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
pleasure, merriment, laughter, amusement, as of our
grief, pain, anxiety and tears, is none other than the
brain”
Hippocrates
However, progress in understanding of fatigue in
neurological disorders offers the prospect of developing
appropriate investigational methodology and treatment
strategies. Here, we review the neurology of fatigue and its
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
10–15 million visits to family doctors every year.2 The
disorder can be part of medical and neurological disease
(eg, anaemia, multiple sclerosis), an integral feature of the
disease itself (eg, poststroke, chronic fatigue syndrome),
mainly the result of a psychiatric disturbance in function
(eg, somatoform disorder), or a side-effect of drugs
prescribed for previous disorders—eg, antihypertensives,
-adrenergic blockers, lipid-lowering agents, proton-
pump inhibitors, beta interferon, anxiolytics,
antipsychotics, and surprisingly, antidepressants.1
The prevalence of fatiguing neurological disorders is
not known, but probably represents a substantial
proportion of all patients who present with chronic fatigue
in whom other systemic diseases and psychiatric and
drug-related causes have been excluded. In the UK, at
least 40 000 patients with multiple sclerosis have excessive
fatigue that severely limits activity.3 More than 90% of
patients with paralytic and non-paralytic poliomyelitis
develop a delayed syndrome characterised by excessive
fatigue (postpoliomyelitis fatigue).4 Worldwide, several
million patients are presently afflicted with this disorder,
with an estimated 350 000 in the USA alone.5 Fatigue
after stroke (poststroke fatigue) is an important cause of
long-term morbidity in cerebrovascular diseases.6
Our understanding of the neurobiological basis of
fatigue is imperfect, and treatments are limited. As a
result, the disorder has been regarded by some as a
medically unexplained symptom due to somatisation.
Lancet 2004; 363: 978–88
Division of Clinical Neurosciences, University of Glasgow, Glasgow
G51 4TF, UK (A Chaudhuri DM, P O Behan DSc)
Correspondence to: Dr A Chaudhuri
(e-mail: ac54p@udcf.gla.ac.uk)
The perception of fatigue is subjective: no exact
definition exists because of overlap between the lay
notion of tiredness and the clinically relevant symptom
of fatigue. It is not the same as muscle weakness,1
depression, or muscle fatigability, and it is not a non-
specific outcome of chronic illness.7 For clinical use,
fatigue is best defined as difficulty in initiation of or
sustaining voluntary activities. If the activity is linked to
a reward—eg, winning a race—then fatigue could be
pleasurable.
To understand fatigue, we might regard voluntary
effort as a controlled variable that is affected by many
control systems. Figure 1 shows interplay between
various physiological control systems that regulate work
output. Work output is a dependent variable of applied
effort that is controlled by motivational input (internal
and external) and feedback from motor, sensory, and
cognitive systems that establishes the level of perceived
exertion. Typical physical activity depends on structural
and functional integrity of sensory and motor systems.8
Perceived exertion is an important feedback control for
the level of applied effort. Additional control systems
Search strategy and selection criteria
This review is based on our reading of existing medical texts
and a search of PubMed and MEDLINE for articles with the
keywords “fatigue”, “chronic fatigue”, and “neurology”
between October, 1997, and March, 2003. More than
4000 articles were originally identified, and a shortlist of
core published work of possible relevance to this review
was prepared after discussion with several colleagues with
international expertise in this area. Only articles published
in English were considered, and where appropriate,
publications before October, 1997, were traced.

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 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
as temperature and internal mileu (homoeostasis and
autonomic function).
Voluntary activity is dependent on smooth flow of
nerve impulses in the major sensory and motor systems.
Sensory signals from skin, cardiorespiratory systems,
muscles, and joints, and special senses (skin, eyes, and
ears), provide afferent input. After cognitive processing of
this information, the primary motor cortex activates
brainstem motor nuclei and anterior horn cells in the
spinal cord (efferent pathway). Signal from lower motor
neurons reaches muscle through peripheral nerves and
the neuromuscular junction (figure 2). Within the
muscle, a series of metabolic events then provides
chemical energy for contraction. Any interruption to this
complex chain of events could affect the level of applied
effort and perceived exertion (figure 1).
