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  1. 1. REVIEW Review Fatigue in neurological disorders Abhijit Chaudhuri, Peter O Behan Chronic fatigue is a typical symptom of neurological diseases, and is most disabling in multiple sclerosis, postpoliomyelitis, poststroke, and in chronic fatigue syndrome. Disorders of neuromuscular junction transmission and metabolic diseases cause muscle fatigability, which is characterised by failure to sustain the force of muscle contraction (peripheral fatigue). Fatigue is also seen in diseases that affect the central, peripheral, and autonomic nervous systems (central fatigue). Enhanced perception of effort and limited endurance of sustained physical and mental activities are the main characteristics of central fatigue. Metabolic and structural lesions that disrupt the usual process of activation in pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centre are implicated in the pathophysiological process of central fatigue. A state of pre-existing relative hypocortisolaemia might sensitise the hypothalamic-pituitary-adrenal axis to development of persistent central fatigue after stress. The contributions of physiological, cognitive, and affective changes underlying fatigue are variable, and treatment is largely symptomatic and rehabilitative. “It ought to be generally known that the source of our However, progress in understanding of fatigue in pleasure, merriment, laughter, amusement, as of our neurological disorders offers the prospect of developing grief, pain, anxiety and tears, is none other than the appropriate investigational methodology and treatment brain” strategies. Here, we review the neurology of fatigue and its Hippocrates present management. Chronic fatigue is reported in more than 20% of people Definition of fatigue seen in primary care,1 and in the USA accounts for The perception of fatigue is subjective: no exact 10–15 million visits to family doctors every year.2 The definition exists because of overlap between the lay disorder can be part of medical and neurological disease notion of tiredness and the clinically relevant symptom (eg, anaemia, multiple sclerosis), an integral feature of the of fatigue. It is not the same as muscle weakness,1 disease itself (eg, poststroke, chronic fatigue syndrome), depression, or muscle fatigability, and it is not a non- mainly the result of a psychiatric disturbance in function specific outcome of chronic illness.7 For clinical use, (eg, somatoform disorder), or a side-effect of drugs fatigue is best defined as difficulty in initiation of or prescribed for previous disorders—eg, antihypertensives, sustaining voluntary activities. If the activity is linked to -adrenergic blockers, lipid-lowering agents, proton- a reward—eg, winning a race—then fatigue could be pump inhibitors, beta interferon, anxiolytics, pleasurable. antipsychotics, and surprisingly, antidepressants.1 To understand fatigue, we might regard voluntary The prevalence of fatiguing neurological disorders is effort as a controlled variable that is affected by many not known, but probably represents a substantial control systems. Figure 1 shows interplay between proportion of all patients who present with chronic fatigue various physiological control systems that regulate work in whom other systemic diseases and psychiatric and output. Work output is a dependent variable of applied drug-related causes have been excluded. In the UK, at effort that is controlled by motivational input (internal least 40 000 patients with multiple sclerosis have excessive and external) and feedback from motor, sensory, and fatigue that severely limits activity.3 More than 90% of cognitive systems that establishes the level of perceived patients with paralytic and non-paralytic poliomyelitis exertion. Typical physical activity depends on structural develop a delayed syndrome characterised by excessive and functional integrity of sensory and motor systems.8 fatigue (postpoliomyelitis fatigue).4 Worldwide, several Perceived exertion is an important feedback control for million patients are presently afflicted with this disorder, the level of applied effort. Additional control systems with an estimated 350 000 in the USA alone.5 Fatigue after stroke (poststroke fatigue) is an important cause of Search strategy and selection criteria long-term morbidity in cerebrovascular diseases.6 Our understanding of the neurobiological basis of This review is based on our reading of existing medical texts fatigue is imperfect, and treatments are limited. As a and a search of PubMed and MEDLINE for articles with the result, the disorder has been regarded by some as a keywords “fatigue”, “chronic fatigue”, and “neurology” medically unexplained symptom due to somatisation. between October, 1997, and March, 2003. More than 4000 articles were originally identified, and a shortlist of Lancet 2004; 363: 978–88 core published work of possible relevance to this review was prepared after discussion with several colleagues with Division of Clinical Neurosciences, University of Glasgow, Glasgow international expertise in this area. Only articles published G51 4TF, UK (A Chaudhuri DM, P O Behan DSc) in English were considered, and where appropriate, Correspondence to: Dr A Chaudhuri publications before October, 1997, were traced. (e-mail: 978 THE LANCET • Vol 363 • March 20, 2004 • For personal use. Only reproduce with permission from The Lancet.
  2. 2. REVIEW Internal environment Internal input External input (homoeostatic) control (motivational and limbic) (incentive) (eg, endocrine and autonomic) + – initiation of withdrawal of + – voluntary effort voluntary effort facilitator suppressor Work output Physiological set point for applied effort + – + – facilitator suppressor facilitator suppressor External environment Feedback of perceived exertion control (eg, temperature) Sensory input Cognitive processing (special sensory and Motor output somatosensory) Figure 1: Interplay of physiological variables that control work output that regulate work output are environmental factors such muscle, a series of metabolic events then provides as temperature and internal mileu (homoeostasis and chemical energy for contraction. Any interruption to this autonomic function). complex chain of events could affect the level of applied Voluntary activity is dependent on smooth flow of effort and perceived exertion (figure 1). nerve impulses in the major sensory and motor systems. Pathological fatigue is, thus, best understood as an Sensory signals from skin, cardiorespiratory systems, amplified sense of normal (physiological) fatigue that muscles, and joints, and special senses (skin, eyes, and can be induced by changes in one or more variables ears), provide afferent input. After cognitive processing of regulating work output. Fatigue could develop during this information, the primary motor cortex activates a disease because of dissociation between the level brainstem motor nuclei and anterior horn cells in the of internal input (motivational and limbic) and that of spinal cord (efferent pathway). Signal from lower motor perceived exertion from applied effort (figure 1). When neurons reaches muscle through peripheral nerves and there is loss of interest and motivation, as in depression, the neuromuscular junction (figure 2). Within the the subjective sense of fatigue is generated mainly as a result of reduced internal input. Even with usual levels of motivation, motor control, and sensory input, premature fatigue might arise because of unpleasant ambient temperature, dysautonomia, and underlying endocrine disturbances (figure 1). Clinical approach to fatigue Fatigue is not specific to the underlying clinical disorder: thus, a structured approach is essential for appropriate assessment of a patient who presents with chronic fatigue (figure 3). With few exceptions, initial review of these patients will take place in primary care. Early muscle fatigability is typical in myopathic disorders, defects in neuromuscular junction transmission (myasthenic syndromes), diseases of peripheral nerves, and lower motor neurons (figure 4). In such cases, reduction of muscle force output is usually associated with muscle weakness, which has been called muscle fatigue or myopathic fatigue.1 Peripheral fatigue could be an appropriate term for muscle fatigability due to disorders of muscle and neuromuscular junction. Objective reduction in motor power in muscle fatigability can be measured as the rate of decline in peak force generated during maximum voluntary muscle contraction. By contrast, the subjective sense of fatigue is essentially perceived at the level of the CNS—ie, it is a central fatigue. This fatigue can be present in disorders of the Figure 2: Integration of sensory and motor pathways for peripheral, autonomic, and central nervous system. It is physical activities consistently seen with lesions in pathways associated with THE LANCET • Vol 363 • March 20, 2004 • 979 For personal use. Only reproduce with permission from The Lancet.
