Neurological Dysfunction in Chronic Fatigue Syndrome
Journal of Chronic Fatigue Syndrome, Vol. 6, No. 3/4, 2000, pp. 51-68

Abhijit Chaudhuri, DM, MD, MRCP; Peter 0. Behan, DSc, MD, FACP, FRCP

© 2000 by The Haworth Press, Inc. All rights reserved.

SUMMARY.
Chronic fatigue syndrome (CFS), popularly known in Europe as myalgic
encephalomyelitis (ME), is a common but not a new illness. CFS/ME was
classified as a neurological disease by the World Health Organisation in
1993. Neurological dysfunction is considered the principal mechanism of
both physical and mental fatigue in this condition. This article reviews
the neurological symptoms of the epidemic and sporadic forms of the
illness. Paroxysmal changes in the severity of symptoms (fatigue and
neuropsychiatric) are the hallmark features in the natural history of this
disease. Ion channel abnormality leading to neuronal instability in
selective anatomical pathways (basal ganglia circuitry) is proposed as the
possible mechanism of fluctuating fatigue and related symptoms in CFS.


KEYWORDS. Ion channels, myalgic encephalomyelitis, basal ganglia


INTRODUCTION.
Chronic fatigue syndrome (CFS) is a common disorder, occurring worldwide.
It is however, not a new illness and had probably existed in the papyrus
Ebers (circa 1400 BC) (1). Early cases of this syndrome were only recorded
during epidemic outbreaks. The first epidemic of CFS to strike the Western
civilisation dates back to the time of Henry VIII in England when one of
his wives, Anne Boleyn, fell ill during an attack of what was called the
“English Sweats” (2). In the nineteenth century, neurasthenia was the
popular name for this illness, introduced by a New York neurologist,
George Beard (3). In the middle of the twentieth century, neuromyasthenia
replaced neurasthenia as the preferred term to take into account the
muscle fatigue (myasthenia) that was an important symptom of this
syndrome. Sporadic, pre-epidemic and epidemic forms of neurasthenia were
already recognised in the late nineteenth century though it was the
epidemic form that was most common (4). The geographic location where an
epidemic had occurred provided names (e.g., Akureyri disease or Royal Free
Hospital Disease); in addition, the names often reflected the suspected
pathology of the illness (e.g., atypical poliomyelitis or
poliomyelitis-like disease, myalgic encephalomyelitis). It is the sporadic
form of the disease that is commonly encountered in present clinical
practice.

Neurological symptoms and subtle neurological signs are well recognised in
both the epidemic and sporadic forms of CFS (5). Neurological signs in
some of the well studied epidemic outbreaks were, however, more dramatic.
Another characteristic distinguishing feature of the epidemic outbreaks
was the rapid evolution of neurological symptoms within the first week of
the illness, often simulating poliomyelitis (6-8). We shall therefore
discuss the neurological dysfunction in the epidemic and sporadic forms of
CFS separately.

____________________________________

Abhijit Chaudhuri is Clinical Lecturer in Neurology and Peter 0. Behan is
Professor of Neurology (Retired), University Department of Neurology,
Institute of Neurological Sciences, Southern General Hospital, Glasgow G51
4TF, United Kingdom. Address correspondence to: Abhijit Chaudhuri (E-mail:
mailto:ac54p@udcf.gla.ac.uk ).

_____________________________________

EPIDEMIC FORM
Typically, the epidemic forms got underway in the early summer or late
autumn, a period when infections are common. All age groups may be
affected; however, few cases were seen under 12 years of age.  Observation
suggested spread by personal contact or by droplet infection. High attack
rate was consistently noted among nurses and ancillary institutional
personnel, an observation that may be valid also in sporadic cases (9).
Infection, either respiratory, diarrhoeal or meningitic, was the presumed
cause for epidemic neuromyasthenia and the incubation period was
calculated to be 5-7 days (10). Women outnumbered men and cardinal
manifestations clearly pointed to the involvement of nervous, muscular,
and reticuloendothelial system. Fatigue and lassitude were the hallmarks.
Fever and lymphadenopathy were present in a number of cases with the onset
of symptoms, supporting an infective aetiology.