Pathological fatigue is, thus, best understood as an
amplified sense of normal (physiological) fatigue that
can be induced by changes in one or more variables
regulating work output. Fatigue could develop during
a disease because of dissociation between the level
of internal input (motivational and limbic) and that of
perceived exertion from applied effort (figure 1). When
there is loss of interest and motivation, as in depression,
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

Figure 2: Integration of sensory and motor pathways for
physical activities
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
peripheral, autonomic, and central nervous system. It is
consistently seen with lesions in pathways associated with

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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
● 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
● 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
● Take appropriate action
Multiple sclerosis Multiple sclerosis
Normal results Partial seizures Chronic fatigue
● Consider assessment with
Periodic paralysis syndrome
peripheral electrophysiology (EMG/NCS) Migraine

Myopathic EMG with or without high creatine kinase Screening assessment

● Consider muscle biopsy
● Blood tests; electrocardiogram; blood pressure
● Forearm ischaemic exercise test (supine and standing); in children, chart height
and neurology referral and weight
● Review results, take eyewitness accounts and
check drug history; monitor progress
● 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)

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 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.

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 REVIEW
Panel 1: Neurological disorders of central fatigue
Symptomatic
Cerebral vasculitis and cerebrovascular diseases
Channelopathies
Developmental disorders (cerebral palsy, Chiari
malformations)
Dysautonomic states
Encephalitis lethargica
Granulomatous disorders (neurosarcoid, Wegener’s
granulomatosis)
Hypothalamic and pituitary diseases
Intracranial infections (meningitis and encephalitis)
Metabolic encephalopathy and mitochondrial diseases
Migraine
Motor neuron disease
Multiple sclerosis
Multiple system atrophy
Myotonic dystrophy
Narcolepsy and related sleep disorders
Paraneoplastic (limbic encephalitis, opsoclonus-myoclonus)
Parkinson’s disease and other parkinsonian disorders
Posterior head injury
Post-Guillain Barré syndrome fatigue
Postinfective fatigue states (poliomyelitis, Lyme disease,
Q fever, and viral fatigue)
Postoperative (posterior fossa and cardiopulmonary bypass
surgery)
Idiopathic
Chronic fatigue syndrome/myalgic encephalomyelitis
Central fatigue
Assessment
A feeling of constant exhaustion is a characteristic
of central fatigue. Neurological disorders associated
with this feature are listed in panel 1. Severity of central
fatigue is not associated with the nature or severity
of underlying disease. Occasionally, central fatigue can
be focal, affecting vision in one eye or motor power in
one limb, arising during sustained visual or motor tasks.
This occurrence is typically seen in patients with
multiple sclerosis.11 After cortical stroke, patients
with aphasia rapidly develop mental fatigue while
speaking. Word-finding difficulty and anomia are
other examples of task-specific mental fatigue seen in
patients with postpoliomyelitis fatigue12 and chronic
fatigue syndrome.13 Individuals with central fatigue have
deterioration or periodic fluctuations in severity of
fatigue under physiological and psychological stimuli.13
Furthermore, patients with chronic fatigue syndrome
also have various combinations of pain, postexertional
malaise, disturbed sleep pattern, short-term cognitive
impairment, and daily headache.14 In more than a
third of cases, fatigue arises suddenly or subacutely, and
nearly 80% of patients relate their symptoms to a
preceding infection.15 Low motivation, loss of pleasure
(anhedonia), early morning awakenings, self-imposed
avoidance of social contacts, inappropriate guilt, and
suicidal ideations are important clues to identify
depressive fatigue.
Neuroimaging in central fatigue is mainly done to
exclude structural and demyelinating lesions, and
MRI of the brain is the procedure of choice. Present
research methods include proton magnetic resonance
spectroscopy and functional neuroimaging (positron
emission tomography and single photon emission CT
scans) of the brain.
982
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Panel 2: Fatigue severity score7
● My motivation is lower when I am fatigued
● Exercise brings on my fatigue
● I am easily fatigued
● Fatigue interferes with my physical functioning
● Fatigue causes frequent problems for me
● My fatigue prevents sustained physical functioning
● Fatigue interferes with carrying out certain duties and
responsibilities
● Fatigue is among my three most disabling symptoms
● Fatigue interferes with my work, family, or social life
Patients choose a number from 1 to 7 that shows their degree of
agreement with every statement, where 1 indicates strongly disagree
and 7 strongly agree. There is no cutoff value.
