The Neuropharmacology of Chronic Fatigue Syndrome

By Jay A. Goldstein, MD - Los Angeles, California Dr. Goldstein, a neuropsychopharmacologist, has a large southern California CFIDS practice. More detail is provided in his recent book, Chronic Fatigue Syndromes: The Limbic Hypothesis (Binghamton, NY; The Haworth Medical Press, 1993), from which he adapted this list. This book may be purchased from the Association.

The Diagnosis of Chronic Fatigue Syndrome As A Limbic Encephalopathy

At first, the diagnosis of CFS appears to be insurmountably difficult. Fatigue can be caused by so many different disorders. After the first 50 patients or so are seen, diagnosis seems easy, but it is not. A recent study of 200 patients with the chief complaint of "fatigue" revealed a physical illness in only 10 of them.1 Most fatigued patients have normal workups, and it seems that the symptom profile of CFS is fairly distinctive, particularly if prolonged fatigue after exercise, cognitive impairment, and recurrent flu-like illnesses with sore throat are noted. The presence of fibromyalgia tender points is always helpful in making an assessment. The reliability of the diagnosis is also enhanced if the initial symptoms developed rapidly in the context of a flu-like illness, and if premorbid nasal allergy was present.

Ambiguity in the diagnosis arises if the onset of the illness was gradual, if there are no flu-like symptoms, no fibromyalgia tender points, and if there is a history of psychiatric disorder antedating the illness. Patients from extremely dysfunctional families where there was child abuse are most difficult to diagnose, since these individuals are prone to develop somatization disorder.

NIH Workshop Recommendations

A workshop was held at the National Institutes of Health in 1991 to refine the diagnostic criteria for CFS. Patients with psychosis, substance abuse, and post-infectious fatigue with a definite etiology and an ongoing process were excluded from being diagnosed as having chronic fatigue syndrome. Fibromyalgia and post-infectious fatigue from an illness that has been adequately treated or should have resolved were included. Depression in the context of CFS was no longer exclusionary; it was suggested that note be made of whether it occurred concurrently with CFS, existed previously, or had resolved. Those diagnosed as having a somatization disorder were included, although it was not made explicit how these patients should be distinguished from those with CFS.

Clinical evaluation suggested was:
  1. Minimum laboratory tests. Those listed were CBC with differential, ESR, chemistry panel, TSH, and ANA and RF in those with myalgias. Ferritin levels and HIV testing were not included.

  2. Screening for psychiatric distress done with a standard instrument. One structured interview was suggested, such as the Diagnostic Interview Schedule (DIS).

  3. Tender points exam. This evaluation should minimize the symptoms of lymphadenalgia, which was probably confirmed by palpation of unrecognized tender points. Lymphadenopathy is rather uncommon in my experience.

  4. Serial examinations for emergence of other diagnoses, e.g., SLE or MS.

The group did not believe any laboratory tests are of value in confirming the diagnosis of CFS, although appropriate lab tests were suggested to rule out other diagnoses. Tests regarded as experimental were immunologic and virologic tests, brain scans of all sorts, and neuroendocrine tests. Neuropsychological tests were not discussed, and no mention was made of the cognitive impairment experienced by most CFS patients, a glaring and inexplicable omission. The indications for polysomnography in this patient group were not considered. It was noted that objective measurements to assess CFS severity have not been validated.

The workshop participants concluded that CFS is not a homogeneous entity and that there is overlap with fibromyalgia and non-psychotic depression, but that lab results from all groups are indistinguishable. Self-report was thought to be the best method of assessing illness severity. Standardization of assessment techniques, including stratification of patients as to whether fibromyalgia, depression, criteria for somatization, and post-infectious fatigue were present, were thought to be important. No mention was made of the hyperventilation provocation test.

As in previous efforts by such committees, the conclusions were extremely conservative and did not address important issues. CFS was still appropriately regarded as a syndrome, but no suggestion about etiology was even attempted. This deficiency reflects the division of opinion among those studying the illness, but workers with more "radical" views were not invited and came at their own expense if they were able. There was no discussion of abnormalities in brain function being an aspect of CFS. This glaring omission was inexplicable to those of us who regard CFS as having important, if not primary, neurologic components. That these NIH recommendations may have become obsolete even before they were disseminated is suggested by the publication of experiments showing a specific kind of immune activation in CFS2 and symptomatic and laboratory improvement in CFS with the immunomodulatory and antiviral drug Ampligen.3 Culturing of the "stealth" virus in 50 percent of patients and in no healthy controls was also a significant development.4 Even though psychological test results and brain imaging findings have been reported at meetings, none of the investigators who are involved in such work were invited to the workshop. The suggestions of this panel were so similar to recommendations generated by a panel in Great Britain the previous year and published in the Journal of the Royal Society of Medicine5 that it has been speculated that the NIH meeting was held as window dressing for a fait accompli. The major addition of the NIH meeting was the mention of fibromyalgia (FM), a condition often associated with CFS that I will address shortly.

Associated Illnesses

Associated illnesses are extremely common, and virtually all of them could be caused by limbic encephalopathy. Let us consider some of them.

Fibromyalgia

When I examine a patient suspected of having CFS, the presence of 11 out of 18 fibromyalgia tender points, with no tenderness at neutral points, is the only reliable physical sign and occurs in about two-thirds of this population. I feel much more confident about making the CFS diagnosis if the fibromyalgia tender points are present. Fibromyalgia may also be related to other conditions, primarily rheumatologic, but is also associated with infections, particularly viral. Bacterial, parasitic, and especially borrelia infections should also be considered. Fibromyalgia also may be seen in hypothyroidism. It can be distinguished without much difficulty from myofascial pain syndrome, which is local or regional, as well as from inflammatory and metabolic myopathies. Trigger points and fibromyalgia tender points may be activated by autonomic dysfunction causing decreased muscle blood flow. Raynaud's phenomenon is often associated with CFS/FM and can further reduce diagnostic ambiguity. (This physical sign was also not mentioned in either the NIH or British conference.) Positive Romberg tests, abnormal Hallpike maneuvers, and bilateral lower quadrant tenderness, either related to irritable bowel syndrome, pelvic disorders (especially endometriosis), or abdominal wall myofascial pain, are commonly encountered. A frequent cause of pelvic pain in this population is pelvic floor tension myalgia, especially of the pyriform muscle. Palpation of the muscles associated with Temporomandibular Pain and Dysfunction Syndrome (TMPDS) will frequently reveal tenderness, and this patient group should be investigated for bruxism.

