, many cancers, acute infectious mononucleosis, and even AIDS. Documentation of an illness by objective criteria is important not only to confirm the diagnosis, but also to reassure the patient about other disorders they may or may not have. Reassurance is itself therapeutic and proportional to the degree of objective support found for a diagnosis.

Though there may be no scientifically validated treatment options for CFS (a situation which may soon change with the recent conclusion of the Ampligen trials), there are many therapeutic rationales based on test abnormalities which can defend empiric therapy. Such rationale exist for T-cell activation, certain immune deficiency states, herpes-group virus reactivation and even nonspecific brain injury. In the everyday practice of medicine, empiric therapy is often warranted in severe or functionally devastating illness. It is common practice to use unproven but rational therapies to treat clinical diagnoses such as a migraine, PAS, atypical depression, and many other disorders. Finally, documentation of abnormalities associated with CFS can assist the patient in disability arguments.

Disability Law Judges almost never respond favorably to disabling disorders without objective findings. This is even more the case for emerging disorders. The ability to successfully argue for disability is an extremely important aspect of therapy for this disorder. We have several examples of patients coming off disability and returning to work in part because the disability concept can itself be therapeutic.

(3) CFS is a "self-limited illness" which nearly always responds to rest, good nutrition, and proper exercise. As such, little is gained from extensive testing other than to disprove the presence of other disorders.
This misperception of CFS patients is pervasive among many clinicians and the lay public. A debilitating illness lasting years or longer is in fact not self-limited, and it deserves considerable medical attention. Some patients appear to be permanently disabled by this disorder. It may not completely or permanently resolve even in most patients who do see improvement over time. There are theoretical reasons to be concerned and vigilant about long-term health issues in all CFS patients.

Also, and intuitively, it seems to us to be helpful to intervene early in the course of CFS, even if only to dispel the false idea that any exercise will help this disorder and to counsel patients on lifestyle adjustment and symptom relief, especially for sleep disorder. Good documentation of this disorder lays the groundwork for future empiric intervention should it be necessary and gives a baseline with which to compare future results.

The CDC Case Definition

A case definition for CFS proposed by researchers at the CDC and elsewhere was published in 1988 1 . This clinical case definition consists of both major (all must be met) and minor (some but not all must be met) criteria. Difficulties in the application of this case definition include: How does one define a 50 percent or greater reduction in activity? Exactly how far does one go to exclude other disorders? What does one do with patients with remote onset--say in childhood—of chronic fatigue who would be excluded by the current case definition? Should some minor criteria be moved to major criteria and others dropped entirely? What does one do with patients who have confounding medical and psychiatric problems which might explain some if not all of their symptoms? What does one do with patients who lack severity criteria or sufficient signs and symptoms? What signs or symptoms and what other objective tests should be added to sharpen the diagnosis?

While some of these questions have been partially addressed by the authors of the CDC case definition, most persist and are handled differently by different investigators. Despite the problems with the present case definition, we believe that it generally functions to separate most cases from possible or probable non-cases. We recommend continued use of the criteria but designate probable non-cases who meet criteria and probable cases who do not meet criteria as atypical cases or non-cases of CFS.

Further subdivision of atypical cases by severity and confounding medical or psychiatric issues is probably a worthwhile endeavor and has been adopted by the CDC in their surveillance studies.

Clinical Observations Helpful in the Diagnosis of CFS

We have had the opportunity to make a number of clinical observations in over 1,200 cases of CFS which we believe are helpful in the diagnosis of CFS. None of these findings can be used individually to diagnose a case, but they add collective weight to the final clinical judgment. Some patients will have a normal physical examination and many will have essentially normal routine laboratory values.