Neuropsychological assessment in central fatigue is
desirable if cognitive impairment is reported or
suspected. This dysfunction is usual in individuals with
multiple sclerosis, with an estimated prevalence of
65%.16 These patients frequently show mental fatigue in
the cognitive domains of memory, learning, attention,
and information processing. In a 4-h session of cognitive
testing, people with this disorder fared poorly on tests of
verbal memory and conceptual planning, and their
performance declined over time during the test (mental
fatigue).17 By contrast, patients with postpoliomyelitis
fatigue have no impairments of verbal memory and
enhanced cortical function but have important deficits in
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
be independent of the anatomic location of the
ischaemic lesion (supratentorial or brainstem).19,20
Apathy is a characteristic symptom of Parkinson’s
disease, and neuropsychological profiles indicate fronto-
subcortical dysfunction as its possible anatomic
correlate.21 Cognitive impairment has also been noted in
patients with chronic fatigue syndrome without
psychiatric comorbidity.22,23
Because fatigue is typical in dysautonomia, supine
and standing blood pressure should be taken in these
patients. Presence of orthostatic symptoms could also
indicate need for formal autonomic and cardiac tilt-table
tests. Autonomic impairment can be primary (primary
autonomic failure, Parkinson’s disease, and multiple
system atrophy) or secondary to other neurological
diseases (hemispheric infarct, hypothalamic and posterior
fossa lesions, peripheral neuropathy) and medical
disorders (diabetes, renal failure, neurosyphilis, and
HIV infections). Patients who do not have postural
hypotension but still have orthostatic symptoms or simple
faints (syncope) can be assessed by tilt-table testing for up
to 30 min with monitoring by electrocardiography.
Children and adolescents with chronic fatigue syndrome
are sensitive to orthostatic challenge and can develop
neurally mediated hypotension.24
In some people, formal sleep studies might be needed
to exclude a primary sleep disorder presenting with fatigue
and excessive daytime sleepiness. The multiple sleep
latency test is a useful diagnostic method for narcolepsy.
Findings of sleep studies might also indicate frequent
episodes of apnoea or oxygen desaturation in patients with
central fatigue and neuromuscular weakness (acid maltase
deficiency, motor neuron disease, postpoliomyelitis
fatigue, and myotonic dystrophy). Nocturnal myoclonus
is a postpoliomyelitis sequelae, and nearly a third of these
patients have periodic limb movements in sleep.25
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Self-completed questionnaires are sometimes used for
subjective assessment of fatigue; one that has been widely
used in the assessment of multiple sclerosis fatigue
(fatigue severity score)7 is listed in panel 2. Self-reported
methods have major limitations, especially questionnaires
that fail to regard fatigue as a multidimensional state
with cognitive, physical, and psychological components.
With self-assessment questionnaires, to be sure about
a true change is difficult, especially when symptom
severity fluctuates greatly (regression to mean effect).
Questionnaire-based surveys can also introduce bias into a
study population because of participants’ knowledge that
they are being studied (Hawthorne effect).
Pathophysiology
Poststroke fatigue is a recognised complication after
subcortical, brainstem, and thalamic ischaemia.6,26 In
many patients with excellent neurological and psy-
chological recovery, poststroke fatigue could be the only
major disability. Fatigue is a symptom of diseases that
affect the basal ganglia27 and that interrupt the connection
between the prefrontal cortex and thalamus. Lesions in
the basal ganglia can also disturb limbic integration for
cortically-driven voluntary activities.28 The outcome of
posteroventral pallidotomy for treatment of Parkinson’s
disease suggests that unlike unilateral surgery,29 bilateral
pallidotomy is followed by profound fatigue, sleepiness,
changes in behaviour, and poor initiative in executive
functions despite improvement in motor control.30 These
alterations accord with neurobehavioural changes
reported by Denny-Brown31 after ablation of the caudate
nuclei in the basal ganglia of experimental models. A
brainstem fatigue generator model has been postulated in
postpoliomyelitis fatigue and postviral fatigue syndromes.
The model implicates viral damage to the dopaminergic
pathways, the ascending reticular activating system in the
midbrain, brainstem, lenticular nuclei, basal ganglia,
thalamus, hypothalamus, and cortical motor areas.32
Fatigue is sometimes noted in patients with posterior
fossa lesions, after surgery, and in Chiari malformations.