Skin Disorders

The major skin disorder is herpes simplex, both oral and genital. Herpes zoster is also fairly common. Psoriasis, urticaria, and atopic dermatitis are seen more often than in the general population, and diffuse alopecia is seen more frequently than all of these conditions put together. Some of my patients have had to buy wigs. Minoxidil lotion may be of benefit. An inflammatory obliteration of fingerprints, as described by Paul R. Cheney, MD, occasionally occurs. The alopecia may sometimes be related to adrenal androgens and may be treated with low dose dexamethasone.

Headaches

Severe headaches are quite common. These are usually of the tension-type, but can also be migrainous, related to TMPDS, or possibly to benign intracranial hypertension. I have seen only one CFS patient with cluster headache. Particularly in the CFS patient with a history of headache after a motor vehicle accident, myofascial trigger points in the head and neck should be examined.

Eye Problems

Ocular complaints are common, but physical exam is usually negative unless one uses Frenzel glasses to look for nystagmus. Conjunctival injection and blepharitis is usually associated with nasal allergy. Schirmer tests are often positive. Some of these symptoms, including blurred vision, may be associated with sternomastoid trigger points in the sternal division. Although uncommon in CFS, these trigger points should be examined and treated if present.

Ear, Nose, and Throat Complications

The major otologic finding relates to TMPDS causing otalgia. Palpation of the medial and superior masseter muscles will help to make the diagnosis. Vertigo, tinnitus, and auditory discrimination disorders are common in CFS, although trigger points in the clavicular division of the sternomastoid can disturb proprioception and cause postural dizziness. Tinnitus can be caused by trigger points in the superior masseter.

Local nasal problems include allergic rhinitis or perennial rhinitis, intolerance of odors or fumes, and alteration in the sense of smell or taste. Rhinitis is extremely common and should not always be treated symptomatically. I order CT scans of the sinuses more frequently now in the fatigued patient with rhinitis; they are much more accurate than sinus X-rays for diagnosing occult sinusitis. Many CFS symptoms, especially fatigue, will often improve when sinusitis is diagnosed and treated. On the other hand, numerous patients have had surgical procedures which have benefitted them transiently, if at all. Patients with environmental illnesses sometimes describe a generalization of their intolerances. Could this be due to kindling in the pyriform cortex?

While sore throat is quite common, pharyngitis is not. A common cause of throat pain (and ear stuffiness) in CFS is a trigger point in the medial pterygoid muscle, medial to the mandibular ramus and lateral to the last molar tooth. Patients will often have associated tenderness of the masseter and lateral pterygoid, but only the medial pterygoid refers pain to the tongue, pharynx, and hard palate. Ear stuffiness occurs if spasm of the medial pterygoid blocks the opening action of the tensor veli palatini on the eustachian tube. Sore throat developing after exertion is a diagnostic aspect of CFS. Mild erythema is difficult to distinguish from variations of normal, and exudate is almost never encountered. Aphthous stomatitis is extremely common, as is periodontal disease. Both of these disorders are immunologically mediated. Patients often complain of coated tongues, which are only occasionally positive for candida. Taste disturbances, particularly hypogeusia, occur and are refractory to treatment.

Sometimes pain in the region of the anterior cervical lymph nodes may be caused by trigger points in the digastric muscle, which can be activated by bruxism and mouth breathing, as occurs in patients with nasal obstruction of various sorts. Digastric trigger points can be found in association with those in the medial pterygoid. They may be palpated by feeling behind the angle of the mandible upwards toward the earlobe, while pushing inward toward the neck muscle.

Lymphadenalgia, while more common than in the general population, is often confused with muscle tenderness and carotidynia. Some physicians are unfamiliar with the latter entity. The carotid bulb is enlarged and tender, and palpation of the bulb intra-orally, on the floor of the mouth opposite the first molar, will elicit marked tenderness. Salivary gland disorders occur, primarily decreased production of saliva, but also various types of enlargement. Hypothyroidism, sometimes of the autoimmune variety, is often encountered, but goiter or thyroid masses are not.

Pulmonary Complaints

The major abnormality related to the pulmonary system is chronic cough. This symptom may sometimes be related to asthma or chronic bronchitis, apparently more common in the CFS population, but also to postnasal drip or a hypersensitivity of the cough receptors. Dyspnea, either at rest or on exertion, is the most frequent complaint, but is probably mediated centrally. Asking the patient to hyperventilate in the office is helpful, although how to treat hyperventilation syndrome is problematic. Almost half of CFS patients hyperventilate. Hyperventilation may cause bronchial constriction. Since the limbic system regulates the automatic control of respiration, hyperventilation could be a limbic dysregulation and may result in an overlap in the diagnosis of CFS and panic disorder. Hyperventilation is seen much more commonly with CFS patients with fibromyalgia.

Cardiac Abnormalities

Cardiac complaints primarily concern arrhythmias, usually supraventricular tachycardias. Although a large number of patients will have mitral valve prolapse, the role of this process in causing tachycardia in the CFS population is questionable. Some patients respond to beta blockers, but whether these treat a hyper-adrenergic state rather than the myocardium or mitral valve is unclear. Primary myocardial disorders are uncommon in CFS, although myocarditis does occur, usually viral. A limbic or paralimbic etiology for arrhythmias is much more attractive, particularly since these episodes may occur in the context of a panic disorder or what could be considered to be a forme fruste, e.g., "panic attack without anxiety." Chest pain does not usually seem to be pulmonary or cardiac, although coronary artery spasm and microvascular angina should be considered. CFS chest pain is more often esophageal or myofascial. Some patients will have symptoms of pleurodynia intermittently without fever or friction rub and with a normal chest X-ray. "Costochondritis" per se does not occur, since there is no swelling of the costochondral junction. Another way to make the diagnosis of this disorder is by the "crowing rooster" maneuver to put the costochondral junctions on stretch. If this test is negative, one can assume that costochondral tenderness is secondary to tenderness of the sternalis muscle, the function of which is obscure. Chest pain can be produced by hyperventilation.

