Undifferentiated Fatigue — Written Clinical Reasoning

Part A — Chronic fatigue with post-exertional malaise

The diagnosis

This woman meets the diagnostic criteria for myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) following a post-viral (post-COVID) trigger. The 2015 IOM report and the 2021 NICE NG206 guideline define the condition by the four core criteria [3]:

1. The severe, disabling fatigue of more than 6 months that is not alleviated by rest and that substantially impairs the occupational or the personal activity.
2. The post-exertional malaise (PEM) — the delayed worsening (12 to 72 hours) after the exertion, with the slow recovery over days. The cardinal feature, present here in the four-day recovery after the exercise.
3. The unrefreshing sleep.
4. Either the cognitive impairment (the brain fog here) or the orthostatic intolerance. [1]

The diagnosis is a positive clinical diagnosis based on the specific criteria, not a diagnosis of exclusion after years of negative investigations. The 2021 NICE NG206 guideline is explicit that the diagnosis should be made and the management begun as soon as the criteria are met. The post-COVID trigger is consistent with the substantial overlap between the post-COVID condition and the ME/CFS — a significant proportion of the post-COVID patients meet the ME/CFS criteria [5].

The further investigation — targeted, not blanket

The Tier 1 screen is normal, which is reassuring. The further investigation is the targeted Tier 2 only when the clinical suspicion is high. In this patient, with no weight loss, no fever, no night sweats, no organ-specific symptoms, and a normal Tier 1, the blanket Tier 2 panel (the ANA, the tumour markers, the viral panels, the cortisol, the sex hormones) is not indicated — the yield is low, the false positives drive the harm, and the diagnosis of ME/CFS is established clinically by the positive criteria. [1]

The one consideration is the sleep study. Her STOP-Bang of 2 is below the threshold for the polysomnogram, but her unrefreshing sleep is a core criterion of the ME/CFS and the investigation of the sleep disorder may be warranted if the clinical picture suggests the comorbid sleep apnoea (the snoring, the witnessed apnoea, the obesity). In this slim woman with no snoring, the polysomnogram is not the first step. [1]

The management — the 2021 NICE NG206 framework

The management of the ME/CFS is the: [1]

1. The energy management and the pacing. The patient stays within her current energy envelope (the level of the activity she can sustain without triggering the PEM). The pacing is the opposite of the graded exercise — it is the maintenance, not the incremental increase. The registrar explains the energy envelope as a daily budget that cannot be exceeded without triggering the crash.
2. The activity management. The practical strategies to prioritise, plan and pace the daily activities, with the occupational therapy and the energy conservation techniques.
3. The symptom control. The pain (the simple analgesia, the neuropathic agents for the nerve pain, the physiotherapy), the orthostatic intolerance (the compression garments, the adequate hydration and the salt, the fludrocortisone or the midodrine in selected patients), the sleep (the sleep hygiene, the avoidance of the forced sleep restriction).
4. The cognitive behavioural therapy as a supportive treatment, NOT a curative treatment. The CBT helps the patient cope with the chronic illness, the pacing, the symptom management and the psychological adjustment. The registrar who offers the CBT as a cure has misread the guideline.
5. The sleep management. The sleep hygiene without the forced restriction or the extension.
6. The coordinated multidisciplinary approach. The GP, the specialist ME/CFS service, the physiotherapy, the occupational therapy, the psychology, the dietetics. [1]

The key counselling point: The 2021 NICE NG206 guideline withdrew the graded exercise therapy (GET) for the ME/CFS because of the risk of the harm from the post-exertional malaise. The patient must NOT be prescribed the fixed-incremental-increase exercise programme. The registrar who applies the pre-2021 paradigm (the PACE trial and the 2007 NICE CG53) will worsen the patient. This is the single most testable fact and the single most important safety point. [1]

The shared decision-making and the safety-netting

The patient is distressed by the chronicity and the disability, and by the frequent dismissive encounters with the clinicians. The shared decision-making is the: [1]

• The validation of the symptom and the diagnosis — the ME/CFS is a real, recognised multisystem disease, not a psychological failure.
• The explanation of the mechanism (the PEM, the energy envelope, the multisystem involvement).
• The realistic expectation — the ME/CFS is chronic, the recovery is variable and the improvement over months to years is the common trajectory, but the cure is not available.
• The safety-netting — the planned review (every 3 to 6 months in the stable patient, sooner if the symptoms worsen), the red flags to report (the new weight loss, the fever, the night sweats — which would prompt the Tier 2 work-up for the comorbid organic disease), and the support services. [1]

Part B — The Addison disease discriminator

The pivotal clinical question

When the fatigued patient has the weight loss, the postural drop and the pigmentation, the diagnosis is the primary adrenal insufficiency (Addison disease) until proven otherwise. The 2016 Endocrine Society guideline (Bornstein et al.) is the reference [4].

The discriminators: [1]

• The fatigue and the weight loss — the insidious onset.
• The hyperpigmentation — the palmar creases, the buccal mucosa, the gingiva, the recent scars, the areolae. From the elevated pro-opiomelanocortin.
• The postural hypotension — from the mineralocorticoid deficiency.
• The salt craving — a characteristic and often-missed symptom.
• The hyponatraemia with the hyperkalaemia — from the mineralocorticoid deficiency.
• The hypoglycaemia. [1]

The diagnostic test

The 250 microgram short Synacthen (tetracosactide) test: the cortisol at 0, 30 and 60 minutes after the intravenous or the intramuscular tetracosactide. The peak cortisol below 500 nmol per litre confirms the adrenal insufficiency. The morning cortisol above 500 nmol per litre effectively excludes; below 100 nmol per litre is highly suggestive. The ACTH (elevated in the primary disease) and the 21-hydroxylase antibodies (for the autoimmune aetiology) are the adjuncts. [1]

The management and the crisis prevention

The hydrocortisone (15 to 25 mg daily in two or three divided doses) and the fludrocortisone (50 to 200 micrograms daily). The patient education on the sick-day rules (the doubling of the hydrocortisone during the illness, the emergency intramuscular hydrocortisone, the medical alert) and the adrenal crisis prevention is the life-saving component. The registrar who treats the fatigue and the weight loss of the Addison disease as the depression — and prescribes the antidepressant without the cortisol check — has missed a fatal diagnosis. [1]