  3. 3. REVIEW History and examination Objective motor weakness, abnormal neurological signs, or both? Yes No Weakness +/– fatigability muscle Increased muscle tone Does the history suggest episodes of tone not increased Exaggerated reflexes/reflex weakness or episodes of fatigue? Normal or poor reflexes asymmetry movement disorder No abnormal movements Possible cognitive impairment Weakness Fatigue No obvious cognitive impairment Consider Consider Blood studies Early neurological evaluation Electrolyte disorders Orthostatic intolerance G FBC, ESR, creatine kinase, electrolytes indicated (multiple sclerosis, Hypoglycaemia Hyperventilation (Na+ and K+), Ca2+, phosphate, cerebrovascular disease, Neuromuscular Anxiety, depression thyrotropin, thyroxine, glucose; LFT Parkinson’s disease, junction and Heart disease G Additional samples for acetylcholine motor neuron disease) muscle disorders Sleep disorder receptor antibody (if fatigable ptosis, Cataplexy and related Endocrine disease ophthalmoplegia, or both are present) sleep disorders Liver disease Transient ischaemic Pre-syncope Abnormal results attack Dysautonomia G Take appropriate action Multiple sclerosis Multiple sclerosis Normal results Partial seizures Chronic fatigue G Consider assessment with Periodic paralysis syndrome peripheral electrophysiology (EMG/NCS) Migraine Myopathic EMG with or without high creatine kinase Screening assessment G Consider muscle biopsy G Blood tests; electrocardiogram; blood pressure G Forearm ischaemic exercise test (supine and standing); in children, chart height and neurology referral and weight G Review results, take eyewitness accounts and check drug history; monitor progress G Consider specialist referral if symptoms persist Figure 3: Assessment of muscle fatigability and fatigue FBC=full blood count. ESR=erythrocyte sedimentation rate. LFT=liver function tests. EMG=electromyography. NCS=nerve conduction study. arousal and attention, reticular and limbic systems, and Dorsal root ganglion, the basal ganglia (figure 5). Central fatigue, however, is sensory neuropathy not simply a sense of physical exhaustion: it also has an important cognitive component (mental fatigue). In some patients, this component is generally the most distressing aspect of their symptom because they find themselves limited in their ability to sustain concentration and endure mental tasks. Although it is a subjective perception, effects of central fatigue can be measured by assessment of cognitive and motor-task processing over a given period. Peripheral fatigue Assessment In clinical assessment, a distinctive topographic pattern of Anterior horn cell myopathic weakness is a strong clue for the peripheral (motor neuron disease) origin of fatigue. Disorders of the neuromuscular junction are typical examples of muscle fatigability, and in myasthenia gravis, repeated or persistent activity of a muscle group leads to progressive weakness, but Peripheral strength is partly restored after rest (pseudoparalysis). nerve Contractures on muscle activity are suggestive of (neuropathy) metabolic muscle diseases. Typically, the affected muscle group remains shortened for several minutes after a series of strong contractions. Presence of muscle fatigability, Neuromuscular junction muscle cramps, and contractures are characteristic of (myasthenic syndromes) muscle phosphorylase deficiency (McArdle’s disease). Muscle Visible stiffness and slowness of muscle contraction (metabolic during changes in posture can be present in myopathy) hypothyroidism (contraction myoedema), usually with Figure 4: General sites of pathology in muscle fatigability and percussion myoedema and delayed relaxation of the neuromuscular fatigue (peripheral fatigue) 980 THE LANCET • Vol 363 • March 20, 2004 • For personal use. Only reproduce with permission from The Lancet.