Gastrointestinal Difficulties

Gastrointestinal complaints are very common, and symptoms of irritable bowel syndrome (IBS) form an integral part of the CFS spectrum of symptoms. IBS should be included in the diagnostic criteria for a revised CFS case definition. There are some helpful pointers on physical exam. The tenderness on abdominal palpation will sometimes resolve if the pressure of the examining fingers is continued. This sign does not occur with focal disease of the viscera. Myofascial etiologies for abdominal pain should always be looked for. Tenderness of the abdominal wall can be elicited by asking the patient to sit up halfway while palpation continues. Testing for trigger points in the external and internal obliques and in the iliocostalis will often be rewarding, as described by Travell and Simons.6 Relief of the pain by local anesthetic infiltration may be helpful diagnostically, if one remembers that visceral disorders can cause somatic pain, and that the discomfort can sometimes be deceptively assuaged by trigger point elimination techniques. Patients with fibromyalgia are most prone to develop abdominal pain of muscular origin.

Pelvic Disorders

It is important to suspect pelvic disease. Perhaps the most common pelvic disorder in CFS is endometriosis, so common that I have postulated that the two disorders are related. Macrophages, the "vacuum cleaners" of the abdominal cavity, do not scavenge the normally refluxed endometrium which emits from Fallopian tube orifices during menstruation, and endometrial implants then occur. This defect in macrophage ingestion may occur in both CFS and endometriosis.

Adnexal masses and polycystic ovarian syndrome occur with greater frequency in CFS. Almost certainly, these disorders are related to dysregulation of GnRH secretion, as has been discussed previously. Do not assume that adnexal masses are necessarily ovarian cysts in this population, however. Although the disorder is still uncommon, a much higher percentage of my patients in a CFS practice have developed ovarian carcinoma than I experienced while practicing family medicine. Some of these tumors have grown with startling rapidity. CFS patients continue to have CFS after their cancer treatment is completed.

Genitourinary Complaints

Dysmenorrhea is also more common in CFS patients, even if endometriosis is not present. Although one could postulate that these women had excessive amounts of prostaglandins in their sloughed endometrium, a neural explanation is more plausible. A type of hollow visceral neuropathy could affect the uterus and/or there could be a disorder of descending pain modulation such as has been hypothesized to occur in fibromyalgia. Sometimes there will be diffuse tenderness on pelvic exam with no apparent cause.

A cause for pelvic pain which is often overlooked is pelvic floor tension myalgia. Patients with this disorder will often report dyspareunia and may be labeled as having a somatization disorder if they have a negative pelvic ultrasound and laparoscopy. If the pelvic floor, particularly the pyriformis muscle, is palpated in such a patient, it will be exquisitely tender and will respond well to trigger point injection or caudal epidural block. This type of pain sometimes begins after surgery in which the woman's legs are abducted for a time, such as a vaginal hysterectomy. It can be confused with lumbar radiculitis, since the sciatic nerve may be compressed between the sciatic notch and the pyriform muscle. Numerous other myofascial causes of pelvic, perineal, low back, and thigh pain are discussed in volume 2 of the Trigger Point Manual by Travell and Simons. They are also common in CFS.

The primary genitourinary complaint in the male with CFS involves prostatic discomfort, frequency, and nocturia. Although many of these men are treated for prostatitis, very few of them have had a culture-proven infection, either of the urine or of prostatic fluid. Many have not had a three-glass test. My impression is that prostatitis, either chronic bacterial or abacterial, is considerably less common than prostatodynia. Acute bacterial prostatitis is seen no more frequently than in the general population. Prostatic tenderness is often detected in CFS patients but induration or nodules with or without fever, are not common. Alpha-blocking drugs such as prazosin (Minipress) or terazosin (Hytrin) are effective in diagnosis and treatment. Testalgia occurs infrequently, but is not accompanied by structural changes. This pain may be neuropathic, but the stealth virus has been isolated from the remaining testicle of a patient who had already had one orchidectomy for disabling pain. Intense scrotal and testicular pain was reported in a nine-year old boy with a right parietal lobe seizure focus.7 Lack of libido and erectile dysfunction are common complaints as well. When we have done nocturnal penile tumescence evaluation with Rigiscans, they have been abnormal.

The urethral syndrome in women is also more common in CFS. The causes of this disorder are numerous and include various kinds of inflammation, from chlamydia to interstitial cystitis. "Detrusor dyssynergia" is often found. It is treated with anticholinergic antispasmodics, alpha blockers (as in prostatodynia), and calcium channel blockers. A few patients will have intractable detusor hyperflexia with incontinence. Such patients could be considered for intravesical capsaicin.8 There may be tenderness of the muscles of the urogenital diaphram, which would include the ischiocavernosus and the bulbocavernosus. These muscles are rarely examined, but could respond to the same sorts of trigger point elimination techniques as are used elsewhere.

Rectal exam is helpful in CFS to make the diagnosis of proctalgia fugax. This disorder is usually a myofascial pain syndrome of the levator ani. Many patients report sudden severe episodes of rectal pain which are usually brief, but may last as long as a half-hour or so. This problem, formerly consigned to the psychosomatic "wastebasket" until it was conceptualized and examined properly, is surprisingly common if one asks. It does not usually accompany burning rectal dysesthesias, another cardinal symptom of somatization disorder, although it may. Trigger point elimination techniques are helpful in treating proctalgia fugax. Levator ani trigger points, as well as those in the coccygeus muscle, can cause coccygeal pain, common in CFS. Stretch, post-isometric relaxation, massage, and high-voltage pulsed galvanic stimulation are treatment modalities suitable for pelvic floor trigger points.

