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Table 5 Differential diagnosis in patients with prolonged fatigue of unknown cause

From: Investigating unexplained fatigue in general practice with a particular focus on CFS/ME

Easily missed conditions that may cause unexplained fatigue Comments
Ehlers Danlos Syndrome type 3 - Joint hypermobility type Unclear how this predisposes to chronic fatigue and CFS/ME but muscle strengthening around joints and the back can be helpful but not curative.
Hypothyroidism, Addison’s disease and Pituitary dysfunction Care with post traumatic head injury leading to pituitary dysfunction – check for significant head injury even years beforehand. Consider synacthen and glucagon stimulation tests.
Sjogren’s syndrome, early PBC, other CTD Note that dry eyes and mouth without overt Sjogren’s syndrome can be seen in CFS/ME. The autoimmune profile, serum immunoglobulin assessment and ESR should help check for these possibilities.
Coeliac disease People with anti-TTg antibodies but without overt celiac disease evident on duodenal biopsy can sometimes see an improvement in their fatigue on gluten avoidance
Generalised anxiety disorder (GAD) and depression Important to note that anxiety and depression can complicate CFS/ME and treatment for these can help fatigue overall.
Primary disorders of sleep While obstructive sleep apnea can be associated with fatigue and day time sleeping, frequent sleep arousals without significant episodes of apnea can also lead to persistent daytime fatigue.
Early dementia, multiple sclerosis and Parkinson’s disease MS can be associated with marked fatigue, however, the twitching, sensory symptoms and blurring in CFS/ME are brief lasting less than a couple of hours while those in MS last days and weeks. Diagnosing CFS/ME in the elderly is more difficult and several neurological conditions can cause marked fatigue. Fatigue is frequent in early Parkinson’s disease.
Postural orthostatic tachycardia (POTS) This may be a primary condition with associated fatigue but without the other symptoms of CFS/ME. However POTS is also not uncommon in those with moderate and severe CFS/ME as is vaso-vagal syncope.
Other conditions There are several conditions in this category that include cardiac dysfunction, temporomandibular disorder but which are very rare.