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Infectious Disease and Neurocognition
Major criterion #2:
• Other clinical conditions that produce similar symptoms must be excluded by thorough evaluation based on history, physical examination, and appropriate laboratory ndings.
Minor criteria:
• Mild fever
• Sore throat
• Painful lymph nodes in the anterior or posterior cervical or axillary distribution
• Unexplained generalized muscle weakness
• Muscle discomfort or myalgia
• Prolonged (24 hours or greater) generalized fatigue aer levels of exercise that would have been
easily tolerated in the patient’s premorbid state
• Generalized headaches (of a type, severity, or pattern that is dierent from headaches the patient
may have had in the premorbid state)
• Migratory arthralgia without joint swelling or redness
• Neuropsychologic complaints (one or more of the following: photophobia, transient visual
scotomata, forgetfulness, excessive irritability, confusion, diculty thinking, inability to concentrate, depression)
• Sleep disturbance (hypersomnia or insomnia).
3. Oxford consensus criteria (Sharpe et al., 1991)
Either:
• Fatigue, denite onset, severe and disabling
• Aects physical and mental functioning
• Less than 6 months’ duration (symptoms present at least 50 percent of the time).
Or:
• Fullls the criteria for CFS and:
• Denite evidence of infection at onset or presentation (a patient’s self- report is unlikely to be sufciently reliable)
• e syndrome is present for a minimum of 6 months aer infection
• Infection corroborated by laboratory evidence.
• Other symptoms, particularly:
• Myalgia
• Altered mood
• Sleep disturbance (not deemed essential to the CFS diagnosis).
• Exclusions:
• Patients with established medical conditions known to produce chronic fatigue
• Severe anemia
• Schizophrenia
• Bipolar disorder
• Substance misuse
• Eating disorder
• Proven organic brain disease.
4. Centers for Disease Control and Prevention, 1994 (Fukuda et al., 1994)
Also referred to as the 1994 International Research Case Denition and commonly as Fukuda et al. or
the International Consensus Criteria (ICC).
Fibromyalgia and Chronic Fatigue 399
Overview of inclusions:
• Fatigue plus four out of four case- dening symptoms:
• PEM lasting more than 24 hours
• Unrefreshing sleep
• Signicant impairment of short- term memory or concentration
• Muscle pain
• Pain in the joints without swelling or redness
• Headaches of a new type, pattern, or severity
• Tender lymph nodes in the neck or armpit
• A sore throat that is frequent or recurring.
• Duration:
• Patient must be ill with symptoms for a minimum of 6 months (clinical evaluation starts at
1 month— prolonged fatigue).
• Fatigue:
• Exhibited for 6 months of new onset characterized as severe and persistent or relapsing in nature
• Unexplained aer clinical evaluation
• Unrelated to ongoing exertion
• Not substantially relieved by rest
• Results in substantial reduction in occupational, educational, social, or personal activities.
• Post- exertional malaise:
• Not required but one of the eight case- dening symptoms.
• Minimum number of symptoms is ve.
Exclusions:
• Active medical condition that explains chronic fatigue— untreated hypothyroidism, sleep apnea,
narcolepsy, medication side eects
• Previous diagnosis not unequivocally resolved (e.g., chronic hepatitis, malignancy)
• Past or current major depressive disorder with psychotic or melancholic features, bipolar disorder, schizophrenia, delusional disorders, dementias, anorexia nervosa, bulimia nervosa
• Alcohol or substance abuse within 2 years of illness onset or any time aer
• Severe obesity (body mass index (BMI) > 45).
Accepted comorbidities:
• Fibromyalgia, anxiety disorders, somatoform disorders, non- psychotic or melancholic depression, neurasthenia, multiple chemical sensitivity disorder, treated Lyme disease or syphilis before
chronic sequelae, isolated unexplained lab or physical abnormality insucient to suggest exclusionary diagnosis.
5. German Ministry diagnostic procedure (Fock & Krueger, 1994)
Initial diagnostics:
• One standardized medical history
• Routine initial physical examination.
Further investigations:
• Clinical chemistry: ESR, assured protein and electrophoresis, glucose, sodium, potassium, calcium, phosphorus, iron, magnesium, selenium, tin, ferritin, SGPT; γGT, CK, urea, creatinine
• Hematology: total blood count and dierential blood count
• Immunology: Multitest Merieux, immunoglobulins (IgG, IgM, IgA), CRI; autoantibodies (ANA,
ENA, anti- thyroid)
• Endocrinology: plasma 1,25 dihydroxy- vitamin D3, TSH
Infectious Disease and Neurocognition
• Serology: EBV- IgG- anti- EA, EBNA, HHV- 6- IgG, CMV- IgG, IgM, Borrelia burgdorferi
(depending on the anamnesis also HIV- 1,2)
Additional examinations as symptoms indicate.