Changes in ascending serotonergic tone and amount of
substance P have been implicated in the mechanism of
fatigue in Chiari malformations.33 This explanation could
also account for fatigue after posterior head injury.
Central fatigue is a characteristic of hypothalamic,
pituitary, and diencephalic syndromes. In hypothalamic-
pituitary diseases, it is associated with endocrine distur-
bances and changes in bodyweight and sleep pattern.
Fatigue, sleepiness, and anorexia are the ubiquitous triad
of symptoms of neurological disorders, which are
attributable to reduced concentrations of cytokines,
substance P, leptins, and prostaglandins. Development of
sudden and profound chronic fatigue in physically active
and highly motivated sportspeople (overtrained athlete
syndrome) is also affected by hypothalamic and related
neuroendocrine changes.34
Narcolepsy is a sleep disorder that is characterised by
excessive daytime somnolence, fatigue, and sudden
unexplained motor weakness induced by strong emotions
or laughter (cataplexy). Primary narcolepsy in human
beings could be caused by selective degeneration of
neurons that are activated by hypocretin (orexin) in
the perifornical area of the lateral hypothalamus.35
Hypocretins regulate the sleep-wake cycle by promotion
of wakefulness and inhibition of rapid eye movement
sleep. Furthermore, these substances have a role in
neuroendocrine regulation, feeding behaviour, energy
balance, and sympathetic outflow. Although the complex
role of hypocretins in neuroendocrine and autonomic
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REVIEW
homoeostasis remains to be elucidated, these substances
clearly provide an important biological link between the
symptoms of fatigue and poor arousal or excessive
sleepiness.
Fatigue is sometimes seen in people with disorders
associated with an underactive hypothalamic-pituitary-
adrenal axis. In this situation, fatigue could be attributable
to the proinflammatory cytokines that become activated
by reduced corticotropin releasing factor and low
cortisol concentrations. This hypothesis seems to accord
with experimental evidence that in immune-mediated
disorders, acute stress can be beneficial because rises
in corticotropin releasing factor attenuate the
T-helper-1 cell response.36 However, we do not know if
chronic stress (vs acute stress) eventually downregulates
the hypothalamic-pituitary-adrenal axis, leading to
persistent fatigue.37 This axis is underactive in patients
with chronic fatigue syndrome,38 post-traumatic stress
disorder,39 fibromyalgia,40 and postpoliomyelitis fatigue.41
Fatigue is not improved by steroid supplements except in
patients with primary or secondary adrenal insufficiency,
and trials of corticosteroids in chronic fatigue syndrome42
and postpoliomyelitis fatigue43 have not been effective.
Possible electrophysiological correlates of central fatigue
have been studied in some detail in patients with multiple
sclerosis. Primary fatigue is an important and frequent
symptom in this disorder, affecting nearly 90% of patients.44
Fatigue in multiple sclerosis is judged the most serious
and disabling symptom in at least 40% of patients.45
Furthermore, fatigue can be the first presenting symptom in
the disorder or suggestive of relapses.46 Acute episodes of
fatigue in multiple sclerosis also take place in isolation,
compared with other forms of neurological relapses in the
disorder (weakness, loss of vision, or ataxia)47 and are not
caused by inflammatory cytokines.48 Fatigue in multiple
sclerosis is heat sensitive, yet electrophysiological findings
do not show frequency dependent conduction block in
demyelinated central motor pathways.49 Results of event-
related electroencephalographic studies during simple finger
movements (right thumb extension) in patients with
multiple sclerosis showed cortical dysfunction characterised
by hyperactivity during movement execution and a
failure of inhibitory mechanisms in the postmovement
period.50 Neither P300 latency nor central motor
conduction is greatly enhanced by fatigue, but patients with
multiple sclerosis have extended reaction times to auditory
motor tasks.51 Slowing of background rhythm on
electroencephalography has been noted in some patients
with chronic fatigue syndrome,15 and right hemispheric
slow-wave abnormality correlated with daily fatigue
severity scores and plasma prolactin concentrations of
postpoliomyelitis patients.52
No specific MRI change correlates with central fatigue.