  4. 4. REVIEW Basal ganglia Subcortical grey Ammonia concentration in venous blood also rises after (Parkinson’s and white matter ischaemic forearm exercise. Failure of amounts of both disease) disease (stroke, ammonia and lactate to increase suggests an inadequate demyelination) test attributable to suboptimum hand-grip exercise. A typical lactate response without a postexercise rise in Limbic system venous ammonia concentration indicates myoadenylate (limbic deaminase deficiency. In aerobic (non-ischaemic) encephalitis) maximum forearm exercises, measurement of pre- exercise and postexercise oxygen saturation of venous blood is helpful as a screening test for mitochondrial myopathy in which venous oxygen saturation shows little change from baseline after exercise because of failure to Thalamus and enhance oxygen extraction at the level of the respiratory Hypothalamus RAS (stroke, chain.9 During exercise, cerebral metabolism is affected (narcolepsy) tumours) by both mental effort to exercise and sensory input from Brainstem nuclei skeletal muscles.10 (myotonic dystrophy) Posterior fossa Pathophysiology of muscle fatigability (Chiari malformation, Myasthenic disorders and primary muscle diseases posterior head injury) are typical examples of peripheral neuromuscular fatigue. In addition to fatigable muscle weakness, Figure 5: General sites of pathology in central fatigue patients with Lambert-Eaton myasthenic syndrome have RAS=reticular activating system. generalised fatigue that could be related to an underlying dysautonomia. Electrophysiological studies are usually tendon reflexes. An increment of power with repeated diagnostic of myasthenia gravis and Lambert-Eaton voluntary muscle contraction is characteristic of myotonia myasthenic syndrome. and Lambert-Eaton myasthenic syndrome. Paroxysms Premature exertional muscle fatigability, exercise- of fatigue, muscle fatigability, and limb weakness are induced cramps, and myalgia are the symptom triad of features of hypokalaemic periodic paralysis. metabolic myopathies. These symptoms are absent at rest Repetitive electrical stimulation of selected motor and are induced by exercise. Most metabolic myopathies nerves at low frequency (3 Hz)—also known as are caused by disorders of carbohydrate and lipid Jolly test—is a standard electrophysiological procedure metabolism and present with episodic muscle weakness for screening myasthenic disorders. Needle examination and fatigability. Patients can seem clinically normal of the muscle (electromyography) is useful to distinguish between attacks. Serum creatine kinase concentration and between neuropathic and myopathic causes of muscle histological findings are usually normal during the muscle weakness. In McArdle’s disease and phospho- interval between attacks in patients with deficiencies of fructokinase deficiency, electromyography is typically carnitine palmitoyltransferase II and very long chain acyl- silent during cramp-like muscle contracture. Single fibre coenzyme A dehydrogenase. electromyography is a special technique of recording Exertional fatigue, muscle fatigability, and exercise single muscle fibre action potentials and is a sensitive, intolerance, with or without muscle weakness, are but less specific, test for neuromuscular junction symptoms of neurological diseases attributable to transmission disorders. mutations in mitochondrial DNA. Muscle biopsy findings In exercise tests, patients with disorders of glycogen are diagnostic in mitochondrial myopathy and should be metabolism are seldom able to exercise beyond 1 min in considered even if muscle strength, creatine kinase, and the forearm ischaemic test. Failed lactate production electromyography are normal. However, in many patients, suggests metabolic block in the glycogenolytic or symptoms of weakness, fatigue, and exercise intolerance glycolytic pathway, as is seen in McArdle’s disease. can seem non-specific, and diagnosis is delayed until they progress and evolve into distinctive mitochondrial Disorder Treatment syndromes or muscle weakness. The topographic pattern Autoimmune myasthenia Symptomatic—anticholinesterases of muscle weakness in mitochondrial myopathy differs gravis (generalised) (pyridostigmine) from other metabolic myopathies and involves muscles Definitive—thymectomy after plasma exchange outside the pelvic and shoulder girdles—eg, muscles of the (unless surgery is contraindicated due to age eye and diaphragm. and/or other risks) Immunosuppression—corticosteroids and azathioprine initially, later maintained on Management azathioprine Diagnosis of neuromuscular fatigue is usually established Lambert-Eaton Symptomatic—aminopyridines and by a combination of clinical assessment and laboratory myasthenic syndrome cholinesterases; immunosuppression, plasma tests. In some cases, muscle biopsy will be necessary. exchange, or both for primary autoimmune Treatment of neuromuscular fatigue is usually directed Lambert-Eaton myasthenic syndrome; treatment of underlying malignant disease in to management of underlying diseases (table). Several paraneoplastic disorder drugs—eg, -adrenergic blockers, neuromuscular Polymyositis and Immunosuppression—corticosteroids and blocking agents, certain antibiotics, antipsychotics, and dermatomyositis azathioprine; intravenous human antidepressants—are known to worsen symptoms of immunoglobulins in resistant cases myasthenia gravis. Anaesthetic procedures should be Muscular dystrophies Supportive; early respiratory care and nocturnal ventilatory support carefully reviewed in people with fatigue. Failure to Metabolic myopathies Supportive; dietary manipulation in selected recover from anaesthesia is a recognised complication in cases patients with myotonic dystrophy, neuromuscular Mitochondrial disorders Supportive; coenzyme Q10 junction transmission disorders, and postpoliomyelitis Treatment of neuromuscular (peripheral) fatigue fatigue. THE LANCET • Vol 363 • March 20, 2004 • 981 For personal use. Only reproduce with permission from The Lancet.