Musculoskeletal Abnormalities

The number of musculo-skeletal abnormalities related to fibromyalgia or myofascial pain syndrome is enormous. The physician must know how to elicit them on physical exam, or the patient may be diagnosed as having a somatoform pain disorder or a somatization disorder. The writings of Rosomoff, et al,9 attest to the misdiagnosis of myofascial pain syndromes in the chronic pain patient because trigger point tenderness was not appropriately elicited by the examining physician. Other findings on musculoskeletal exam are not different than the general population. Arthropathies are not common. Electromyograms are normal, not even suggesting focal muscle spasm or ongoing denervation. Sometimes bilateral leg pain may be due to a sensory neuropathy. Evidence for this hypothesis is that this symptom is often improved by capsaicin cream (Zostrix).

Neurologic Abnormalities

Neurologic exam is usually normal. Hard neurologic signs and muscle atrophy are rarely seen. Benign fasciculations are fairly common, as are tremors, usually of the essential variety, although iatrogenic hyperthyroidism is seen now and then. Parkinson disease should be suspected in the middle-aged and older tremulous patient with central fatigue and cognitive dysfunction but no sore throat or flu symptoms. A Hallpike test is sometimes abnormal in vertiginous patients, as is the Romberg test. Muscle weakness is common, but is not accompanied by diffuse tenderness as would be seen in a myositis, and often it is not related to exertion as in the metabolic myopathies, or gets worse with repeated use as would be encountered in myasthenia gravis. Occasionally patients will have these disorders, and they should not be overlooked. Checking for temporal artery pulsations in selected CFS patients with headaches is a good idea, although cranial arteritis in this population is rare. Unsustained clonus is occasionally seen, as is deep tendon reflex asymmetry and anisocoria. I have two patients with persistently present extensor plantar reflexes and no other evidence of neurologic disease. Patients should be followed for the development of multiple sclerosis, or, more commonly in my experience, immune polyneuropathy. Diagnosis may b e made more difficult by the rare patient with an elevated CPK for no apparent reason. Muscle biopsies in this group show evidence of mild denervation but are borderline normal. Two such muscle biopsies have been positive for the stealth virus. The Tensilon test is sometimes positive in CFS and should not be interpreted as being diagnostic of myasthenia gravis. Muscle weakness in CFS may sometimes be treated with pyridostigmine bromide (Mestinon) when the usual diagnostic criteria for myasthenia gravis cannot be met. Surprisingly, Mestinon may alleviate mental "fogginess" as well, apparently by altering peripheral autonomic input to the CNS, or by inducing the adrenal glands to secrete more corticosteroids and catecholamines. It may also increase secretion of growth hormone.

Associated Carpal Tunnel Syndrome

Carpal tunnel syndrome (CTS) and thoracic outlet syndrome (TOS) are fairly common in CFS. The reason why the contents of the carpal tunnel should be compressed in CFS is obscure, as it is when CTS is associated with many other disorders. It is possible that the median nerve may have a heightened sensitivity to pressure. TOS is almost always related to muscle spasm and is seen in the setting of fibromyalgia. The usual maneuvers to elicit symptoms are applicable in CFS, although I have had few patients with severe enough symptoms to warrant ulnar nerve conduction velocities.

Hematologic Abnormalities

CFS patients often complain of easy bruisability or spontaneous ecchymoses. Clotting studies are usually normal, although some individuals have a mild thrombo-cytopenia which is apparently autoimmune. Platelet function studies are sometimes abnormal.

Psychiatric Complications

Psychiatric disorders are extremely common in a CFS population. Mood disorders, anxiety disorder, panic disorder, and borderline personality disorder are seen most frequently. I find somatization disorder to be rare, diagnosed without the previous caveats, as are related problems such as other somatoform disorders, hypochondriasis, and hysteria. It is important to obtain prior medical records. I have learned to suspect a psychiatric disorder in patients who claim to have no previous medical contact. An occasional delusional patient will believe that he has chronic fatigue syndrome caused by forces plotting against him, and a patient should be questioned about such false beliefs if his history sounds odd. Many patients could be diagnosed as having a post-traumatic stress disorder on the basis of a history of child abuse. Phobias are also common, especially agoraphobia and driving phobia.

Although it is thought to be important to distinguish CFS from depression, as we have seen, this task is not too difficult unless one calls CFS an atypical depression, in which case it would have to be very atypical. The "Columbia Criteria" are increasingly used to make the diagnosis of atypical depression. The patient must have (a) mood reactivity when depressed and (b) (two of these positive, one for probable) hyperphagia, hypersomnia, leaden paralysis of the limbs, abnormal rejection sensitivity for most of his life.10 These patients do not respond well to cyclic antidepressants, and do better with monoamine oxidase inhibitors, cognitive therapy,11 and possibly selective serotonin reuptake inhibitors.12 It could be a little harder to differentiate CFS from some cases of panic disorder, in which autonomic symptoms are more prominent. A case could be made that whether one makes the diagnosis of CFS or depression, panic disorder, or somatization depends on the physician's orientation, especially in patients who do not report flu-like symptoms, sore throat, worsening of symptoms the next day by exercise, and alcohol intolerance.

The physician evaluating CFS patients should have a good understanding of anxiety. A useful primer is Panic Disorder in the Medical Setting, by Wayne Katon, published in 1989 by the U.S. Department of Health and Human Services. These diagnostic issues are not just hair-splitting, since treatment decisions must be made and health and disability insurance issues depend on whether the patient has a "nervous or mental disorder." It is thus often necessary to do diagnostic tests beyond what has been recommended by the NIH, even though they may be labeled "experimental." Furthermore, since CFS appears to be multi-causal, it would be of value to know which patients had a virus detected.