In a study of patients with Parkinson’s disease, 48% of
patients reported excessive fatigue,53 which was associated
with abnormal glucose metabolism or blood flow changes
in the putamen and supplementary motor areas.54 When
matched for age, sex, duration of fatigue, and pyramidal
functional disability, patients with multiple sclerosis have
higher T2 lesion volumes on MRI correlating with the
fatigue severity score.55 Fatigue could be most common
in patients with multiple sclerosis with grey-matter
lesions. Compared with non-fatigued patients, fluoro-
deoxyglucose-positron emission tomography brain scans
of fatigued individuals with multiple sclerosis showed
substantially reduced areas of metabolism in the bilateral
prefrontal cortex, premotor and supplemental motor
cortex, putamen, and in the white matter extending from
rostral putamen to the head of the caudate nucleus.56
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Functional MRI in fatigued people with this disorder also
shows impaired interaction between functionally related
cortical and subcortical areas, with an inverse correlation
between fatigue severity score and relative activation of
ipsilateral thalamus during simple motor tasks with
normally functioning hands.57
Proton magnetic resonance spectroscopy has been used
to study metabolic brain function in vivo. Neuronal
hypometabolism and axonal damage takes place at the
earliest clinical presentation of multiple sclerosis that is
almost independent of inflammatory changes.58
Furthermore, global brain hypometabolism seems to be a
good marker for relapse in multiple sclerosis.59 In two
independent studies of proton magnetic resonance
spectroscopy of regional brain areas in adults60,61 and one in
children62 with chronic fatigue syndrome, rises in amounts
of choline were reported. Regional brain increases in
choline concentrations seen by proton magnetic resonance
spectroscopy also correlated with size of the genetic defect
in myotonic dystrophy,63 in which symptoms of fatigue,
somnolence, and cognitive impairment are usually the most
disabling.64 Choline peaks in proton magnetic resonance
spectroscopy are derived from cell membrane lipids
(phosphocholine).
The lethargic mouse is a possible model for study of the
molecular and genetic mechanisms of fatigue. This
phenotype is produced by a mutation in the voltage-gated
calcium channel subunit.65 Affected mice also have
cerebellar ataxia and seizures due to absence epilepsy. Ion
channelopathy is a possible mechanism of central fatigue in
patients after ciguatera fish poisoning.66 Ciguatera toxin
irreversibly binds membrane sodium channels in the open
mode. Central fatigue, sleep disorder, and cognitive
impairment are seen in autoimmune limbic encephalitis
and Morvan’s syndrome, which are associated with anti-
bodies against voltage-gated potassium channels.67
A combination of muscle fatigability and central fatigue
is seen in several disorders—eg, Addison’s disease,
postpoliomyelitis fatigue, and motor neuron disease. In
Addison’s disease, exercise-induced fatigue is related to
impaired muscle contractility attributable to possible cell
membrane instability from electrolyte shifts; however,
patients also perceive higher levels of fatigue due to a
central mechanism.68
The role of afferent sensory input in the perceived
sensation of central fatigue is best shown in patients with
inflammatory demyelinating peripheral neuropathies in
which disease pathological findings remain mainly
restricted to the peripheral nervous system. Symptoms of
central fatigue comparable with postviral fatigue (chronic
fatigue syndrome) are reported by more than 80% of
patients, many of whom have stable neuropathy and motor
disability.69 Segmental demyelination in large diameter
peripheral nerves slows down and disperses proprioceptive
afferent sensory traffic, but pain transmission by the
unmyelinated nociceptive (type C) fibres remains
undisturbed. This sensory mismatch generates a high
perception of effort probably because unpleasant or painful
sensations associated with motor activities are registered
earlier than normal.
With respect to genetic predisposition to central fatigue,
in twin studies of idiopathic chronic fatigue, the
concordance rate in monozygotic twins was reported
to be about 50%,70 suggesting that both genetic and
environmental factors are important. Genetic mechanisms
could operate by enhancing susceptibility to a chronic
fatigue state under conditions of stress, other
environmental trigger (eg, infection and immunisation), or
both.
984
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Other biological factors affecting central fatigue
Anxiety and reactive (exogenous) depression are
associated with several medical disorders such as the
dysthyroid state and multiple sclerosis, and stress is
regarded as a common link between biological and
psychosocial events.71 Tissue cortisol reserves and rate
of synaptic inactivation of norepinephrine seem to
be important biological traits that could predispose
to development of chronic fatigue after significant
physiological or psychological stress.