  5. 5. REVIEW Panel 1: Neurological disorders of central fatigue Panel 2: Fatigue severity score7 G My motivation is lower when I am fatigued Symptomatic G Exercise brings on my fatigue Cerebral vasculitis and cerebrovascular diseases G I am easily fatigued Channelopathies G Fatigue interferes with my physical functioning Developmental disorders (cerebral palsy, Chiari G Fatigue causes frequent problems for me malformations) G My fatigue prevents sustained physical functioning Dysautonomic states G Fatigue interferes with carrying out certain duties and Encephalitis lethargica responsibilities Granulomatous disorders (neurosarcoid, Wegener’s G Fatigue is among my three most disabling symptoms granulomatosis) G Fatigue interferes with my work, family, or social life Hypothalamic and pituitary diseases Intracranial infections (meningitis and encephalitis) Patients choose a number from 1 to 7 that shows their degree of Metabolic encephalopathy and mitochondrial diseases agreement with every statement, where 1 indicates strongly disagree and 7 strongly agree. There is no cutoff value. Migraine Motor neuron disease Multiple sclerosis Neuropsychological assessment in central fatigue is Multiple system atrophy desirable if cognitive impairment is reported or Myotonic dystrophy suspected. This dysfunction is usual in individuals with Narcolepsy and related sleep disorders multiple sclerosis, with an estimated prevalence of Paraneoplastic (limbic encephalitis, opsoclonus-myoclonus) 65%.16 These patients frequently show mental fatigue in Parkinson’s disease and other parkinsonian disorders the cognitive domains of memory, learning, attention, Posterior head injury and information processing. In a 4-h session of cognitive Post-Guillain Barré syndrome fatigue testing, people with this disorder fared poorly on tests of Postinfective fatigue states (poliomyelitis, Lyme disease, verbal memory and conceptual planning, and their Q fever, and viral fatigue) performance declined over time during the test (mental Postoperative (posterior fossa and cardiopulmonary bypass fatigue).17 By contrast, patients with postpoliomyelitis surgery) fatigue have no impairments of verbal memory and Idiopathic enhanced cortical function but have important deficits in Chronic fatigue syndrome/myalgic encephalomyelitis attention and information processing speed.18 Cognitive impairment and mental fatigue are seen in stroke patients even with single or small infarcts, which seem to Central fatigue be independent of the anatomic location of the Assessment ischaemic lesion (supratentorial or brainstem).19,20 A feeling of constant exhaustion is a characteristic Apathy is a characteristic symptom of Parkinson’s of central fatigue. Neurological disorders associated disease, and neuropsychological profiles indicate fronto- with this feature are listed in panel 1. Severity of central subcortical dysfunction as its possible anatomic fatigue is not associated with the nature or severity correlate.21 Cognitive impairment has also been noted in of underlying disease. Occasionally, central fatigue can patients with chronic fatigue syndrome without be focal, affecting vision in one eye or motor power in psychiatric comorbidity.22,23 one limb, arising during sustained visual or motor tasks. Because fatigue is typical in dysautonomia, supine This occurrence is typically seen in patients with and standing blood pressure should be taken in these multiple sclerosis.11 After cortical stroke, patients patients. Presence of orthostatic symptoms could also with aphasia rapidly develop mental fatigue while indicate need for formal autonomic and cardiac tilt-table speaking. Word-finding difficulty and anomia are tests. Autonomic impairment can be primary (primary other examples of task-specific mental fatigue seen in autonomic failure, Parkinson’s disease, and multiple patients with postpoliomyelitis fatigue12 and chronic system atrophy) or secondary to other neurological fatigue syndrome.13 Individuals with central fatigue have diseases (hemispheric infarct, hypothalamic and posterior deterioration or periodic fluctuations in severity of fossa lesions, peripheral neuropathy) and medical fatigue under physiological and psychological stimuli.13 disorders (diabetes, renal failure, neurosyphilis, and Furthermore, patients with chronic fatigue syndrome HIV infections). Patients who do not have postural also have various combinations of pain, postexertional hypotension but still have orthostatic symptoms or simple malaise, disturbed sleep pattern, short-term cognitive faints (syncope) can be assessed by tilt-table testing for up impairment, and daily headache.14 In more than a to 30 min with monitoring by electrocardiography. third of cases, fatigue arises suddenly or subacutely, and Children and adolescents with chronic fatigue syndrome nearly 80% of patients relate their symptoms to a are sensitive to orthostatic challenge and can develop preceding infection.15 Low motivation, loss of pleasure neurally mediated hypotension.24 (anhedonia), early morning awakenings, self-imposed In some people, formal sleep studies might be needed avoidance of social contacts, inappropriate guilt, and to exclude a primary sleep disorder presenting with fatigue suicidal ideations are important clues to identify and excessive daytime sleepiness. The multiple sleep depressive fatigue. latency test is a useful diagnostic method for narcolepsy. Neuroimaging in central fatigue is mainly done to Findings of sleep studies might also indicate frequent exclude structural and demyelinating lesions, and episodes of apnoea or oxygen desaturation in patients with MRI of the brain is the procedure of choice. Present central fatigue and neuromuscular weakness (acid maltase research methods include proton magnetic resonance deficiency, motor neuron disease, postpoliomyelitis spectroscopy and functional neuroimaging (positron fatigue, and myotonic dystrophy). Nocturnal myoclonus emission tomography and single photon emission CT is a postpoliomyelitis sequelae, and nearly a third of these scans) of the brain. patients have periodic limb movements in sleep.25 982 THE LANCET • Vol 363 • March 20, 2004 • For personal use. Only reproduce with permission from The Lancet.