Looking For Viruses and Other Invaders

Identification of viruses should be very helpful, since nervous and mental disorders are not usually considered to be associated with infections, although there is increasing evidence that some cases of schizophrenia are. At the present time, the most available tests are cultures for CFS-associated retrovirus, the stealth virus, and polymerase chain reactions (PCR) for EBV, CMV and HHV-6. Although PCR is quite helpful, its reliability is determined by the sensitivity of the assay, which can be modulated by the pathologist. False positives occur, and one wonders whether herpesviruses should be treated with antiviral agents on the basis of a PCR result without physical signs of infection, especially when potentially toxic agents such as ganciclovir or foscarnet might be used. Ribavirin has also been used by some.
A positive culture is better diagnostic information, especially when the virus being cultured is not seen in apparently normal people, as CMV can be. Stealth virus has not yet been detected in asymptomatic individuals. HHV-6 can be detected by monoclonal antibodies in an experimental giant cell assay, although once again, there are ambiguities about whether this virus should be treated; are the potential benefits greater than the risks? Can the morbidity of CFS be improved by decreasing the load of transactivating co-viruses (as in AIDS)? Should a lumbar puncture be done if blood results are negative? These questions are currently unanswered. Rubella viremia could be investigated if symptoms began subsequent to rubella vaccination. Other forms of post-vaccinal CFS seem to be immunologically, not virally, mediated.

Detecting viral gene products, such as glycoproteins, is another method of viral diagnosis. No such products have yet been identified in CFS. They should be more easily identified when the stealth virus is sequenced. An assay for the gp120 antigen has been developed. gp120 antibodies are negative in CFS.

Viral antibody titers are virtually useless in CFS. There appears to be an impairment of the suppression of antibody production, particularly to herpesviruses, in CFS. At present, I do not order these tests.

I do order titers for Lyme disease and (sometimes) toxoplasmosis. I will treat the patient with IgG and IgM antibody to borrelia burgdorferi on repeat testing even when there is no history of the typical rash and no findings of arthritis. The morbidity of the patients I see is so great, and the risk of oral or IV antibiotics so small, that a therapeutic trial is often justified. Sometimes it works, other times not. The issue is further confused by the fact that patients with unequivocal Lyme disease can still have a CFS picture after treatment which has cured their arthritis. The common neurologic abnormalities in Lyme disease, radiculitis, meningitis and cranial neuritis, are not frequently seen in a CFS patient.

I see an occasional patient with persistently elevated IgG and IgM antibodies to toxoplasmosis. Thus far, I have not treated these patients and have not seen any progression to the physical signs caused by the organism. I have referred some of these patients to infectious disease specialists, but they are perplexed, also.

Isolation of intestinal parasites by stool exam and antibody titers is often valuable. Some cases of apparent CFS have been cured by anti-parasitic therapy, as has been described by Leo Galland.10 I have not used purged stools or special laboratories, but do sometimes order anti-giardia antibodies. I have done numerous rectal mucus swabs and have abandoned the procedure because of its low yield. The mechanism by which intestinal parasites can cause CFS is unknown, but may be cytokine-mediated. Sometimes a patient will have "non-pathogenic" parasites isolated. Current dogma is that these organisms should not be treated if they do not cause GI symptoms, but if they cause an immune response which could produce CFS, perhaps they should be treated.

Routine Lab Tests

A New Zealand researcher reports abnormalities in red cell morphology in CFS that could be associated with a low sedimentation rate.14 Although these findings have been called artifactual by some, one of the defects ("cup forms") often responds to vitamin B12 injections, which also are reported to relieve symptoms. This morphologic abnormality suggests a membrane defect which may be resolved by a methyl group donor. Trials of the methyl donor S-adenosylmethionine in FM have been beneficial.15

Routine lab tests include CBC, UA, chemical profile, ANA, rheumatoid factor, TSH, HIV serology, and serum ferritin. CFS and panic disorder patients16 often have significant elevations in serum cholesterol from premorbid levels. Possible mechanisms of hypercholesterolemia in CFS include production of IgG or IgM that binds to heparin, thereby decreasing activity of lipoprotein lipase. Heparin is an attractive therapy in CFS if mast cell abnormalities are suspected, but heparin has been fairly unsuccessful in the treatment of interstitial cystitis, thought by some to be related to bladder mast cell dysfunction. Hypercholesterolemia in CFS could also be caused by increased secretion and decreased catabolism of VLDL, perhaps due to altered function of BAT. IL-1, acting either peripherally or centrally, has produced elevations of free fatty acids in mice, without acting directly on the pancreas.17 CFS patients do not have increased atherosclerosis, however. I will not discuss various tests of immune activation in great detail. The sed rate is often very low. Immune complexes and positive anti-nuclear antibodies are encountered very frequently. Anti-lymphocyte antibodies are negative. Elevated levels of various cytokines and their receptors are often seen. Some researchers maintain that these have prognostic significance and can also serve as a measure of disease activity, but I am not so sure, at least in my patient population. The multitest CMI for delayed-type hypersensitivity can be useful, especially when the patient is initially anergic. I am

not sure how to use information such as low (or high) natural killer cell function or levels of the soluble CD8 receptor. I do not find mitogen stimulation test or T & B cell subset analysis to be helpful. I have not ordered tests for cytokine generation by lymphocytes. I am concerned that there may be wide variability between labs in reporting results of many of these more esoteric tests of immune function.

