Neuromuscular junctional disorders are characterized by the failure of transmission across the neuromuscular junction and may be presynaptic (e.g., Lambert-Eaton myasthenic syndrome) or postsynaptic (e.g., myasthenia gravis). This results in muscle fatigue of peripheral origin. However, patients with myasthenia gravis experience additional cognitive fatigue following completion of demanding cognitive work, suggesting a component of central fatigue [59]. Supplementation of Vitamin D may benefit fatigue in patients with myasthenia gravis showing Vitamin D deficiency [60].

Chronic, persistent fatigue occurs in many patients with acquired immune-mediated neuropathies (e.g., Guillain–Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and monoclonal gammopathies). Some authors have suggested that fatigue in these patients is related to axonal loss [61], but neurophysiological studies of the peripheral nerves are often normal, suggesting that central mechanisms are at play [62]. Medically supervised home exercise programs may be beneficial in these patients [63]. Modafinil has shown some benefit in alleviating fatigue in patients with hereditary motor sensory neuropathy type 1 (also known as Charcot–Marie–Tooth Disease-1), the most common inherited neuropathy [64]. Metabolic myopathies are characterized by the occurrence of “exercise intolerance,” cramping, painful contractions, and myalgias after exercise, while being asymptomatic at rest. This exercise intolerance may occur in the absence of motor weakness or abnormal physical findings, and may be perceived as fatigue by patients. Genetic testing is often required for diagnosis. Similarly, patients with inherited channelopathies (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia congenita, and Andersen–Tawil syndrome) present with paroxysmal attacks of periodic generalized weakness as well as muscle fatigability brought on by exposure to cold, carbohydrate-rich meals, exercise or rest, depending on the exact disorder. Except for the hypokalemic periodic paralysis, these patients also have myotonia on EMG and can be diagnosed by genetic testing. Muscle weakness in these disorders may last from a few minutes to a few hours during each attack, with a normal neurological examination finding including normal strength testing in between the attacks. The symptoms are often treated with acetazolamide, although the exact mechanism of action of this agent in these conditions is unknown [44]. Fatigue has also been described in a large number of patients with a variety of inherited myopathies such as facioscapulohumeral dystrophy and myotonic dystrophy [65]. Both fatigue and excessive daytime sleepiness are common with myotonic dystrophy type 1 (DM1), most likely due to prominent sleep dysfunction that accompanies sleep-disordered breathing, numerous microarousals, and PLMS. DM1 patients have short sleep latencies on MSLT as well as sleep onset REM periods (SOREMPs), suggesting a narcoleptic phenotype [66].

The prevalence of daily fatigue in COPD has been reported as high as 80 %, and nearly half of COPD patients describe it as their most disabling symptom, affecting cognitive, physical, and psychosocial well-being and quality of life. It worsens with underlying disease severity and predicts higher hospitalization rates [101, 102]. The etiology of fatigue in COPD is incompletely understood, but is most likely multifactorial. Exercise intolerance in patients with COPD has been shown to be predictive of fatigue [103]. In addition, coexistent mood disorders and sleep disorders such as RLS [104] and sleep-disordered breathing (in particular the combination of COPD and OSA, known as the “overlap syndrome,” a common cause of severe nocturnal hypoxemia, sleep disruption, and subsequent EDS) increase the likelihood of fatigue. Severe COPD is also associated with complaints of insomnia and nonrestorative sleep [105]. Treatment of fatigue in COPD is closely linked to the improvement of pulmonary status and comorbid sleep and mood dysfunction. Multidimensional programs that include pharmacotherapy to improve lung function, pulmonary rehabilitation, and CBT for insomnia have shown promising results [106].

Fatigue is an important symptom in patients with heart failure (HF) including approximating 70–90 % of all patients which adds to the overall debilitation caused by orthopnea, peripheral edema, nocturnal cough, and exertional dyspnea. Fatigue is indicative of a poor prognosis in HF, but a consistent relationship between fatigue and degree of cardiac dysfunction has not been demonstrated [107, 108]. The proposed causes of fatigue in HF include impaired peripheral perfusion during exercise, reduced oxidative capacity of skeletal muscle, impaired muscle strength, and possibly reflex mechanisms associated with alterations in the metabolism of skeletal muscle. However, fatigue may persist despite optimization of cardiac output [109]. Comorbid sleep disorders contribute to fatigue in HF, with sleep-disordered breathing (including primary central apneas and Cheyne–Stokes respirations), nocturia, and insomnia being the most common. In addition, pharmacotherapy of HF, especially with beta-blockers, has been linked to fatigue. Fatigue and depression occur independently in HF [110]. Nonpharmacological interventions such as individualized exercise training programs for all patients with stable CHF may combat fatigue [111].

The debilitating fatigue experienced by patients with chronic renal failure and end-stage renal disease (ESRD) is likely due to multiple chronic metabolic and physical derangements, such as anemia, cachexia, and abnormal calcium and phosphate metabolism. Nearly half of the patients on hemodialysis complain of major fatigue, often associated with depression and poor sleep quality [112]. Primary sleep disorders such as OSA and RLS/PLMS may lead to both insomnia and EDS, worsening fatigue [113]. Optimal treatment of fatigue in ESRD patients on hemodialysis is unclear, but may include strengthening of social support, exercise programs, erythropoietin, and l-carnitine supplementation [114].