  6. 6. REVIEW Self-completed questionnaires are sometimes used for homoeostasis remains to be elucidated, these substances subjective assessment of fatigue; one that has been widely clearly provide an important biological link between the used in the assessment of multiple sclerosis fatigue symptoms of fatigue and poor arousal or excessive (fatigue severity score)7 is listed in panel 2. Self-reported sleepiness. methods have major limitations, especially questionnaires Fatigue is sometimes seen in people with disorders that fail to regard fatigue as a multidimensional state associated with an underactive hypothalamic-pituitary- with cognitive, physical, and psychological components. adrenal axis. In this situation, fatigue could be attributable With self-assessment questionnaires, to be sure about to the proinflammatory cytokines that become activated a true change is difficult, especially when symptom by reduced corticotropin releasing factor and low severity fluctuates greatly (regression to mean effect). cortisol concentrations. This hypothesis seems to accord Questionnaire-based surveys can also introduce bias into a with experimental evidence that in immune-mediated study population because of participants’ knowledge that disorders, acute stress can be beneficial because rises they are being studied (Hawthorne effect). in corticotropin releasing factor attenuate the T-helper-1 cell response.36 However, we do not know if Pathophysiology chronic stress (vs acute stress) eventually downregulates Poststroke fatigue is a recognised complication after the hypothalamic-pituitary-adrenal axis, leading to subcortical, brainstem, and thalamic ischaemia.6,26 In persistent fatigue.37 This axis is underactive in patients many patients with excellent neurological and psy- with chronic fatigue syndrome,38 post-traumatic stress chological recovery, poststroke fatigue could be the only disorder,39 fibromyalgia,40 and postpoliomyelitis fatigue.41 major disability. Fatigue is a symptom of diseases that Fatigue is not improved by steroid supplements except in affect the basal ganglia27 and that interrupt the connection patients with primary or secondary adrenal insufficiency, between the prefrontal cortex and thalamus. Lesions in and trials of corticosteroids in chronic fatigue syndrome42 the basal ganglia can also disturb limbic integration for and postpoliomyelitis fatigue43 have not been effective. cortically-driven voluntary activities.28 The outcome of Possible electrophysiological correlates of central fatigue posteroventral pallidotomy for treatment of Parkinson’s have been studied in some detail in patients with multiple disease suggests that unlike unilateral surgery,29 bilateral sclerosis. Primary fatigue is an important and frequent pallidotomy is followed by profound fatigue, sleepiness, symptom in this disorder, affecting nearly 90% of patients.44 changes in behaviour, and poor initiative in executive Fatigue in multiple sclerosis is judged the most serious functions despite improvement in motor control.30 These and disabling symptom in at least 40% of patients.45 alterations accord with neurobehavioural changes Furthermore, fatigue can be the first presenting symptom in reported by Denny-Brown31 after ablation of the caudate the disorder or suggestive of relapses.46 Acute episodes of nuclei in the basal ganglia of experimental models. A fatigue in multiple sclerosis also take place in isolation, brainstem fatigue generator model has been postulated in compared with other forms of neurological relapses in the postpoliomyelitis fatigue and postviral fatigue syndromes. disorder (weakness, loss of vision, or ataxia)47 and are not The model implicates viral damage to the dopaminergic caused by inflammatory cytokines.48 Fatigue in multiple pathways, the ascending reticular activating system in the sclerosis is heat sensitive, yet electrophysiological findings midbrain, brainstem, lenticular nuclei, basal ganglia, do not show frequency dependent conduction block in thalamus, hypothalamus, and cortical motor areas.32 demyelinated central motor pathways.49 Results of event- Fatigue is sometimes noted in patients with posterior related electroencephalographic studies during simple finger fossa lesions, after surgery, and in Chiari malformations. movements (right thumb extension) in patients with Changes in ascending serotonergic tone and amount of multiple sclerosis showed cortical dysfunction characterised substance P have been implicated in the mechanism of by hyperactivity during movement execution and a fatigue in Chiari malformations.33 This explanation could failure of inhibitory mechanisms in the postmovement also account for fatigue after posterior head injury. period.50 Neither P300 latency nor central motor Central fatigue is a characteristic of hypothalamic, conduction is greatly enhanced by fatigue, but patients with pituitary, and diencephalic syndromes. In hypothalamic- multiple sclerosis have extended reaction times to auditory pituitary diseases, it is associated with endocrine distur- motor tasks.51 Slowing of background rhythm on bances and changes in bodyweight and sleep pattern. electroencephalography has been noted in some patients Fatigue, sleepiness, and anorexia are the ubiquitous triad with chronic fatigue syndrome,15 and right hemispheric of symptoms of neurological disorders, which are slow-wave abnormality correlated with daily fatigue attributable to reduced concentrations of cytokines, severity scores and plasma prolactin concentrations of substance P, leptins, and prostaglandins. Development of postpoliomyelitis patients.52 sudden and profound chronic fatigue in physically active No specific MRI change correlates with central fatigue. and highly motivated sportspeople (overtrained athlete In a study of patients with Parkinson’s disease, 48% of syndrome) is also affected by hypothalamic and related patients reported excessive fatigue,53 which was associated neuroendocrine changes.34 with abnormal glucose metabolism or blood flow changes Narcolepsy is a sleep disorder that is characterised by in the putamen and supplementary motor areas.54 When excessive daytime somnolence, fatigue, and sudden matched for age, sex, duration of fatigue, and pyramidal unexplained motor weakness induced by strong emotions functional disability, patients with multiple sclerosis have or laughter (cataplexy). Primary narcolepsy in human higher T2 lesion volumes on MRI correlating with the beings could be caused by selective degeneration of fatigue severity score.55 Fatigue could be most common neurons that are activated by hypocretin (orexin) in in patients with multiple sclerosis with grey-matter the perifornical area of the lateral hypothalamus.35 lesions. Compared with non-fatigued patients, fluoro- Hypocretins regulate the sleep-wake cycle by promotion deoxyglucose-positron emission tomography brain scans of wakefulness and inhibition of rapid eye movement of fatigued individuals with multiple sclerosis showed sleep. Furthermore, these substances have a role in substantially reduced areas of metabolism in the bilateral neuroendocrine regulation, feeding behaviour, energy prefrontal cortex, premotor and supplemental motor balance, and sympathetic outflow. Although the complex cortex, putamen, and in the white matter extending from role of hypocretins in neuroendocrine and autonomic rostral putamen to the head of the caudate nucleus.56 THE LANCET • Vol 363 • March 20, 2004 • 983 For personal use. Only reproduce with permission from The Lancet.