Cytokine Abnormalities

The main serum cytokine elevations noted in the literature have been IL-1 alpha, IL-2, alpha interferon, and IL-6. A recent report, which also noted elevations in serum transforming growth factor-beta (TGF-beta) also included release of cytokines in peripheral blood mononuclear cell cultures.18 Elevations in IL-1 alpha were reported in 35 percent of the Ampligen patients, and correlated with a good response to treatment. I attempted to measure most of these cytokines several years ago with Drs. James Peter, Michael Palladino, and John Martin, but found the results too inconsistent to be of clinical utility. Since serum inhibitors of cytokines are common, the measurement of mRNA for such transmitters, as is being done by Dr. Cheney, will be more valuable. My initial hypothesis was that CFS is a cytokine-mediated illness, but cytokine measurement in CFS and FM, as of now, is not useful. mRNA techniques may help in sub-typing CFS. I published a hypothesis of CFS as a TGF-beta excess syndrome several years ago.19 The effect of cytokines in the brain can be profound at very low levels and can cause suppression or activation of peripheral immune responses. Immune suppression has been described with IL-1 infused in picogram quantities into the lateral ventricle of rats.20 These effects were blocked by infusion of alpha-melanocyte stimulating hormone (alpha-MSH), a known IL-1 antagonist. Infusion of IL-1 at these levels did not elevate body temperature and may have actually decreased it. Plasma corticosteroid levels were elevated in the infused animals (unlike CFS patients), but 50 percent of the immune suppression noted in intact animals was seen in adrenalectomized animals, probably mediated by the sympathetic nervous system. Cellular immune responses in splenic lymphocytes were suppressed by a lower dose of IL-1 than that needed to suppress the function of peripheral lymphocytes. Modulation of an autonomic neural pathway from brain to spleen, as demonstrated by Felten, et al21 was suggested.

The roles of interleukin-1 alpha and beta in the brain have recently been reviewed by N. J. Rothwell.22 These subtypes of IL-1 have similar effects for the most part, but may exert them by different mechanisms, and produce them at much lower concentrations than in the periphery. Central actions of IL-1 as listed include:

  1. Local effects in brain: altered EEG and neuronal activity, inhibition of long-term potentiation, cortical inhibitory postsynaptic function, neurotransmitter release/turnover, induction of NGF, self-induction (of IL-1 beta), astrogliosis, and neovascularization. IL-1 further opens the chloride channel of the GABAA receptor when the receptor is already occupied by GABA.23 IL-1 is probably involved in antagonizing vasospasm by stimulating nitric oxide synthase.

  2. Metabolic actions: fever, increased metabolic rate (thermogenesis), sympathetic activation of brown fat, hypophagia, and altered gastric function.

  3. Endocrine actions: hypothalamic-pituitary hormone release (CRH, GnRH, TSH, ACTH), pituitary-adrenal activation, and insulin release.

  4. Behavioral actions: sleep and sickness behavior (e.g., reduced exploration). Central IL-1 may also decrease pain.24

  5. Immune actions: peripheral IL-6 release, decreased peripheral IL-2 production, reduced natural killer cell activity, leukocytosis, and hepatic acute phase protein synthesis.

Some of these actions appear to apply to CFS and others not. The idea that CNS cytokines are involved in the pathogenesis of CFS is very persuasive, however, and since so many transmitter substances may be involved in the modulation of IL-1 activity, the role of this cytokine cannot be dismissed. As in peripheral blood, CNS cytokine measurement has yielded conflicting results. Concentrations of CSF IL-1 inhibitory substances have not been reported.

Other Distinct Abnormalities

Laboratories are looking for abnormalities in lymphocyte metabolism. Perhaps the most useful assay will be for 2'-5'oligo-adenylate synthetase/RNase L, which was significantly elevated in Ampligen responders. [Eds. Note: See related article in this issue by C.V. Herst, PhD discussing this test and its implications.] A protein kinase C deficit has been noted in the failure of lymphocytes from patients with fibromyalgia to generate interleukin-2.25 The p15E retroviral envelope protein impairs IL-1 signal transduction by blocking protein kinase C.26 This finding is of interest since tung oil, a phorbol ester (which stimulates protein kinase C) has been implicated in the etiology of CFS in some patients. Serine proteases can be demonstrated by immunogold staining in natural killer cells stimulated with IL-2 and are thought to be the means by which those cells destroy targets. NK cells from CFS patients with low NK function are being investigated to see if these enzymes are deficient.27 I generally measure quantitative immunoglobulins to check for monoclonal gammopathies as well as deficiencies, particularly of IgA, since IgA deficient patients are at risk for receiving gamma globulin exogenously. I have stopped doing anti- IgA antibodies because they are too expensive, and find IgG subclass levels and response to pneumococcal vaccine to be an academic exercise which has little bearing on patient response. Abnormal results in these tests may, however, convince insurance companies to pay for gamma globulin therapy on the basis of an immunodeficiency.

I sometimes do studies to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. Dexamethasone suppression tests are usually normal. ACTH stimulation tests are sometimes abnormal, but treatment of the patient with corticosteroids based on this result is only occasionally helpful. CRH is not generally available, but ACTH reserve could be tested indirectly by a metyrapone test. The few TRH tests I have done have been normal. Prolactins are occasionally elevated, but not often enough to order them routinely. Patients sometimes have galactorrhea with or without hyperprolactinemia, and none of my patients has had a pituitary adenoma. Neuroendocrine dysfunction is best assessed with the patient in a stressed, not a resting state, since CFS may, in one sense, be viewed as a dysregulation of homeostatic mechanisms.

SPECT Scan Abnormalities

I believe that tests of brain function are quite helpful. The best one may be the SPECT (Single Photon Emission Computerized Tomography) scan. In this procedure we administer Xenon133 by inhalation and do a computerized scan of cerebral blood flow using a brain-dedicated SPECT scanner. Using other types of SPECT scanners does not provide adequate resolution. We then ask the patient to perform cardiopulmonary exercise testing, looking for a lowered anaerobic threshold, respiratory alkalosis suggesting hyperventilation, and irregular respiratory rhythms at maximum exercise suggesting disordered central regulation of respiration. After physiologic parameters return to baseline, we repeat the Xenon133 study and may also do one with technetium HMPAO. Pre- and post-exercise neuroendocrine measurements are performed, and if the patient is able to return in the next day or two, we omit the technetium study and do another Xenon133 scan. Although we have not completed testing all comparison groups, SPECT results are quite distinctive. There is resting hypoperfusion in the anterior temporal lobes, more often seen in the right. There is also hypoperfusion in the prefrontal cortex. The hypoperfusion is usually worsened by exercise.