Physical Findings - Contrary to suggestions by some investigators, abnormalities on physical examination, although sometimes subtle, are usually present:
  1. Fever at or above 99.2 F in 38% of patients
  2. Subnormal temperatures
  3. Intermittent tachycardia
  4. Low blood pressures
  5. Abnormal oral pharynx exam, including: buccal mucosal ulcerations; posterior cobblestoning, erythema and "crimson crescents" over soft palate; tongue coatings or blisters; and rare thrush
  6. Fluctuating anisocoria over time in dim light
  7. Photophobia
  8. End gaze nystagmus
  9. Posterior cervical lymphadenia with slight, palpable enlargement, usually asymmetric
  10. Axillary lymphadenia with slight, palpable enlargement, usually asymmetric
  11. Tender points typical for fibromyalgia
  12. Mild to severe skin atrophy of distal finger tips, loss of fingerprints
  13. Diffuse abdominal tenderness
  14. Hyperreflexia is very common, worse in lower extremities, and with occasional unsustained clonus
  15. Mild tremulousness on drift testing
  16. Intention tremor
  17. Mitral valve prolapse
  18. Sallow skin tone
  19. Brittle, thinning hair with reddish tint
  20. Excessive titubation or actual inability to maintain Romberg or tandem stance and tandem walk (probably represents an apraxia or vestibular disturbance and very common in these patients)
  21. Tentativeness or inability to serial seven subtract, especially while attempting Romberg test, is very common
  22. Facial and torso rashes, mostly macular erythema and acneform eruptions
Routine Laboratory Tests - Findings may be subtle but are often present
  1. Low sedimentation rates in 40% (0-3 mm/hr); modestly elevated (20-40) in 10%, usually will fall over time
  2. Akaline urines are common (PH>7.0)
  3. Mild leukocytosis or leukopenia
  4. Macrocytosis with elevated MCV
  5. Mild LFT elevations, rarely persist
  6. Atypical lymphocytes
  7. Elevated blood lipids
  8. Low normal free T4 and TSH
  9. Low level ANAs, may not persist
  10. Rare positive Lyme antibodies - failure to respond to accepted therapy
Immunologic Dysfunction

Immunologic tests have been frequently applied to patients with CFS in part because they are frequently abnormal and in part because the signs and symptoms of CFS can be explained as a consequence of immunologic function or dysfunction. Fever, sore throat, swollen glands, aching muscles and joints, sleep disturbance, and even neuropsychological complaints can all be attributed to immunologic responses generally ascribed to T-cell activation with excess cytokine production (i.e., IL-1 alpha, IL-2, interferon-alpha). Whether this excessive immune response is itself the cause (auto-immune or neuroendocrine defects) of CFS or perhaps the effect of a chronic viral infection or even compensation, by whatever means, for an acquired immune deficiency remains uncertain.

We propose here a set of tests that look for evidence of T-cell activation along with discrete immune defects.  All of these tests are available from commercial laboratories and defended by published medical literature.2-20 Although specific immune tests do not always correlate with disease severity, nor is any single test always abnormal, they become more valuable when used as an array or set of tests used to determine a pattern of immune dysfunction.

Tests of Immunity T-cell activation

1. IL-2 receptor, T8-receptor -elevated
2. One and two-color flow cytometry
  • CD3/DR, CD8/DR - elevated
  • CDllb, CD8/CDllb - depressed
  • CD3 - elevated
  • CD56 - elevated
  • CD4/CD45R - depressed
  • CD20 elevated (3) 
  • Interferon-alpha, IL-1-alpha - elevated (4) 
  • Intracellular 2-5A, Rnase-L antiviral activity - elevated
Discrete Immune Defects
  1. Hypogammaglobulinemia (IgG)
  2. IgG subclass deficiencies
  3. Anergy and hypoergy by epicutaneous skin testing
  4. Mitogen stimulation deficiencies (T and B cell deficiencies)
  5. Natural Killer (NK) cytotoxic deficiencies
  6. Circulating immune complexes

Viral Activation or Re-activation

Viral activity or activation is suggested in CFS due in part to the abrupt onset of a flu-like, mono-like, or encephalitic-like illness which usually precedes the development of this disorder, its signs and symptoms over time, and the nature of the immune response observed. The common symptoms of debilitating fatigue, swollen glands, sore throat, and headache have suggested re-activation of mono-causing herpes viruses (EBV, HHV-6, or CMV), which are usually contracted much earlier in life. It is probable that these lymphotropic herpes viruses are involved in most cases of CFS but are not the cause of CFS. It is likely that they are merely reflecting T-cell activation itself or loss of immunologic control of these viruses due to a state of immune deficiency by whatever cause. It is conceivable that an as-yet-unknown virus has initiated CFS much as HIV initiates AIDS. Such a virus is likely to be subtle, immunotropic, and neurotropic. Retroviruses are all of these things, and attention has focused on them in recent years.

The following is a set of tests that look for evidence of re-activation of herpes-group viruses as well as evidence of a possible retrovirus infection. The retroviral assays include DNA amplification technology and evidence of non-specific cytopathic effects in cell culture consistent with a family of retroviruses recently associated with CFS. Again, more important than the results of a single test is the pattern of herpes-group virus re-activation, evidence of retroviral gene sequences, and evidence of retroviral cytopathology in nonspecific culture assays, all of which support the role of viral activation in CFS. Whether this activity is cause or effect, however, is still open to question. It should be noted that lymphotropic herpes viruses and retroviruses can activate or transactivate each other and are therefore synergistic.