6. Reeves et al. (2003) (modifications of Centers for Disease Control and
Prevention, 1994)
• Recommends several standardized and validated instruments be used in assessments of fatigue,
disability, and symptoms.
• Claries the permanent and temporary medical exclusions for CFS diagnosis including psychiatric diagnoses.
• Recommends approaches for standardizing the assessment of the nature and severity of fatigue.
7. Canadian consensus (Carruthers et al., 2003)
Overview of inclusions:
• Fatigue, post- exertional malaise
• Sleep dysfunction
• Pain
• Two or more neurological/ cognitive manifestations:
• One or more from two categories of autonomic, neuroendocrine, and immune manifestations.
Duration:
• At least 6 months (preliminary diagnosis can be earlier)
• Fatigue
• Signicant new- onset persistent or recurrent physical or mental fatigue
• Unexplained aer clinical evaluation
• Substantially reduces level of activity.
Post- exertional malaise— required.
Minimum number of symptoms is eight.
Exclusions:
• Active disease processes that explain symptoms, species:
• Addison’s disease, Cushing syndrome, hypo- or hyperthyroidism, iron deciency, anemia,
iron overload, diabetes mellitus, cancer, sleep apnea, rheumatoid arthritis, lupus, polymyositis,
polymyalgia rheumatic, AIDS, multiple sclerosis, tuberculosis, chronic hepatitis, Lyme disease,
primary psychiatric disorders, substance abuse.
Accepted comorbidities:
• Fibromyalgia, myofascial pain, temporomandibular joint syndrome, irritable bowel syndrome,
interstitial cystitis, irritable bladder syndrome, Raynaud’s phenomenon, mitral valve prolapse,
migraines, allergies, multiple chemical sensitivities, Hashimoto’s thyroiditis, sicca syndrome,
depression.
8. Afari and Buchwald (2003)
• Debilitating fatigue
• Cognitive symptoms
• Musculoskeletal symptoms
• Sleep symptoms
• No specic diagnostic tests or biological markers
• Rule out other causes of fatigue.
Fibromyalgia and Chronic Fatigue 401
9. Jason et al. (2006)
Clinically evaluated, unexplained, persistent or relapsing chronic fatigue over the past 3 months that:
• Is not the result of ongoing exertion
• Is not substantially alleviated by rest
• Results in substantial reduction in previous levels of educational, social and personal activities.
e concurrent occurrence of ME/ CFS symptoms, which must have persisted or recurred during the
past 3 months:
• Post- exertional malaise and/ or post- exertional fatigue with a loss of physical or mental stamina,
rapid/ sudden muscle or cognitive fatigability, with a tendency for other associated symptoms to
worsen. e recovery is slow, oen taking 24 hours or longer.
• Unrefreshing sleep or disturbance of sleep quantity or rhythm disturbance.
• Pain (or discomfort) that is oen widespread and migratory in nature. At least one of the following symptoms:
• Myofascial and/ or joint pain
• Pain, stiness, or tenderness. Must be present in more than one joint and lacking edema or other
signs of inammation
• Abdominal and/ or head pain (eye pain/ sensitivity to bright light, stomach pain, nausea, vomiting,
or chest pain).
• Two or more neurocognitive manifestations:
• Impaired memory (self- reported or observable decrease in ability to recall information or events
on a short- term basis)
• Diculty focusing (disturbed concentration)
• Diculty nding the right word
• Frequently forgetting what wanted to say
• Absent mindedness
• Slowness of thought
• Diculty recalling information
• Need to focus on one thing at a time
• Trouble expressing thought
• Diculty comprehending information
• Frequently lose train of thought
• New trouble with math or other educational subjects.
• At least one symptom from two of the following three categories:
• Autonomic manifestations:
• Neurally mediated hypotension
• Postural orthostatic tachycardia
• Delayed postural hypotension
• Palpitations with or without cardiac arrhythmias
• Dizziness, feeling unsteady on the feet– disturbed balance
• Shortness of breath.