We have recently compared groups of depressed and non-depressed CFS patients over the age of 45 to a comparison group of patients with major depressive disorder. The technetium HMPAO SPECT scans of the depressed patients showed bilatral orbitofrontal hypoperfusion. The CFS patients had only right dorsolateral prefrontal hypoperfusion rather than orbitofrontal. These results were highly significant. The implications of this study are perhaps that amygdalar lesions are more involved in depression, while hippocampal lesions are pathogenetic in CFS, and that hemispheric asymmetry is present in CFS. To quote Joaquin Fuster: "Nauta (1964) pointed out, on the basis of primate data, that the orbitofrontal cortex is connected mainly to the amygdala complex and related subcortical structures, whereas the dorsal prefrontal convexity is connected to the hippocampal and parahippocampal cortex ... The functional significance of prefrontal connections with the limbic system is still unclear, but in all probability these connections involve the prefrontal cortex in neural functions that maintain and protect the organism's internal milieu. The reciprocal connection between the dorsolateral prefrontal cortex and the hippocampus, through the entorhinal cortex, are probably involved in cognitive functions ... ."28 If the abnormalities seen on SPECT are primarily related to the regulation of regional cerebral blood flow, a differential expression of the potentially vasoconstrictive IL-1ra mRNA29 may be involved. Other IL-1 inhibitors, such as TGF-beta and IL-10, which also inhibit the vasodilator nitric oxide, should be considered as well.

One of the minor criteria in the CDC case definition for CFS is severe post-exercise fatigue lasting 24 hours or longer. This symptom is reflected in post-exercise SPECT scans which usually have much greater degrees ofhypoperfusion than baseline, as seen in Xenon133 scans done the same day and the next. Limited numbers of post-treatment scans suggest that improvement in regional cerebral hypoperfusion is correlated with lessening of symptoms. It appears that the hypoperfusion is a reflection of an underlying metabolic abnormality, since agents that increase cerebral blood flow do not reliably improve CFS symptoms. The temporal lobes and orbitofrontal cortex are part of the limbic system. The dorsolateral prefrontal cortex is a heteromodal association area related to the paralimbic cortex. Brain SPECT allows a quantification of functional abnormality which is not based solely on self-report. It has significant relevance to the work of Renoux on lateralization of cortical immune function30 as well as to lateralization of 5HT2 receptors.31

Evoked Response Testing

Topographic brain mapping with evoked responses is almost always abnormal in CFS patients. The temporal lobes, left more than right, are most frequently abnormal on visual and auditory evoked response measurement by BEAM (Brain Electrical Activity Mapping), which compares these results in 36- millisecond segments to a normal population and then calculates the difference from this group, which to be significant is two or more standard deviations from normal. The technology of the BEAM scanner allows evoked response data to be examined in 2-millisecond segments if desired. Paper EEG, computerized EEG, and somatosensory evoked responses are usually normal. There is often an absent or asymmetric n-120 wave in the VER, thought to indicate attentional disorders, and a similarly abnormal p-180 wave in the VER, suggesting an encephalopathic process. BEAM abnormalities are seen more frequently in other cortical areas than on SPECT.

Evoked response testing in the usual manner (without BEAM), can also be abnormal. The types of abnormalities may help in distinguishing CFS from multiple sclerosis, which in its early stages may be quite similar to CFS. We have found a highly significant abnormality in the P100 wave in the auditory evoked responses of 12 out of 12 CFS patients, suggesting a hippocampal localization. A group from London has reported abnormalities in latency or amplitude of P300 wave in the cognitive event-related potentials but not in sensory-related potentials of about 50 percent of 37 CFS patients tested. MS patients have more widespread derangements in evoked responses and should be able to be distinguished from individuals with CFS on this basis as well as several others.

PET Scans

PET (Positron Emission Tomography) scans are also abnormal in a distinctive fashion, implicating limbic structures most frequently as being hypometabolic. The medial frontal lobe, hippo-campus, amygdala, and cingulate gyrus are usually involved, as are the anterior caudate nucleus and areas of the parietal lobe. Sometimes the premotor cortex and anterior cerebellum are also hypometabolic. PET scans utilize radioactive fluorodeoxyglucose, which is injected intravenously prior to computerized scanning. The expense of the test and duration of action of the tracer preclude doing the type of exercise testing that we do with SPECT scans. The limits of resolution of the PET scanner that I use is 6mm, not good enough to image small structures such as the nucleus accumbens. Newer PET scanners will be able to resolve down to 2mm, a distinct improvement. Both PET and SPECT technology will be revolutionized by the use of isotopes which label receptors. The multiple serotonin and dopamine receptors are of interest, and compounds to label them are available now. We shall start using them shortly.

Lesions Detectable By MRI

Magnetic resonance imaging (MRI) of the brain demonstrates increased numbers of high signal intensity lesions in young people that are not necessarily in the characteristic locations for demyelinating disease. These UBOs (Unidentified Bright Objects) are of uncertain etiology, and he neuroradiologist must be educated to ensure that they will be noticed. They are often ignored as a normal variant of no significance. UBOs were an indicator of a positive response to Ampligen.

Hippocampal volumes may be reduced, implying a poorer prognosis, and special coronal cuts must be ordered to assess this cortical area. A technique recently described is measurement of cerebral blood flow by MRI. How MRI blood flow measurement would compare with SPECT and whether post -exercise MRI blood flow studies would be feasible remains to be seen. A group of CFS patients are being examined with a new technique, magnetoencephalography. We also plan to study brain metabolism with NMR spectroscopy.