Headache and dizziness appeared first; soon a myasthenic-like muscle
dysfunction was noted in all where repetitive muscle contraction produced
countenances of temporary weakness. This delay in muscle impulse
generation was considered to be cerebral rather than myoneural. Symptoms
of aseptic meningitis (photophobia, headache and normal cerebrospinal
fluid) were seen in some, and a few patients had more severe symptoms
suggestive of an encephalomyelitis with cranial nerve disturbances (ocular
and facial palsies), diplopia, nystagmus, myoclonus, palatal paralysis and
extensor plantar responses. Occasional cases appeared encephalopathic,
called “benign subacute encephalitis” by Jelinek (11). This encephalopathy
in the epidemic and sporadic disease was suspected to be toxic by workers
like Shelokov who considered enteric bacteria as a source of the
neurotoxin (12).

Neuropsychiatric symptoms were always present. These consisted of slowness
of thinking, speaking and reading; anxiety was very com-mon. Concentration
and visual attention were impaired; patients com-plained that one sentence
must be read and reread before it could be registered. Recent memory was
defective, calculation at times impossible and patients were unable to
attend to conversations or follow simple spoken instructions. Patients
frequently experienced restless-ness and insomnia at night and lethargy
and somnolence during the day. The reversal of sleep rhythm was most
severe during the first month. Other psychiatric symptoms included
disinhibited behavior  (emotional lability), weeping, irritability,
apprehension, depression andneurosis. Interestingly, many of these
symptoms, including weeping, occurred paroxysmally and were considered to
be predominantly or-ganic in origin.

In the cranial nerves, olfactory abnormalities have never been recorded.
Blurred vision, diplopia and tiredness on reading were common complaints.
Both pain and paresthesia were reported in the trigeminal distribution.
Nonatrophic, transient facial weaknesses were seen. The
auditory-vestibular nerve was probably the most frequently affected nerve.
Vertigo and dizziness were early symptoms. A clinical picture with vertigo
of sudden onset, usually accompanied by nausea, vomiting and followed by
symptoms of lassitude and fatigue was described with infective epidemics
dominated by gastrointestinal on respiratory infections (13). Vertigo and
incoordination led to loss of balance in stance and gait. Painful
dysphagia and heaviness of tongue (“glossoplegia”) were also mentioned.

In the sensory system, pain was common and usually appeared in the second
week, occurring in the muscles of the shoulder cap, neck, upper arm, back
or extremities. The pain was transient and migratory. But at times, both
pain and muscle spasm was severe enough to render muscles inactive,
seemingly paralysed. Hyperpathia and hyperalgesiawere common. Fog
suggested “vegetative neuritis” as the name for this neurological syndrome
(cited by Holt, 1965 [5]) to emphasise the frequent affection of the
autonomic nervous system. Symptoms in-cluded vasomotor instability,
angiospasm and secondary instability of body temperature with intolerance
to heat and cold.

Movement disorders were not uncommon in the epidemic forms of the disease.
Tremor was common and one epidemic was known by the descriptive term,
encephalitis tremens (14). Chorea or choreiform movements were recorded to
last as long as one year. Cogwheel rigidity was observed as well. Other
movement disorders recorded in the literature include myoclonus, myokymia
or fasciculations, torsiondystonia, and involuntary jerking. Hyperkinetic
movements at the beginning was often followed by bradykinesia or lost
motion, again to be replaced by hyperkinesia before resolution.

Provocative reports from the laboratory tests of epidemic neuromyasthenia
linking its association with an infective agent were claimed (15) but
whether the symptoms were the manifestation of a neurological infection
remained unproven. Although the possibility that epidemic neuromyasthenia
was a mass hysteria or psychoneurosis was espoused, this was dismissed by
most investigators and physicians other than the psychiatrists. Morbidity
was significant, relapses were characteristic and for several weeks or
months, the recovery period of most patients was characterised by fatigue,
emotional lability, with slow gradual recovery. Chronic relapsing course
was associated with exertion, inclement weather, menstruation in women and
stresses. Disuse atrophy of muscles was rarely observed. As relapses
recurred, apprehension, depression, anxiety and hostility complicated
patient’s illness. Death was extremely uncommon and when it occurred, it
was months after the onset of symptoms and unrelated to neuromyasthenia.
Pathological observations were inadequate but were reported to show
non-specific, haemorrhagic congestion of the cortex and meninges. The
lesions producing neural signs have never been demonstrated. However,
neurons of the deep subcortical areas, spinal cord and autonomic nervous
system were empirically implicated on clinical grounds.

