Proposed Diagnostic Criteria for ME/CFS

Diagnosis requires that the patient have the following three symptoms:

1. A substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest,

2. Post-exertional malaise,* and

3. Unrefreshing sleep*

At least one of the two following manifestations is also required:

1. Cognitive impairment* or

2. Orthostatic intolerance

* Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.

Diagnostic algorithm

Hypothesis.

Exposure to infection leads to concomitant and persistent immune dysfunction and changes in the gut microbiome. Immune dysfunction affects both innate and adaptive immune systems that are sex-dependent.  It is hypothesized that these changes are driven by antigen persistence of the infectious pathogen, These immune and microbial alterations impact the brain, leading to decreased concentrations of metabolites which impacts brain function. The catecholamine nuclei release lower levels of catechols, which impacts the autonomic nervous system and manifests with decreased heart rate variability and decreased baroreflex cardiovascular function, with downstream effects on cardiopulmonary capacity.  Using functional brain imaging, researchers at NINDS also found that the temporoparietal junction was hypoactive during motor tasks in the ME/CFS group,   It is not the kind of weakness that you see in patients with strokes—if the person is forced to do so, they can exert full strength.   But the hypoactivity of the temporoparietal junction limits the brain from exerting that complete effort because too much effort, either cognitive or motor, wipes them out.

Supine and standing transcranial dopplers to assess for cerebral perfusion; complete autonomic reflex testing, including quantitative sudomotor axon reflex test; and a two-day cardiopulmonary test. These tests have shown significant difference between patients with ME/CFS and healthy controls in prior studies. 

On March 12, RECOVER announced the opening of two phase 2 trials under the umbrella of RECOVER-AUTONOMIC, which will involve testing potential treatments in adults who have dysautonomia following COVID-19 infection. 

Important elements of the Clinical History

Impairment in function with profound fatigue:

1. How fatigued are you?

2. What helps your fatigue the most (resting, lying down, quiet situations, not exercising or avoiding exercise)? 

3. What makes the fatigue worse? 

4. What are you able to do now? 

5. How does it compare with what you were able to do before? 

6. Think back to what you were able to do before you became sick. 

   • How much has this illness affected: (a) your ability to work? (b) your ability to take care of yourself/your family and to do chores? 

7. What happens when you try to push through the fatigue?

Post-exertional malaise:

1. What happens to you as you engage in normal physical or mental exertion? or after? 

2. How much activity does it take you to feel ill? 

3. What symptoms develop from standing or exertion?

4. How long does it take to recover from physical or mental effort?

5. If you go beyond your limits, what are the consequences? 

6. What types of activities do you avoid because of what will happen if you do them 

Unfrefreshing sleep:

1. Do you have any problems getting to sleep or staying asleep?

2. Do you feel rested in the morning or after you have slept?

3. Tell me about the quality of your sleep.

4. Do you need too much sleep?

5. Do you need to take more naps than other people? (There may be other sleep disruptors as well.) 

Cognitive impairments:

1. Do you have problems doing the following activities: driving, watching a movie, reading a book/magazine, completing complex tasks under time constraints, following/participating in conversation, doing more than 1 thing at a time?

2. Compared with before your illness, how is your performance at work or school now? 

Orthostatic intolerance:

1. How do you feel when you have been standing still for more than a few minutes? 

2. What happens to you after you get up rapidly after lying down or sitting for a long time?

3. How long can you stand before feeling ill? For example, can you do the dishes? Can you stand in line for a bus or movie? Are you able to grocery shop or go to a mall?

4. How does hot weather affect you?

5. Do you study or work lying down, in bed or a recliner? Why? 

6. Do you prefer to sit with knees to your chest or legs under you? 

All questions should explore frequency and severity. To fulfill 2015 National Academy of Medicine diagnostic criteria, symptoms must be of at least moderate severity and present at least 50% of the time. 

Clinicians should ask additional questions to understand the nature of fatigue; for instance, “What do you mean by fatigued?” and “On a scale of 0 (no energy) to 10 (full energy), how fatigued are you?”

Adapted from the National Academy of Medicine Report Guide for Clinicians, 97 with permission of the National Academy of Sciences. 

Routine Diagnostic Tests Recommended for All Patients 

CBC with diff, CMP, Rheumatoid factor, Four-point salivary cortisol (eg, wakening, at noon, 4:00 PM, and bedtime), AM cortisol, ANA, ENA, TSH, FT4, CRP, ESR, Vit D, ferritin, HIV, CK, acute hepatitis panel, lyme, TB, giardiasis, WNV, syphilis, EBV, parvovirus B19, coccidiomycosis, Celiac panel, 24-Urine heavy metal screen, mold, mycotoxins, lead, mercury, UA.