Low cortisol concentrations predict development of
post-traumatic stress disorder after serious physical and
psychological trauma.39 Patients with sepsis who were
randomised to receive corticosteroids did significantly
better than those given placebo in terms of chronic
fatigue and other neurobehavioural symptoms after
recovery.39 A state of pre-existing hypocortisolaemia could
sensitise glucocorticoid receptors at a pivotal locus
in the hypothalamic-pituitary-adrenal axis and the stress
response, and this state may precipitate development of
chronic fatigue after acute illness or serious traumatic life
events.
Molecules such as reserpine that deplete synaptic
monoamines induce fatigue and depression. In animals, the
monoaminergic system is overactive during initial stress,
but if stress is continued, post-synaptic 2 adrenoceptors
are downregulated in response to continued synaptic
availability of increased norepinephrine. This result has
the same functional effect of low norepinephrine
concentrations in synapses. An acquired mutation in
inactivation of synaptic norepinephrine has been reported
in a patient with the syndrome of orthostatic intolerance
and tachycardia.72 Postural tachycardia syndrome is typical
in women aged 20–50 years, many of whom also had
chronic fatigue.73
Neuroendocrine axis assessment is one of the best and
safest approaches for assessment of specific neuro-
transmitter function in the CNS.74 On the basis of
neuroendocrine responses in fatiguing disorders, we can
derive a biological model of central fatigue (figure 6). In
susceptible individuals, environmental stressors induce
changes in the neuroendocrine axis mainly through the
hypothalamic-pituitary-adrenal axis and the norepinephrine
system. Depending on the type of stressor (acute vs
repetitive/chronic), responses can move in the opposite
direction. Changes in synaptic sensitivities of corticotropin
releasing factor, serotonin, and 2 adrenergic receptors
establish the nature and severity of fatigue-associated
symptoms—eg, muscle pain, sleep disorder, orthostatic
intolerance, and anxiety. In human beings, prolactin is
secreted from the anterior pituitary under conditions of
stress. This secretion is tonically suppressed by dopamine,
which is regarded as the hypothalamic prolactin-inhibitory
factor. Prolactin release under stress is independent of, and
probably happens earlier than, corticotropin releasing
factor-induced release of pituitary adrenocorticotropic
hormone.
Although widely used for anxiety and depression,
conventional antidepressants could precipitate or worsen
fatigue and anxiety because of their side-effects. A
new class of drugs targeting neuropeptide function
is under development: antagonists to substance P,
vasopressin, melanocortin concentrating hormone, and
corticotropin releasing factor. Substance P antagonists
(non-monoaminergic antidepressants) are being tested in
clinical trials.75 Vasopressin antagonists are especially
effective for anxiety in experimental models of stress.76
Melanocortin-concentrating hormone is present in the
hypothalamus and limbic system, and non-peptide
THE LANCET • Vol 363 • March 20, 2004 • www.thelancet.com
 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
two major types of corticotropin releasing factor receptors
in the brain (CRF1 and CRF2), selective CRF2
antagonism by the peptide ASV20 is effective without
blocking pituitary adrenocorticotropic hormone response
in trials in anxiety models.78
Management
Management of central fatigue needs to be tailored for the
best possible outcome. Lifestyle changes are pivotal, and
the patient’s doctor should advise against either too much
rest or attempted overactivity to beat fatigue. Alcohol
worsens central fatigue and should be avoided.
Pharmacological treatment of pain, poor sleep, muscle
spasticity, and involuntary muscle activity is very
important because these physiological variables affect
severity of fatigue. Low doses of tricyclic antidepressants
(amitriptyline, imipramine, or trazodone), antiepileptics
(carbamazepine, gabapentin, or valproic acid), short-
acting benzodiazepines (clonazepam), or baclofen are
frequently used, sometimes in combination. In some
patients, acupuncture and transcutaneous nerve
stimulation can be useful adjuncts for pain control.
Shorter acting benzodiazepines could also be effective for
nocturnal myoclonus and periodic limb movements
during sleep in central fatigue.25 The doctor has to be
careful not to inadvertently aggravate existing fatigue.
regularly prescribed codeine-containing analgesics, long-
acting benzodiazepines, and most frequently used
tranquillisers—should be avoided.