In summary, epidemic neuromyasthenia had a distinctive clinical picture
consisting of “headache, myalgia, myasthenia, encephalopathy,
lymphadenopathy, relapse, morbidity and survivance” (5). It was; however,
not strictly a monophasic illness since six years after the Akureyri
outbreak, clinical findings in survivors showed persistence of fatigue,
muscle pain, nervousness and disturbances of skin sensitivity (16),
symptoms that are commonly present in patients with the current diagnosis
of CFS acquired sporadically.

SPORADIC FORM
The sporadic cases differ in the severity of their neurological symp- toms
from the epidemic group. Neurological examination in these patients are
more often normal. Only partly this difference may be related to the fact
that patients are diagnosed at least six months after the onset of their
symptoms to fulfill the current case definition of CFS (17). Like the
epidemic form, more women than men are affected with sporadic CFS (18).
The onset may be acute in up to one-third, occurring over hours to days
but more subacute or insidious in the rest. Preceding infections, commonly
viral, may be seen up to 80% of patients, often during a period of severe
physical or mental stress (18). Only a minority of cases report no clear
cut precipitating events. However, compared to the epidemic forms,
sporadic CFS has less favourable prognosis (19).

Fatigue is indeed, the most important and central symptom of CFS. The
fatigue is not only physical but also mental. Typically, there is
significant post-exertional worsening of fatigue lasting for more than 24
hours and continuing for 48-72 hours, even up to 7 days. The type of
fatigue exhibited by patients with CFS is different from the peripheral
neuromuscular type of fatigue; on the other hand, fatigue symptoms in CFS
patients are very similar to that seen in patients with MS or Parkinsonian
disorders (20). We have termed this type of fatigue in chronic
neurological disorders as “central fatigue” that is characterised by the
presence of both physical and mental fatigue unlike the fatigue of
peripheral neuromuscular disorders (e.g., myasthenia gravis or metabolic
myopathies) where mental fatigue is either absent or seldom conspicuous.
Although it is intuitive to assume that the mechanism of physical and
mental fatigue that together constitute “central fatigue” in CFS must be
same and come from the central nervous system, a peripheral contribution
to the physical fatigue in CFS has never been satisfactorily excluded,
especially in post-exertional fatigue lasting longer than 24 hours.
Additionally, an early neurophysiological study in CFS patients had found
increased jitter in single fibre electromyography (SFEMG) suggestive of
abnormal neuromuscular conduction (21) that could not be later
reduplicated. In this respect, physical fatigue in CFS was considered
similar to the fatigue in post-polio syndrome (PPS) where increased jitter
in SFEMG is demon-strable (22) and both peripheral (22) and central (23)
role in post-polio fatigue symptoms have been speculated.

Physical fatigue: That the physical fatigue in CFS is exclusively or
predominantly central is primarily supported by four sets of observations
(24-28). First, CFS patients have delayed central motor conduction similar
to that seen in MS patients (24). Second, there is delayed post-exercise
facilitation of motor evoked potentials in CFS (25). Third, inability of
CFS patients to fully activate skeletal muscles during intense, sustained
exercise despite normal muscle membrane function, excitation-contraction
coupling, intracellular and systemic metabolism (26). Fourthly, lack of
sufficient histological evidence of skeletal muscle injury (27) or
dysfunction (28) in the muscle biopsies of CFS patients.

Peripheral role in sustaining the physical component of fatigue in CFS or
prolonging the post-exertional fatigue, first suspected from the
observation of increased jitter in SFEMG (21), was supported by the
evidence of abnormal oxidative metabolism of muscles (29) further
confirmed by the phosphorus nuclear magnetic resonance spectroscopy (30,3
1) and finally, by the recent demonstration of mild aerobic defects in the
cultured (in vitro) myoblasts from the skeletal muscles of CFS patients
(32).