  7. 7. REVIEW Functional MRI in fatigued people with this disorder also Other biological factors affecting central fatigue shows impaired interaction between functionally related Anxiety and reactive (exogenous) depression are cortical and subcortical areas, with an inverse correlation associated with several medical disorders such as the between fatigue severity score and relative activation of dysthyroid state and multiple sclerosis, and stress is ipsilateral thalamus during simple motor tasks with regarded as a common link between biological and normally functioning hands.57 psychosocial events.71 Tissue cortisol reserves and rate Proton magnetic resonance spectroscopy has been used of synaptic inactivation of norepinephrine seem to to study metabolic brain function in vivo. Neuronal be important biological traits that could predispose hypometabolism and axonal damage takes place at the to development of chronic fatigue after significant earliest clinical presentation of multiple sclerosis that is physiological or psychological stress. almost independent of inflammatory changes.58 Low cortisol concentrations predict development of Furthermore, global brain hypometabolism seems to be a post-traumatic stress disorder after serious physical and good marker for relapse in multiple sclerosis.59 In two psychological trauma.39 Patients with sepsis who were independent studies of proton magnetic resonance randomised to receive corticosteroids did significantly spectroscopy of regional brain areas in adults60,61 and one in better than those given placebo in terms of chronic children62 with chronic fatigue syndrome, rises in amounts fatigue and other neurobehavioural symptoms after of choline were reported. Regional brain increases in recovery.39 A state of pre-existing hypocortisolaemia could choline concentrations seen by proton magnetic resonance sensitise glucocorticoid receptors at a pivotal locus spectroscopy also correlated with size of the genetic defect in the hypothalamic-pituitary-adrenal axis and the stress in myotonic dystrophy,63 in which symptoms of fatigue, response, and this state may precipitate development of somnolence, and cognitive impairment are usually the most chronic fatigue after acute illness or serious traumatic life disabling.64 Choline peaks in proton magnetic resonance events. spectroscopy are derived from cell membrane lipids Molecules such as reserpine that deplete synaptic (phosphocholine). monoamines induce fatigue and depression. In animals, the The lethargic mouse is a possible model for study of the monoaminergic system is overactive during initial stress, molecular and genetic mechanisms of fatigue. This but if stress is continued, post-synaptic 2 adrenoceptors phenotype is produced by a mutation in the voltage-gated are downregulated in response to continued synaptic calcium channel subunit.65 Affected mice also have availability of increased norepinephrine. This result has cerebellar ataxia and seizures due to absence epilepsy. Ion the same functional effect of low norepinephrine channelopathy is a possible mechanism of central fatigue in concentrations in synapses. An acquired mutation in patients after ciguatera fish poisoning.66 Ciguatera toxin inactivation of synaptic norepinephrine has been reported irreversibly binds membrane sodium channels in the open in a patient with the syndrome of orthostatic intolerance mode. Central fatigue, sleep disorder, and cognitive and tachycardia.72 Postural tachycardia syndrome is typical impairment are seen in autoimmune limbic encephalitis in women aged 20–50 years, many of whom also had and Morvan’s syndrome, which are associated with anti- chronic fatigue.73 bodies against voltage-gated potassium channels.67 Neuroendocrine axis assessment is one of the best and A combination of muscle fatigability and central fatigue safest approaches for assessment of specific neuro- is seen in several disorders—eg, Addison’s disease, transmitter function in the CNS.74 On the basis of postpoliomyelitis fatigue, and motor neuron disease. In neuroendocrine responses in fatiguing disorders, we can Addison’s disease, exercise-induced fatigue is related to derive a biological model of central fatigue (figure 6). In impaired muscle contractility attributable to possible cell susceptible individuals, environmental stressors induce membrane instability from electrolyte shifts; however, changes in the neuroendocrine axis mainly through the patients also perceive higher levels of fatigue due to a hypothalamic-pituitary-adrenal axis and the norepinephrine central mechanism.68 system. Depending on the type of stressor (acute vs The role of afferent sensory input in the perceived repetitive/chronic), responses can move in the opposite sensation of central fatigue is best shown in patients with direction. Changes in synaptic sensitivities of corticotropin inflammatory demyelinating peripheral neuropathies in releasing factor, serotonin, and 2 adrenergic receptors which disease pathological findings remain mainly establish the nature and severity of fatigue-associated restricted to the peripheral nervous system. Symptoms of symptoms—eg, muscle pain, sleep disorder, orthostatic central fatigue comparable with postviral fatigue (chronic intolerance, and anxiety. In human beings, prolactin is fatigue syndrome) are reported by more than 80% of secreted from the anterior pituitary under conditions of patients, many of whom have stable neuropathy and motor stress. This secretion is tonically suppressed by dopamine, disability.69 Segmental demyelination in large diameter which is regarded as the hypothalamic prolactin-inhibitory peripheral nerves slows down and disperses proprioceptive factor. Prolactin release under stress is independent of, and afferent sensory traffic, but pain transmission by the probably happens earlier than, corticotropin releasing unmyelinated nociceptive (type C) fibres remains factor-induced release of pituitary adrenocorticotropic undisturbed. This sensory mismatch generates a high hormone. perception of effort probably because unpleasant or painful Although widely used for anxiety and depression, sensations associated with motor activities are registered conventional antidepressants could precipitate or worsen earlier than normal. fatigue and anxiety because of their side-effects. A With respect to genetic predisposition to central fatigue, new class of drugs targeting neuropeptide function in twin studies of idiopathic chronic fatigue, the is under development: antagonists to substance P, concordance rate in monozygotic twins was reported vasopressin, melanocortin concentrating hormone, and to be about 50%,70 suggesting that both genetic and corticotropin releasing factor. Substance P antagonists environmental factors are important. Genetic mechanisms (non-monoaminergic antidepressants) are being tested in could operate by enhancing susceptibility to a chronic clinical trials.75 Vasopressin antagonists are especially fatigue state under conditions of stress, other effective for anxiety in experimental models of stress.76 environmental trigger (eg, infection and immunisation), or Melanocortin-concentrating hormone is present in the both. hypothalamus and limbic system, and non-peptide 984 THE LANCET • Vol 363 • March 20, 2004 • For personal use. Only reproduce with permission from The Lancet.