Tests of Viral Activation or Re-activation Herpes-Group Virus Assays 21-26
  1. Antibody assays for EBV, HHV-6, CMV, HSV-1,2 & VZ looking for elevated titers consistent with recent activity.
  2. Viral DNA amplification for EBV, HHV-6, and CMV using the polymerase chain reaction (PCR), with positive results suggesting viral activity.
  3. Giant cell assays with monoclonal labeling for various herpes-group viruses, with positive results suggesting such viral activity.

Retrovirus Assays 27-30
  1. Cytopathology in fibroblast cell lines consistent with human foamy retroviruses or human intracisternal retroviruses
  2. HTLV-II gag probes, run using low-stringency PCR to detect retroviral gene sequences present in CFS patients which are HTLV-II-like but not HTLV-II. This test will likely give way to specific probes based on conserved sequences of actual retroviral isolates of whatever family cultured from CFS patients.
Exercise-Related Dysfunction

Patients with CFS describe characteristic worsening of their symptoms following exercise as well as exercise limitations. Exercise ergometry with gas analysis has proven useful in CFS to document defects in functional capacity; a functional consequence of debilitating fatigue. Several reports have attracted further interest in this technology as a diagnostic instrument for showing neuroendocrine defects in response to exercise, 31 as well as defects in respiratory control mechanisms within the central nervous system in CFS patients.

Bicycle ergometry with gas analysis has proven useful to document disability in CFS and will likely prove useful to document deep brain dysfunction characteristic of CFS patients.

Tests of Exercise-Related Dysfunction Important measurements using bicycle ergometry with gas analysis
  1. Peak oxygen consumption at maximum exertion
  2. Work rate at anaerobic threshold as against peak work rate.
  3. Oxygen consumption at anaerobic threshold
  4. Work efficiency - independent of conditioning
  5. Breath-to-breath tidal volume variance at peak exercise
Brain Dysfunction

Perhaps no set of symptoms is more disturbing to CFS patients nor more striking to clinicians than the neurocognitive complaints seen in CFS. They characteristically evolve slowly over time and often grow to dominate the clinical scene. At first there is only the mental "fog" of a viral syndrome, but this slowly gives way to the more worrisome complaints of memory disturbance, word searching, processing speed, and spatial disorganization. There also may be neuropsychological complaints including panic attacks, depression, and mood swings. Evidence of characteristic abnormalities on neuropsychometric tests and characteristic profiles on the MMPI have been reported.32,33 Defects on structural34,35 (MRI) and functional scans (SPECT and Topographic Computer EEC) of the brain have also been reported.36,37 As mentioned above, soft neurologic findings are also frequently demonstrated under physical examination. We have proposed a number of approaches to document evidence of brain dysfunction in CFS.

Tests to Document Brain Dysfunction

Structural Scans - MRI is recommended for any patient with an abnormal neurologic examination or significant neurologic symptoms. This is done primarily to rule out structural abnormalities which might mimic CFS signs and symptoms. Many CFS patients (50 percent or more) will exhibit small punctate areas of increased signal, usually in subcortical white matter areas.

Functional Scans - SPECT scans, which primarily measure blood flow, are frequently abnormal (80 to 85 percent), showing areas of decreased perfusion primarily in the temporal and frontal lobes.

Topographic computer EEC brain mapping has shown increased slow-wave activity usually in the anterior leads and especially when patients are engaged in certain cognitive tasks. This usually diffuse slow-wave activity strongly suggests metabolic or toxic encephalopathy.

Neuropsychometric Testing - A complete Halstead Reitan battery or subsets of this battery form the basis of determining the nature and extent of cognitive impairment in CFS. Patients will exhibit characteristic focal and multifocal deficits in which performance on certain subtests will be normal or even well above normal while performance on certain other subtests will be substantially below normal. Performance deficits appear to occur more frequently in particular subtests of this battery.

Knowledge Is Power

CFS clinical and bench researchers are developing an array of tests which are increasingly sensitive and specific for CFS — particularly when used in combination. When patients present with symptoms that suggest CFS, we believe it is in their best interest to selectively employ these tests to confirm the diagnosis and to document the nature and extent of each case. This information: increases both the physician's and patient's confidence in the diagnosis and their ability to track the course of the disease; enables the patient to make appropriate lifestyle adjustments (including defense of disability claims when necessary); and provides the physician with a basis for therapeutic intervention.


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