Treatments for central fatigue directed to physiological
components of underlying disease are limited.
Aminopyridines (also used for treatment of Lambert-Eaton
myasthenic syndrome) are effective in fatigue associated
with multiple sclerosis.79 Amantadine—originally developed
as an antiviral for the influenza virus—is probably the most
effective pharmacological treatment for fatigue with
multiple sclerosis, with benefit reported in nearly a third to
half of all treated patients, although trials were done in few
patients and might have been biased.80 Pemoline, a centrally
active sympathomimetic, has been recommended for
fatigue in multiple sclerosis but is less effective than
amantadine, and no benefit has been shown versus
placebo.81 Methylphenidate has been used occasionally in
fatigued patients with multiple sclerosis and multiple
system atrophy. In a double-blind randomised trial,
pydriostigmine for treatment of postpoliomyelitis fatigue
was of no benefit.82 Bromocriptine, an indirect dopamine
agoinst, was judged helpful in a small double-blind,
placebo controlled trial,83 but in a double-blind placebo-
controlled trial, amantadine was no better than placebo
for fatigue in postpoliomyelitis patients.84 Modafinil is a
central stimulant drug and is the first line of treatment for
excessive daytime sleepiness and in narcolepsy. It seems

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For personal use. Only reproduce with permission from The Lancet.
 REVIEW
to be an effective treatment for fatigue and somnolence in
patients with multiple sclerosis,85,86 Parkinson’s disease,
and myotonic dystrophy, but larger trials are needed
before its efficacy can be confirmed.
Affective components of fatigue might respond to
antidepressants, cognitive behaviour therapy, or a
combination of both. In theory, appropriately structured
cognitive behaviour treatments can improve motivation
and keep perceptive changes to a minimum in fatigued
patients. However, this therapy does not reverse
physiological outcomes of the underlying disease
process. In a study in depressed patients, post-treatment
increases in basal ganglia blood flow were recorded
with interpersonal psychotherapy and venlafaxine (an
antidepressant that selectively inhibits reuptake of
norepinephrine and serotonin), but only psychotherapy
enhanced limbic blood flow.87 Sometimes, depression and
anxiety arise from social circumstances, loss of
employment, and failure to fulfil family responsibilities.
Appropriate social support and occupational rehabilitation
is therefore integral to successful management of fatiguing
neurological diseases.
Level of physical activity is a key issue in management
of fatigue. Patients are likely to be sedentary because of
associated disabilities (eg, weakness and pain), reduced
level of physical endurance, and deterioration of
symptoms that could follow physical exertion. However,
physical inactivity imposed by fatigue leads to chronic
cardiovascular and muscle deconditioning and raised
health risks. A regular pattern of activity is generally
encouraged in all patients: the amount undertaken
should be modest, spread throughout the day, with
greater emphasis on regularity not on level of
performance. Input from therapists can help in
assessment of the level of disability and to identify an
acceptable range of daily physical activity to prevent
physical deconditioning and resultant weakness and
muscle wasting. Physical inactivity has a small but
significant effect of destabilising the chronically enlarged
motor units in muscles that were acutely denervated.88
However, in postpoliomyelitis patients, results of exercise
studies suggest that excessive physical activity and
prescribed exercise have a detrimental effect on fatigue
and level of physical endurance,89 probably because of an
accelerated rate of decline in function of the surviving
motor units.90
Clearly, large randomised treatment trials need to be
done in fatigue, especially in patients with multiple
sclerosis, poststroke fatigue, postpoliomyelitis fatigue, and
chronic fatigue syndrome. Although early results of
cognitive behaviour therapy and graded exercise in
chronic fatigue syndrome seemed promising, little
information is available about the effectiveness of these
interventions for fatigue in the long term, in children and
in severely disabled patients.42 Non-pharmacological
interventions (psychotherapy and exercise) can improve
quality of life, mainly because of improved psychosocial
function91 rather than amelioration of fatigue. Because of
the limitations of self-reported questionnaires as valid
outcome measures in fatigue, we must use additional
methods—eg, serial neuroimaging, neuropsychological
assessments—in future trials to capture real treatment
effects.