  8. 8. REVIEW Stressors (infections, immunisation, trauma, life events) Genetic predisposition of biological variables (HPA axis and glucocorticoid receptors, norepinephrine system) Acute Repetitive/chronic Repetitive/chronic Acute Downregulation of Downregulation of Desensitisation of CRF central CRF receptors central adrenoceptors central 2 adrenoceptor ACTH Pituitary ACTH response Central autonomic tone Proinflammatory Proinflammatory Sensitivity of Cortisol Cortisol cytokines cytokines peripheral adrenoceptors Sensitivity Pain (myalgia) Desensitisation Orthostatic intolerance of 5HT1A Excess sleep of 5HT1A receptors postural tachycardia receptors Sweating Blunted prolactin Exaggerated prolactin Blunted HPA response to 5HT1A response to 5HT1A response to agonist agonist 2 agonist Anxiety and related neuropsychological symptoms Poor Depression motivation Chronic fatigue Figure 6: Biological model of chronic fatigue based on neuroendocrine functions ACTH=adrenocorticotropic hormone. CRF=corticotropin releasing factor. 5HT=5-hydroxytryptamine (serotonin). HPA=hypothalamic-pituitary-adrenal. melanocortin-concentrating hormone 1 receptor Inappropriate analgesics and sedatives—eg, opiates, antagonists are undergoing preclinical assessment.77 Of the regularly prescribed codeine-containing analgesics, long- two major types of corticotropin releasing factor receptors acting benzodiazepines, and most frequently used in the brain (CRF1 and CRF2), selective CRF2 tranquillisers—should be avoided. antagonism by the peptide ASV20 is effective without Treatments for central fatigue directed to physiological blocking pituitary adrenocorticotropic hormone response components of underlying disease are limited. in trials in anxiety models.78 Aminopyridines (also used for treatment of Lambert-Eaton myasthenic syndrome) are effective in fatigue associated Management with multiple sclerosis.79 Amantadine—originally developed Management of central fatigue needs to be tailored for the as an antiviral for the influenza virus—is probably the most best possible outcome. Lifestyle changes are pivotal, and effective pharmacological treatment for fatigue with the patient’s doctor should advise against either too much multiple sclerosis, with benefit reported in nearly a third to rest or attempted overactivity to beat fatigue. Alcohol half of all treated patients, although trials were done in few worsens central fatigue and should be avoided. patients and might have been biased.80 Pemoline, a centrally Pharmacological treatment of pain, poor sleep, muscle active sympathomimetic, has been recommended for spasticity, and involuntary muscle activity is very fatigue in multiple sclerosis but is less effective than important because these physiological variables affect amantadine, and no benefit has been shown versus severity of fatigue. Low doses of tricyclic antidepressants placebo.81 Methylphenidate has been used occasionally in (amitriptyline, imipramine, or trazodone), antiepileptics fatigued patients with multiple sclerosis and multiple (carbamazepine, gabapentin, or valproic acid), short- system atrophy. In a double-blind randomised trial, acting benzodiazepines (clonazepam), or baclofen are pydriostigmine for treatment of postpoliomyelitis fatigue frequently used, sometimes in combination. In some was of no benefit.82 Bromocriptine, an indirect dopamine patients, acupuncture and transcutaneous nerve agoinst, was judged helpful in a small double-blind, stimulation can be useful adjuncts for pain control. placebo controlled trial,83 but in a double-blind placebo- Shorter acting benzodiazepines could also be effective for controlled trial, amantadine was no better than placebo nocturnal myoclonus and periodic limb movements for fatigue in postpoliomyelitis patients.84 Modafinil is a during sleep in central fatigue.25 The doctor has to be central stimulant drug and is the first line of treatment for careful not to inadvertently aggravate existing fatigue. excessive daytime sleepiness and in narcolepsy. It seems THE LANCET • Vol 363 • March 20, 2004 • 985 For personal use. Only reproduce with permission from The Lancet.
  9. 9. REVIEW to be an effective treatment for fatigue and somnolence in fairly consistent, and when a patient with fatigue patients with multiple sclerosis,85,86 Parkinson’s disease, perfectly fits criteria for a psychiatric disorder,92 one can and myotonic dystrophy, but larger trials are needed certainly have confidence in the diagnosis. However, before its efficacy can be confirmed. when a patient’s symptoms or clinical course do not fit Affective components of fatigue might respond to diagnostic criteria, one needs to be cautious.93 We know antidepressants, cognitive behaviour therapy, or a that brain-derived central fatigue is related to circuits combination of both. In theory, appropriately structured that connect basal ganglia, amygdala, thalamus, and cognitive behaviour treatments can improve motivation frontal cortex.27,32 To imply that fatigue is a medically and keep perceptive changes to a minimum in fatigued unexplained, non-organic symptom in patients who do patients. However, this therapy does not reverse not have a primary psychiatric diagnosis would be physiological outcomes of the underlying disease incorrect and inappropriate. As in other complex process. In a study in depressed patients, post-treatment medical disorders, only open minded people—who are increases in basal ganglia blood flow were recorded willing to consider observations and explanations at with interpersonal psychotherapy and venlafaxine (an many different levels—are likely to succeed in offering antidepressant that selectively inhibits reuptake of the right solutions.94 norepinephrine and serotonin), but only psychotherapy enhanced limbic blood flow.87 Sometimes, depression and Conflict of interest statement anxiety arise from social circumstances, loss of None declared. employment, and failure to fulfil family responsibilities. Appropriate social support and occupational rehabilitation Acknowledgments We thank the David and Frederick Barclay Foundation for supporting is therefore integral to successful management of fatiguing fatigue research in neurological diseases; and the following colleagues neurological diseases. who reviewed the manuscript and gave us advice on their areas of Level of physical activity is a key issue in management expertise: W M H Behan (professor of muscle pathology, University of of fatigue. Patients are likely to be sedentary because of Glasgow, Glasgow, UK); T G Dinan (professor of clinical pharmacology and therapeutics, University College, Cork, Ireland); and R L Bruno associated disabilities (eg, weakness and pain), reduced (director, Post-Polio Institute and International Centre for Post-Polio level of physical endurance, and deterioration of Education and Research, Englewood Hospital and Medical Center, New symptoms that could follow physical exertion. However, Jersey, USA). physical inactivity imposed by fatigue leads to chronic cardiovascular and muscle deconditioning and raised References health risks. A regular pattern of activity is generally 1 Adams RD, Victor M, Ropper AH. Fatigue, asthenia, anxiety and encouraged in all patients: the amount undertaken depressive reactions. In: Adams RD, Victor M, Ropper AH, eds. should be modest, spread throughout the day, with Principles of neurology, 6th edn. New York: McGraw-Hill, 1997: greater emphasis on regularity not on level of 497–507. performance. Input from therapists can help in 2 Sharma OP. Fatigue and sarcoidosis. Eur Resp J 1999; 13: 713–14. 