Rule out: 

1. Sleep apnea, narcolepsy, periodic limb movement disorder

2. Systemic lupus erythematosus, rheumatoid arthritis, polymyositis, polymyalgia rheumatica 

3. Cardiomyopathy, coronary artery disease, pulmonary hypertension, valvular heart disease, arrhythmias 

4. Primary and secondary cancers 

5. Multiple sclerosis, Parkinson disease, myasthenia gravis, vitamin B12 deficiency, cerebrospinal fluid leak, Chiari malformation, traumatic brain injury, spinal stenosis, craniocervical instability, seizures 

6. Anxiety, depression,a bipolar affective disorder 

7. Anemia (iron deficiency, other treatable forms), iron overload 

8. Severe obesity (body mass index >40 kg/m2 ), overwork, athletic overtraining syndrome, asthma, chronic obstructive pulmonary disease 

https://nap.nationalacademies.org/download/19012

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management - Mayo Clinic Proceedings 

Management of Chronic Multisymptom Illness: Synopsis of the 2021 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guideline (mayoclinicproceedings.org) 

Summary of Treatment and Management Approaches

Postexertional malaise 

Nonpharmacologic approaches to conserve energy and to minimize postexertional malaise 

• Pacing of physical and cognitive activity

• Assistive devices, such as motorized scooters, handicap parking stickers, shower chairs to conserve energy

• Home health aides for those who are more severely ill

• Ear plugs, eye masks, perfume-free environments to decrease sensory stimulation; may need to maintain low sensory environment for the most severely ill.

• School or work accommodations, such as flexible hours, shortened days.

 Pharmacologic approaches:  No specific recommendations

Orthostatic intolerance 

Nonpharmacologic approaches

• Salt and fluid loading, electrolyte drinks 

• Compression stockings

• Positional changes; avoid prolonged sitting or standing 

• Consistent, tailored exercise as long as the patient can perform them without triggering postexertional malaise; may need to exercise lying down, seated, or in water

• Treat comorbidities that may contribute to orthostatic intolerance 

Pharmacologic approaches

• Fludrocortisone, low-dose beta blockers, alpha-adrenergic agonists, pyridostigmine, desmopressin, ivabradine, Intravenous saline.

Sleep issues 

Nonpharmacologic approaches 

• Sleep hygiene practices are a part of treatment but may be marginally effective in most patients; need to be tailored for severely ill and those with orthostatic intolerance 

• Meditation and relaxation exercises 

• Ear plugs and eye masks 

• Light therapy

• Blue light filters 

Pharmacologic therapies

• Trazadone, low-dose tricyclic antidepressants (eg, amitriptyline, doxepin), mirtazapine, antiepileptics (eg, gabapentin, pregabalin), clonazepam, cyclobenzaprine, zolpidem, eszopiclone, tizanidine, suvorexant, topiramate, hydroxyzine, alpha blockers (eg, clonidine, guanfacine, prazosin), diphenhydramine.

Cognitive dysfunction and fatigue 

Nonpharmacologic approaches

• Cognitive pacing (eg, focus on only 1 task at a time, limit reading time)

• Simple memory aids (eg, calendar reminder systems, notes)

• Positional changes: perform cognitive functions lying down and stay hydrated if orthostatic intolerance is a problem 

Pharmacologic approaches 

• Methylphenidate, modafinil, armodafinil, amantadine

• Caffeine if well tolerated

Immune dysfunction 

Nonpharmacologic approaches.  No specific recommendations. 

Pharmacologic approaches: 

• Intravenous immunoglobulin, subcutaneous gamma globulin, inosine pranobex, hydroxychloroquine.

Pain 

Nonpharmacologic approaches:

• Pacing to avoid flare-up of pain

• Hot or cold packs as needed to relieve the specific source of pain

• Physical therapy, massage, myofascial release, acupuncture, dry needling of trigger points 

• Chiropractic treatments   

• Meditation and relaxation

• Neurofeedback techniques may be helpful

Pharmacologic approaches 

• Low-dose naltrexone, serotonin-norepinephrine reuptake inhibitor (eg, duloxetine, milnacipran), antiepileptics (gabapentin, pregabalin), muscle relaxants (eg, cyclobenzaprine, tizanidine, baclofen), medical marijuana, nonsteroidal anti-inflammatory drugs (eg, celecoxib, meloxicam), acetaminophen, amitriptyline, tramadol.

Gastrointestinal issues 

Nonpharmacologic approaches 

• Healthy, varied diet low in processed food. Some patients may be able to minimize gastrointestinal symptoms by eliminating certain foods (eg, 1 or more of caffeine, alcohol, spicy foods, aspartame, sugar, possibly dairy or gluten). 

Pharmacologic approaches:  If small intestinal bacterial overgrowth: rifaximin, oral vancomycin, metronidazol.   

Clinical Template

Chronic complains of dysesthesias with the acute onset and progression to involve whole-body and multi focally.  She has symptoms suggestive of small fiber neuropathy; however exam does not correlate with the extent and distribution of her symptoms.  She meets criteria for mild check encephalomyelitis/chronic fatigue syndrome.  She reports substantial reduction or impairment in her ability to engage in pre illness levels of activity and it has been well over 6 months of symptom onset.  It is accompanied by fatigue which is reportedly profound and not alleviated by rest.  She has post exertional malaise.  She reports exercise intolerance, sleep impairment, whether she has underlying sleep disorders, including sleep apnea, or poor sleep hygiene needs to be investigated further.  Overall, her symptoms are out of proportion to findings of the examination.  Although she has a risk factor for neuropathy being diabetes mellitus, her clinical exam does not demonstrate sensory dysfunction.  She also reports some autonomic symptoms.  It was possible that she may have small fiber neuropathy.  I explained to her that SFN association with condition such as fibromyalgia, ME/CFS.