In a recently published article (33), 10 CFS patients and 10 control
subjects were studied by an isometric fatiguing exercise test. During the
exercise period, the maximum voluntary contractions (MVC) of the
quadriceps were significantly higher in patients than in controls but both
groups showed a parallel decline in force in keeping with a similar
endurance capacity. Recovery was prolonged in the patient group but in
addition, CFS patients showed a reduced MVC initially during the recovery
after exercise and also at 24 hours unlike the control group who achieved
initial MVCs during recovery comparable to the exercise period. This
observation clearly suggests that CFS patients may have a centrally
dependent “fatigue at rest” to account for the baseline difference of MVC
before exercise; a similar endurance capacity in patients and controls
during exercise would exclude any oxidative defect in muscles. However,
the difference in the initial MVCs at the recovery phase and at 24 hours
may be interpreted to suggest a defective peripheral mechanism related to
“recharging” the muscle (resynthesis of the substrate and energy
molecules, i.e., glycogen and ATP). However, decreased post-exercise
facilitation of the motor evoked potentials in CFS on the other hand would
suggest reduced post-exercise cortical excitability (25) and a central
cause for post-exertional malaise. Another evidence that supports a
central role (depressed cortical excitability) in post-exertional fatigue
comes from the study of cognitive performance of CFS patients after
exercise. As compared with healthy individuals, CFS subjects demonstrated
impaired cognitive processing immediately and 24-hours after an exhaustive
treadmill exercise although no differences were seen in the pre-exercise
cognitive tests between the patients and healthy controls (34).

Thus, present data clearly point to a dominant central mechanism in the
symptom of physical fatigue in CFS, both at rest and after exertion.
Nevertheless, is it possible to reconcile the divergent views regarding
the causation of physical fatigue in CFS (central vs. peripheral)? One
explanation is that a basic metabolic or cellular defect that is variably
expressed in the excitable tissues (nerves and muscles) can possibly
account for this difference. Dysfunctional ion channels or disorders of
mitochondrial respiration in CFS may, indeed, provide such a basis.

Mental fatigue: The neuropsychiatric symptoms in sporadic CFS are broadly
similar to those seen during the epidemics though again, symptoms are slow
in evolution and commonly less dramatic. The spectrum of the reported
cognitive deficits include anomia, short-term memory and concentration
difficulties. The degree of symptomatology may vary, but at its most
severe form, CFS patients may be forced to abandon all intellectual
pursuits and children with CFS discontinue schooling. Indeed, CFS is
considered to be one of the commonest reasons for long-term sickness
absence from school in UK (35). Some patients with CFS develop
hypergraphia, i.e., keeping the most detailed records and long
descriptions of all their symptoms and come to the clinic with
interminable notes. Functional neuroimaging studies with PET (36) and
SPECT (37,38) scans were abnormal both in children and in adults with CFS
although the perfusion abnormalities were not specific or unifocal (39).

In our experience, anomia, reduced attention span (for both verbal and
visual tasks), and concentration difficulties constitute the triad of
cognitive dysfunction in CFS. These symptoms are always worse during and
after any sustained physical and emotional stress. CFS patients are slower
in psychomotor tasks, have impaired attention, slower retrieval from
semantic memory, slow logical reasoning and show increased visual
sensitivity (40). Interestingly, CFS patients with no concurrent
psychopathology often have the greatest degree of neuropsychiatric
impairment (41).

In a recently concluded trial of a large cohort of CFS patients, as
compared to the age matched controls, baseline cognitive performance
testing showed clearly impaired concentration, significantly slower speed
of memory with preserved quality of memory. Significant prolongations of
the N2 and P3 components with prolonged reaction time was found in the
endogenous potential study of CFS patients (42). In another study,
selective impairment of the auditory-task processing relative to the
visually processed task was noticed in CFS patients when compared to
patients with multiple sclerosis and controls (43).

Some workers consider the cognitive impairment in CFS supportive of a
diffuse encephalopathic process of metabolic origin (41). There may be a
correlation between the white matter abnormalities in the MRI brain scan
and functional impairment in CFS (BH Natelson, personal communication).
There is also evidence that hormones and neurotransmitters may play a role
since in women with CFS, there is striking exacerbation of not only
physical, but also mental symptoms during the menstrual phase. Women
“whose menstrual phase had not been previously marked by
hyper-irritability and emotional tension complained that they could not
control themselves and flew into rages at what they realised were really
insignificant frustrations and annoyances” (44).