3 Branas P, Jordan R, Fry-Smith A, Burls A, Hyde C. Treatments assessment of the level of disability and to identify an for fatigue in multiple sclerosis: a rapid and systematic review. acceptable range of daily physical activity to prevent Health Technol Assess 2000; 4: 1–61. physical deconditioning and resultant weakness and 4 Bruno RL. Paralytic versus “non-paralytic polio”: a distinction muscle wasting. Physical inactivity has a small but without a difference? Am J Phys Med Rehabil 1999; 79: 4–12. significant effect of destabilising the chronically enlarged 5 Birk TJ. Poliomyelitis and post-polio syndrome: exercise capacity and adaptation: current research, future directions, and widespread motor units in muscles that were acutely denervated.88 applicability. Med Sci Sports Exerc 1993; 25: 466–72. However, in postpoliomyelitis patients, results of exercise 6 Staub F, Bogousslavsky J. Fatigue after stroke: a major but neglected studies suggest that excessive physical activity and issue. Cerebrovascular Dis 2001; 12: 75–81. prescribed exercise have a detrimental effect on fatigue 7 Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue and level of physical endurance,89 probably because of an severity scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 26: 155–56. accelerated rate of decline in function of the surviving 8 Kandel ER, Schwartz JH, Jessell TM. The nervous system. In: motor units.90 Kandel ER, Schwartz JH, Jessell TM, eds. Essentials of neural science Clearly, large randomised treatment trials need to be and behavior. Connecticut: Appleton and Lange, 1995: 71–88. done in fatigue, especially in patients with multiple 9 Taivassalo T, Abbott A, Wyrick P, Haller RG. Venous oxygen levels sclerosis, poststroke fatigue, postpoliomyelitis fatigue, and during aerobic forearm exercise: an index of impaired oxidative metabolism in mitochondrial myopathy. Ann Neurol 2002; 51: 38–44. chronic fatigue syndrome. Although early results of 10 Dalsgaard MK, Nybo L, Cai Y, Secher NH. Cerebral metabolism is cognitive behaviour therapy and graded exercise in influenced by muscle ischaemia during exercise in humans. Exp Physiol chronic fatigue syndrome seemed promising, little 2003; 88: 297–302. information is available about the effectiveness of these 11 Latash M, Kalugina E, Nicholas J, et al. Myogenic and central interventions for fatigue in the long term, in children and neurogenic factors in fatigue in MS. Mult Scler 1996; 1: 236–41. in severely disabled patients.42 Non-pharmacological 12 Bruno RL, Zimmerman JR. Word finding difficulty as a post-polio sequelae. Am J Phys Med Rehabil 2000; 79: 343–48. interventions (psychotherapy and exercise) can improve 13 Chaudhuri A, Behan PO. Neurological dysfunction in chronic fatigue quality of life, mainly because of improved psychosocial syndrome. J Chron Fatigue Syndr 2000; 6: 51–68. function91 rather than amelioration of fatigue. Because of 14 Fukuda K, Strauss SE, Hickie I, et al. The chronic fatigue syndrome: the limitations of self-reported questionnaires as valid a comprehensive approach to case definition and study. outcome measures in fatigue, we must use additional Ann Intern Med 1994; 121: 953–59. 15 Chaudhuri A, Behan WMH, Behan PO. Chronic fatigue syndrome. methods—eg, serial neuroimaging, neuropsychological Proc R Coll Physicians Edinb 1998; 28: 150–63. assessments—in future trials to capture real treatment 16 Bagert B, Camplair P, Bourdette D. Cognitive dysfunction in multiple effects. sclerosis: natural history, pathophysiology and management. CNS Drugs 2002; 16: 445–55. Conclusions 17 Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology 2000; 55: 934–39. Many doctors prefer to invoke a psychiatric explanation 18 Bruno RL, Galaski T, DeLuca J. The neuropsychology of post-polio for fatigue when patients’ symptoms do not fit a typical fatigue. Arch Phys Med Rehabil 1993; 74: 1061–65. medical or neurological diagnostic category. Classic 19 van Zandvoort MJ, Kappelle LJ, Algra A, De Haan EH. Decreased descriptions of major psychiatric disorders have been capacity for mental effort after single supratentorial lacunar infarct 986 THE LANCET • Vol 363 • March 20, 2004 • For personal use. Only reproduce with permission from The Lancet.
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Uses of error Surprising post mortems Martin M Brown As a young surgical houseman, I admitted a 45-year-old after the unexpected retirement of my consultant. It was man after a phone call from his general practitioner (GP), good experience to organise the service and see patients who said the patient had complained of abdominal pain unsupervised. However, with no one to check up on me, I and then collapsed. The GP had told me that the man was could have made many errors. One case in point was a in shock, with a low blood pressure and a thready pulse. patient with severe neuropathy, who happened to be on a When I arrived on the ward to see the patient he was cardiac ward with heart block. I had no idea of the cause sitting up in bed having his details taken by the admitting of his neuropathy until the patient eventually came to post nurse. In my enthusiasm to see the patient so well, I mortem, which showed systemic amyloidosis. brushed the nurse aside before she had even recorded the We could have made the diagnosis by nerve biopsy and patient’s name. To my surprise, there seemed to be possibly alleviated his condition. It was difficult to link nothing wrong with the patient. He said he felt perfectly together two apparently unrelated clinical signs and often well. His pulse and blood pressure seemed normal. I it was only the experience of having seen the combination unwisely dismissed the GP’s story and went off to see before, which led to the diagnosis of rare disorders. Today another patient. An hour or two later, my first patient was however, I can type neuropathy and heart block into a found dead in bed and could not be resuscitated. A post- MEDLINE search engine and the first reference describes mortem examination showed that he had died from a case of amyloid neuropathy, emphasising the value of gastrointestinal haemorrhage. It turned out the nurse had information technology in diagnosis. I decided then that it never come back, we had no details for the patient, and was wrong that junior doctors should see ward referrals could not contact his family. and new patients unsupervised. On Royal College visits I learned several things from this experience. Firstly, the we now assess both the adequacy of the trainees’ routine recording of the administrative details about a supervision and their access to the internet. patient and the initial nursing observations should not be What can be learnt from my errors? Firstly, I often only interrupted. Secondly, the physiological adaptation to found out about my mistakes when someone else had seen reduced blood volume may result in a deceptively well the patient. Secondly, post-mortem examination often looking patient after an initial period of shock. I should reveals a surprising diagnosis, even when the clinician have taken more notice of the GP’s observations and feels sure of the diagnosis after investigation. Thirdly, to measured the patient’s standing, as well as lying, blood learn from mistakes requires feedback. Regular audit is pressure. essential, and a mechanism to feed back a revised As a young neurology registrar, I had the privilege of diagnosis to the previous doctors looking after the patient being almost completely unsupervised for several months would be beneficial. The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK (M M Brown FRCP) 988 THE LANCET • Vol 363 • March 20, 2004 • For personal use. Only reproduce with permission from The Lancet.