• Neuroendocrine manifestations:
• Recurrent feelings of feverishness and cold extremities
• Subnormal body temperature and marked diurnal uctuations
• Sweating episodes
• Intolerance of extremes of heat and cold
• Marked weight change— loss of appetite or abnormal appetite
• Worsening of symptoms with stress.
• Immune manifestations:
Infectious Disease and Neurocognition
• Recurrent u- like symptoms
• Non- exudative sore or scratchy throat
• Repeated fevers and sweats
• Lymph nodes tender to palpitation— generally minimal swelling noted
• New sensitivities to food, odors, or chemicals.
Exclusionary conditions:
• Any active medical condition that may explain the presence of chronic fatigue, such as:
• Untreated hypothyroidism
• Sleep apnea
• Narcolepsy
• Malignancies
• Leukemia
• Unresolved hepatitis
• Multiple sclerosis
• Juvenile rheumatoid arthritis
• Lupus erythematosus
• HIV/ AIDS
• Severe obesity (BMI > 40)
• Celiac disease
• Lyme disease.
• Some active psychiatric conditions that may explain the presence of chronic fatigue, such as:
• Childhood schizophrenia or psychotic disorders
• Bipolar disorder
• Active alcohol or substance abuse— except as below:
• Alcohol or substance abuse that has been successfully treated and resolved should not be considered exclusionary
• Active anorexia nervosa or bulimia nervosa– except as below:
• Eating disorders that have been treated and resolved
• Depressive disorders.
May have presence of concomitant disorders that do not adequately explain fatigue, and are, therefore,
not necessarily exclusionary.
• Psychiatric diagnoses such as:
• School phobia
• Separation anxiety
• Anxiety disorders
• Somatoform disorders
• Depressive disorders.
• Other conditions dened primarily by symptoms that cannot be conrmed by diagnostic laboratory tests, such as:
• Multiple food and/ or chemical sensitivity
• Fibromyalgia.
• Any condition under specic treatment sucient to alleviate all symptoms related to that condition and for which the adequacy of treatment has been documented.
• Any condition that was treated with denitive therapy before development of chronic symptomatic sequelae.
• Any isolated and unexplained physical examination, laboratory, or imaging test abnormality that
is insucient to strongly suggest the existence of an exclusionary condition.
10. International Consensus Criteria (Carruthers et al., 2011)
Overview of inclusions:
• Post- exertional neuroimmune exhaustion
• One or more symptoms from three neurological impairment categories
Fibromyalgia and Chronic Fatigue 403
• One or more symptoms from the immune/ gastrointestinal/ genitourinary impairment categories
• One or more symptoms from energy metabolism/ transport impairments.
Duration (not specied).
Fatigue (not specied).
Post- exertional malaise:
• Required
• Renamed post- exertional neuroimmune exhaustion (PENE).
Minimum number of symptoms is eight.
Exclusions:
• Alternative explanatory diagnoses (untreated), primary psychiatric disorders, somatoform disorder, substance abuse.
Accepted comorbidities:
• Fibromyalgia, myofascial pain, temporomandibular joint syndrome, irritable bowel syndrome,
interstitial cystitis, Raynaud’s phenomenon, mitral valve prolapse, migraines, allergies, multiple
chemical sensitivities, Hashimoto’s thyroiditis, sicca syndrome, reactive depression.
11. Institute of Medicine criteria (Committee on the Diagnostic Criteria
for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome et al., 2015)
e 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. For both adults and children three symptoms
and at least one of two additional manifestations are required.
e three required symptoms are:
• A substantial reduction or impairment in the ability to engage in pre- illness levels of activity (occupational, educational, social, or personal life) which:
• Lasts for more than 6 months
• Is accompanied by fatigue that is:
• Oen profound
• Of new onset (not lifelong)
• Not the result of ongoing or unusual excessive exertion
• Not substantially alleviated by rest
• Post- exertional malaise (PEM):
• Dened as a worsening of symptoms aer physical, mental, or emotional exertion that would not
have caused a problem before the illness.
• PEM oen puts the patient in relapse that may last days, weeks, or even longer. For some patients,
sensory overload (light and sound) can induce PEM.
• e symptoms typically get worse 12– 48 hours aer the activity or exposure and can last for days
or even weeks.
• Unrefreshing sleep:
• e patient may not feel better or less tired even aer a full night of sleep despite the absence of
specic objective sleep alterations.
At least one of the following two additional manifestations must be present:
• Cognitive impairment:
• e patient has problems with thinking, memory, executive function, and information processing, as well as attention decit and impaired psychomotor functions.