Neuropsychological Testing

Neuropsychological testing is important diagnostically as well as in measuring functional impairment for determining the degree of disability. Medical insurance sometimes will not cover such testing even if it is quite abnormal and diagnostic of an organic dementia. In our patients, it reliably differentiates depression as well as other dementing disorders from CFS. Since neuropsychologists vary in their training and approach, computerized testing methods, such as we use, are being developed so that the quality and process can be standardized as well as reduced in cost. Superficial kinds of cognitive testing, such as the Mini-Mental Status exam, are usually normal. CFS patients are prone to overestimate their cognitive abilities. Their making of new memories is extremely fragile and disrupted by proactive interference. They do not benefit from memory cues. The making of new memories is easily disturbed by increasing the amount of information presented. [Eds. Note: Drs. Sandman and Moore address this topic in their article elsewhere in this issue.] Depressed patients underestimate their cognitive abilities and have normal testing, although their response time is slowed. On the basis of test results, indicating a hippocampal lesion, we commonly diagnose our patients as having Temporolimbic Dysfunction, Amnestic Disorder, Metabolic Encephalopathy.

Other types of psychological testing instruments are also used, and the literature is proliferating rapidly. It may be helpful to know if there was a premorbid psychiatric disorder, and if so, what kind. The Diagnostic Interview Schedule (DIS) has been adopted for use in medical patients. It is mainly a research tool. It is a highly structured "no brainer" kind of test which asks specific questions about each symptom endorsed. Psychiatric symptoms and onset of fatigue can be dated. There are problems using the DIS in CFS because the need to modify it to rate a medical illness with cognitive dysfunction may decrease its validity.

We use the Minnesota Multiphasic Personality Inventory (MMPI). It is the best validated of all psychologic tests. We have found there is a unique and probably diagnostic profile in CFS: elevations in scales 1,2,3,4,7 and 8.32 Unless the interpreting psychologist is familiar with this pattern, the test results may be misinterpreted. This pattern suggests chronic illness and cognitive dysfunction. [Eds. Note: Please see related article by Linda Miller-Iger, PhD in this issue.]

Complications with Premorbid Psychiatric Conditions

Are CFS patients with premorbid psychiatric diagnoses more chronic in their course and more resistant to treatment? Experience might suggest that this is so, but the results of the Ampligen experiment do not support this impression. Most studies suggest, however, that premorbid psychiatric illness is more common in CFS patients than in comparison groups with other medical diagnoses, such as rheumatoid arthritis or neuromuscular disorders. It has been suggested that this CFS group may be more prone to "somatize" psychological distress and are thus subject to the "biologic" effects of depression.33 This tendency to report high levels of somatic symptoms has been called "somatosensory amplification." Some view this as a perceptual style amenable to change through cognitive and behavioral interventions. Using this paradigm, those with no premorbid psychiatric illness and an acute onset of CFS symptoms may have a cytokine mediated illness. The unifying concept of a limbic encephalopathy appears to be a new one, and could explain somatosensory amplification as a dysfunction of the insula or other paralimbic areas. Rats with a central defect in the secretion of CRH demonstrate behavior compatible with somatosensory amplification as well as a failure of immune suppression in response to inflammatory stimuli. These rats provide a model of the relationship between stress and the immune system.34

Functional Capacity Evaluation

Another method to evaluate the CFS patient which has not received attention in the literature is the functional capacity evaluation (FCE). FCE is "an assessment of functional ability to perform work activities which include the physical demand factors on which the Dictionary of Occupational Titles is based."

The functional capacity evaluation done on my patients is an intensive 5 to 7 hour assessment. Breaks are allowed as needed. His/her ability to participate in the lengthy evaluation is observed and considered when recommendations are made. The evaluation involves standardized physical and cognitive testing, including the following:

An assessment and recommendations follow the evaluation. The report analyzes the patient's ability to perform the critical job demands required by his/her job description. It is, in essence, a comparison of the patient's present physical and cognitive status to the physical and cognitive demands of his/her work and activities of daily living, including self care.

The FCE is a major determinant in setting up an individualized work hardening program or assessing the patient's ability to return to work and to perform self care.

By ordering this evaluation, I am provided with a definitive baseline of the patient's functional ability. This information is objective and invaluable for determining a patient's present and future work capacity and for determination of level of disability. The evaluation includes an extensive 15- to 20-page report with specific findings from standardized tests, the assignment of a Dictionary of Occupational Title physical demand level, and a summary of the patient's ability and potential ability.

Common findings of an FCE in CFS are significant deterioration in dynamic, repetitive strength testing; marked memory impairment with relative preservation of other cognitive functions on the NCSE; and performance capabilities in the lower (or lowest) percentiles when compared with occupational norms. Most patients relapse for several days after the evaluation. We have not tested anyone whom we thought was malingering.

Conclusion

I know of no other mechanism than a limbic encephalopathy by which the common diagnostic constellation of CFS, FM, IBS, panic disorder, dysthymia, night sweats, depression, hippocampal cognitive disorder, nasal allergy, sleep disorder, sore throats, tinnitus, vertigo, intermittent blurred vision, PMS, alopecia, and endometriosis (to name a few) could be produced. Variations in the manner in which the limbic system is dysfunctional could account for symptom predominance. Local disorders such as those involving nasal immune function or enteric neuropathies could account for limited expression of the symptom complex. Stealth virus can infect organs other than the brain and cause local disease. The spouse of a CFS patient of mine is stealth virus negative by blood culture. He has no symptoms of CFS, but has cryptogenic hepatitis. His liver biopsy is positive for stealth virus. Other organs such as muscle, tongue, and testis can be stealth virus positive. Repeated viral cultures, in the manner of blood cultures, may be necessary to isolate stealth virus in certain individuals. Secondary adrenal insufficiency due to a central mechanism relating to CRH deficiency could also be responsible for many CFS symptoms. There are some patients whose disorder may be a genetic, acquired, or learned somatosensory amplification. These categories may, of course, overlap. I am currently exploring the idea that interference with central IL-1 beta action is characteristic of CFS. It may become apparent that, just as the limbic system integrates function on a neuroanatomic basis, so does a balance of cytokines do so from a neurochemical perspective.

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