Sleep: Unrefreshing sleep is a characteristic symptom in an average
patient with CFS. At the beginning of the syndrome, patients are more
often hypersomnolent and sleep for prolonged periods both during the day
and night. Subsequently, these patients develop altered sleep rhythm with
frequent, short periods of sleepiness during day time and have poor night
time sleep. CFS patients also experience difficulty in falling asleep with
broken sleep pattern and vivid dreams. Disordered sleep pattern, however,
is not the cause of fatigue in CFS. Significant abnormalities in the
polysomnographic studies of CFS patients are seldom seen (45). In one
study, the quality of rapid-eye-movement (REM) sleep was similar in CFS
and healthy controls (46). However, CFS patients have higher levels of
sleep disruption, by both brief and longer awakenings. The mechanism of
sleep disorder in CFS is not properly understood but possible explanations
include (i) hypothalamic disorder causing circadian dysrhythmia and (ii)
imbalance of neuro-transmitters, especially affecting acetylcholine and/or
serotonin.

Cranial nerves: Although an abnormality of the olfactory-limbic pathway is
postulated in patients with multiple chemical sensitivities (47) (often
sharing similar symptoms with CFS), olfactory symptoms are not reported by
CFS patients. Visual symptoms, however, are relatively common. These
include oscillopsia, photophobia and migrainous visual scotoma or
temporary visual obscurations. In a study of patients with chronic primary
fibromyalgia combined with dysesthesia, abnormal smooth pursuit and
saccadic movements were documented in a high proportion of patients as
opposed to controls, suggestive of subtle brain stem dysfunction (48).
Perioral paresthesia and hemifacial sensory symptoms are less frequently
reported (see below).

Vertigo is common and acute episodes in a CFS patient may last for a week
to 10 days on average. Some CFS patients suffer from frequent spells of
vertigo with gait disorder and dysequilibrium as the major physical
symptom besides fatigue, similar to the sufferers of epidemic vertigo
(“Pedersen’s syndrome” [131). A study of the vestibular function test
demonstrated several abnormalities in CFS patients. They had poor
performance in dynamic posturography, with greater number of falls and a
reduction in the earth-vertical-axis (EVA) rotation gain. The CFS group,
in addition, had abnormal optokinetic nystagmusduring the course of the
test. These results were interpreted to be more suggestive of central
rather than peripheral vestibular dysfunction (49).

Motor symptoms: Short episodes of unexplained weakness affecting both
legs, an arm or one side of body are described by some CFS patients who,
on examination, very seldom show any evidence of persistent motor
weakness. Myokymia or benign muscle fasciculations are often reported in
the early phase of the illness. Muscle stretch reflexes are always
preserved and are usually brisk. Unlike some of the epidemic cases,
plantar responses are invariably flexor in CFS. Postural hand tremors are
common and occasional patients may appear Parkinsonian. Rarely, myoclonus
may be a symptom, probably as a result of the supersensitive or
hyperactive serotoninergic (5HT1A) receptors in the brain stem and the
spinal cord.

Gait kinetic studies at slow walking speed and short periods of running in
CFS patients had revealed a number of defects as compared to the sedentary
controls. Run time was significantly slower in CFS patients who also had a
smaller ratio of stride length divided by leg length and smaller knee
flexion during stance and swing phases than controls (50). Another recent
study confirmed the alteration of spatial-temporal parameters of gait in
CFS patients (51). Interestingly, abnormalities were present from the
beginning of the gait, which indicated that they were unlikely to be
caused by the rapid increasing fatigue. This observation further
strengthens the notion of a direct involvement of the central nervous
system in CFS.

Sensory symptoms: These are extremely common. Both diffuse muscle aches
and pain as well as fibromyalgia are frequently reported. New-onset daily
headache, often migraine-type, is another common symptom. Persistent or
paroxysmal hemi-paresthesia, altered acral perception of thermal
sensations (at times with reversal of cold and hot) and symptoms very
similar to migratory neuropathy can be seen in CFS patients. Patients with
ciguatera fish poisoning display symptoms of fatigue, perioral paresthesia
and altered thermal sensibility identical to those reported by CFS
patients (52). Ciguatera toxin, however, is a sodium channel inactivator
(53) and some of the sensory symptoms in these patients are considered to
be due to the sodium channel blockade in the nerves (52).