• Cognitive symptoms can be exacerbated by exertion, eort, prolonged upright posture, stress, or
time pressure.
• Cognitive symptoms may have serious consequences on a patient’s ability to maintain a job or attend school full time.
• Orthostatic intolerance:
Infectious Disease and Neurocognition
• e patient develops a worsening of symptoms upon assuming and maintaining upright posture
as measured by objective heart rate and blood pressure abnormalities during standing, bedside
orthostatic vital signs, or head- up tilt testing.
• Orthostatic symptoms may include lightheadedness, fainting, increased fatigue, cognitive
worsening, headaches, or nausea.
• Orthostatic symptoms are worsened with quiet, upright posture (either standing or sitting)
during day- to- day life and are improved (though not necessarily fully resolved) with lying down.
• Orthostatic intolerance is oen the most bothersome manifestation of ME/ CFS among adolescents.
APPENDIX 2
The Evolution of Fibromyalgia
Diagnostic Criteria
1976
e term bromyalgia is created:
• “Fibro”, meaning brous tissue in Latin
• “Mio” from the Greek word for muscle
• “Algia” meaning pain.
1977
Diagnostic criteria should be based on two key features:
• Non- refreshing sleep
• Tender points to pain.
A limitation of the criteria is that no denition or assessment methods were recommended for these
conditions.
1981
Yunus et al. (1981): primary fibromyalgia (fibrositis) diagnosis criteria
• FMS patients must satisfy the two obligatory criteria, and at least three minor criteria.
• If the patient has only three or four tender points, then ve minor criteria must be met.
• Obligatory criteria:
• Presence of aching, pain, or stiness in three anatomical areas for at least 3 months.
• Absence of causes to explain the condition with normal laboratory tests.
• Major criteria: presence of at least ve typical and consistent tender points.
• Minor criteria:
• Modulation of symptoms by physical activity (aggravated due to physical inactivity and relieved
with moderate physical activity)
• Modulation of symptoms by weather (i.e., worsening of symptoms due to cold, humid weather, and
relief of them by heat) or time factors (i.e., worsening of symptoms in the morning and the evening)
• Aggravation of symptoms by anxiety or stress
• Poor sleep
• General fatigue or tiredness
• Anxiety
• Chronic headache
• Irritable bowel syndrome
• Subjective swelling
• Numbness.
Fibromyalgia and Chronic Fatigue 405
1990
American College of Rheumatology (ACR) diagnostic criteria
• e rst ocial diagnostic criteria. e patient is evaluated for a painful response to a pressure up to
4 kg/ cm2 (exerted with an algometer) on 18 body bilateral points.
• e patient has FM if:
• A painful response is elicited in 11 of 18 points
• ere is a history of generalized pain for at least 3 months in at least three of the four body quad-
rants (or, exceptionally, in two opposing quadrants with respect to the two axes of body division).
2010
ACR diagnostic criteria
• ree conditions need to be met:
• Widespread Pain Index (WPI) ≥ 7 and a Symptom Severity Scale (SSS) score ≥ 5; or WPI between
3 and 6 and SSS score ≥ 9.
• Symptoms have been present at a similar level for at least 3 months.
• e patient does not have a disorder that would otherwise explain the pain.
• For the each of the three symptoms above, indicate the level of severity over the past week using the
following scale:
• 0: no problem
• 1: slight or mild problems: generally mild or intermittent
• 2: moderate: considerable problems, oen present and/ or at a moderate level
• 3: severe: pervasive, continuous, life- disturbing problems.
• Considering somatic symptoms, in general, indicate whether the patient has:
• 0: no symptoms
• 1: few symptoms
• 2: a moderate number
• 3: a great deal of symptoms.
• e SSS score is the sum of the severity of the three symptoms (fatigue, waking unrefreshed, cognitive
symptoms) plus the extent (severity) of somatic symptoms in general. e nal score is between 0 and 12.
2016
ACR revised diagnostic criteria
FM may be diagnosed in adults when all of the following criteria are met:
• Generalized pain, dened as pain in at least four of ve regions, is present.
• Symptoms need to be present at a similar level for at least 3 months.
• A WPI ≥ 7 and a SSS score ≥ 5 or a WPI of 4– 6 and a SSS score ≥ 9.
• A diagnosis of FM is valid irrespective of other diagnoses. A diagnosis of FM does not exclude the
presence of other clinically important illnesses.
Infectious Disease and Neurocognition
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