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.
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Internal environment Internal input External input
(homoeostatic) control (motivational and limbic) (incentive)
and autonomic) + –
initiation of withdrawal of
voluntary effort voluntary effort
Work output Physiological set point
for applied effort
+ – + –
facilitator suppressor facilitator suppressor
Feedback of perceived exertion
control (eg, temperature)
Cognitive processing (special sensory and Motor output
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
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History and examination
Objective motor weakness, abnormal neurological signs, or both?
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
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.
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
strength is partly restored after rest (pseudoparalysis).
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)
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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
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)
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.
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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
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.
Motor neuron disease
Neuropsychological assessment in central fatigue is
Multiple system atrophy
desirable if cognitive impairment is reported or
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
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
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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
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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 • www.thelancet.com
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trauma, life events)
Genetic predisposition of
(HPA axis and glucocorticoid receptors,
Acute Repetitive/chronic Repetitive/chronic Acute
Downregulation of Downregulation of Desensitisation of
central CRF receptors central adrenoceptors central 2
ACTH Pituitary ACTH response Central autonomic tone
Proinflammatory Proinflammatory Sensitivity of
cytokines cytokines peripheral adrenoceptors
Sensitivity Pain (myalgia)
Desensitisation Orthostatic intolerance
of 5HT1A Excess sleep
of 5HT1A receptors postural tachycardia
Blunted prolactin Exaggerated prolactin Blunted HPA
response to 5HT1A response to 5HT1A response to
agonist agonist 2 agonist
Anxiety and related
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 • www.thelancet.com 985
For personal use. Only reproduce with permission from The Lancet.
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
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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)
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