Conclusions
Many doctors prefer to invoke a psychiatric explanation
for fatigue when patients’ symptoms do not fit a typical
medical or neurological diagnostic category. Classic
descriptions of major psychiatric disorders have been
986
For personal use. Only reproduce with permission from The Lancet.
fairly consistent, and when a patient with fatigue
perfectly fits criteria for a psychiatric disorder,92 one can
certainly have confidence in the diagnosis. However,
when a patient’s symptoms or clinical course do not fit
diagnostic criteria, one needs to be cautious.93 We know
that brain-derived central fatigue is related to circuits
that connect basal ganglia, amygdala, thalamus, and
frontal cortex.27,32 To imply that fatigue is a medically
unexplained, non-organic symptom in patients who do
not have a primary psychiatric diagnosis would be
incorrect and inappropriate. As in other complex
medical disorders, only open minded people—who are
willing to consider observations and explanations at
many different levels—are likely to succeed in offering
the right solutions.94
Conflict of interest statement
None declared.
Acknowledgments
We thank the David and Frederick Barclay Foundation for supporting
fatigue research in neurological diseases; and the following colleagues
who reviewed the manuscript and gave us advice on their areas of
expertise: W M H Behan (professor of muscle pathology, University of
Glasgow, Glasgow, UK); T G Dinan (professor of clinical pharmacology
and therapeutics, University College, Cork, Ireland); and R L Bruno
(director, Post-Polio Institute and International Centre for Post-Polio
Education and Research, Englewood Hospital and Medical Center, New
Jersey, USA).
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Uses of error
Surprising post mortems
Martin M Brown
As a young surgical houseman, I admitted a 45-year-old
man after a phone call from his general practitioner (GP),
who said the patient had complained of abdominal pain
and then collapsed. The GP had told me that the man was
in shock, with a low blood pressure and a thready pulse.
When I arrived on the ward to see the patient he was
sitting up in bed having his details taken by the admitting
nurse. In my enthusiasm to see the patient so well, I
brushed the nurse aside before she had even recorded the
patient’s name. To my surprise, there seemed to be
nothing wrong with the patient. He said he felt perfectly
well. His pulse and blood pressure seemed normal. I
unwisely dismissed the GP’s story and went off to see
another patient. An hour or two later, my first patient was
found dead in bed and could not be resuscitated. A post-
mortem examination showed that he had died from
gastrointestinal haemorrhage. It turned out the nurse had
never come back, we had no details for the patient, and
could not contact his family.
I learned several things from this experience. Firstly, the
routine recording of the administrative details about a
patient and the initial nursing observations should not be
interrupted. Secondly, the physiological adaptation to
reduced blood volume may result in a deceptively well
looking patient after an initial period of shock. I should
have taken more notice of the GP’s observations and
measured the patient’s standing, as well as lying, blood
pressure.
As a young neurology registrar, I had the privilege of
being almost completely unsupervised for several months
The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK (M M Brown FRCP)
988
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after the unexpected retirement of my consultant. It was
good experience to organise the service and see patients
unsupervised. However, with no one to check up on me, I
could have made many errors. One case in point was a
patient with severe neuropathy, who happened to be on a
cardiac ward with heart block. I had no idea of the cause
of his neuropathy until the patient eventually came to post
mortem, which showed systemic amyloidosis.
We could have made the diagnosis by nerve biopsy and
possibly alleviated his condition. It was difficult to link
together two apparently unrelated clinical signs and often
it was only the experience of having seen the combination
before, which led to the diagnosis of rare disorders. Today
however, I can type neuropathy and heart block into a
MEDLINE search engine and the first reference describes
a case of amyloid neuropathy, emphasising the value of
information technology in diagnosis. I decided then that it
was wrong that junior doctors should see ward referrals
and new patients unsupervised. On Royal College visits
we now assess both the adequacy of the trainees’
supervision and their access to the internet.
What can be learnt from my errors? Firstly, I often only
found out about my mistakes when someone else had seen
the patient. Secondly, post-mortem examination often
reveals a surprising diagnosis, even when the clinician
feels sure of the diagnosis after investigation. Thirdly, to
learn from mistakes requires feedback. Regular audit is
essential, and a mechanism to feed back a revised
diagnosis to the previous doctors looking after the patient
would be beneficial.
THE LANCET • Vol 363 • March 20, 2004 • www.thelancet.com