Autonomic symptoms: Vagal affarent tone was found to be reduced during
paced breathing in CFS patients (54). Abnormal response to upright table
tilt testing was frequently observed in a study (55). This phenomenon,
called neurally mediated hypotension, led to the development of severe
presyncope with warmth, light-headedness, nausea and sweating in the
tested CFS patients. Other symptoms of dysautonomia in CFS patients
include orthostatic changes in blood pressure (10-20 mm Hg), paroxysms of
sweating especially at night, abnormal colonic motility (similar to
irritable bowel syndrome), increased frequency of urination, erectile
dysfunction in men and dysparuenia in women. A sympathetic overactivity
was observed in CFS patients when they were exposed to stress (56).

Alcohol intolerance: Alcohol intolerance, leading to an early “blackout”
or a next day severe hangover is common in CFS patients, many of whom are
forced to abandon their social drinking. Although the mechanism of alcohol
intolerance in CFS patients has not been understood, serotonin
supersensitivity may be a likely explanation since it has been proposed
that alcoholic blackouts result from a disorder of central serotoninergic
neurotransmission. Plasma levels of the serotonin precursor, tryptophan,
are decreased in male alcoholics with history of blackouts due to ethanol
intoxication (57) and a trial of serotonin reuptake inhibitor zimelidine
had shown improvement in memory function in moderately intoxicated
subjects (58).

Neuroendocrine changes: Abnormalities of neurohypophyseal function has
always been suspected in CFS patients. Indeed, abnormal water excretion,
idiopathic cyclic oedema, sleep disorder, irregular menstrual cycles,
fluctuations in weight and autonomic symptoms in CFS patients led to an
extensive evaluation of multiple neuroendocrine axes and testing for the
anterior and posterior pituitary functions. These showed a variable
subsensitivity of CFS patients to vasopressin, supersensitivity to
serotonin (and possibly to acetylcholine and dopamine) but most
consistently, a hypoactive hypothalamic-pituitary-adrenal (UPA) axis (18).
This hypoactive HPA axis is considered the basis for poor stress response
(“cowering response”) in CFS patients and is also responsible for the
generation of pro-inflammatory cytokines that may exacerbate symptoms like
asthma (59). Chocolate craving is another interesting symptom seen in
approximately a third of all CFS patients (usually women) some of whom
also report mood changes dependent on day-light exposure similar to the
patients with seasonal affective disorder, a condition caused by low
serotonin levels (60). In summary, the neurological symptoms of chronic
fatigue syndrome appear to be multifocal, almost exclusively central and
autonomic with some peripheral features. These symptoms are not uniform
and in a given case, all the symptoms, including fatigue, may fluctuate in
their severity. This variability of symptoms in CFS forms the basis of the
experience of “good days” and “bad days” reported by an average patient.
The fluctuation of symptoms, including fatigue, is the hallmark of CFS.

THE MECHANISM OF NEUROLOGICAL DYSFUNCTION
It is difficult, in the confines of the established disease models, to
offer a simplistic explanation for the neurological dysfunction seen in
patients with the epidemic and the more common, sporadic form of CFS. A
dysfunctional ion channel affecting neurotransmitter release or cytokine
function is one of the possible explanations (61). However, it is also
important to identify the neuroanatomic pathways where dysfunctional ion
channels are operative.

The anatomy of chronic fatigue: In many ways, post-polio syndrome (PPS) of
fatigue still remains an useful paradigm to explore the mechanism of
fatigue in CFS. The neuropathology and research in this area have clearly
pointed to a central role of fatigue that has been supported by a recently
failed trial of pyridostigmine in improving the symptom of fatigue in PPS
despite the fact that peripheral neuromuscular conduction had improved in
treated patients (as measured by jitter in SFEMG) (62). Post-mortem
examination performed 50 years ago showed selective damage to the midbrain
reticular formation, substantia nigra, thalamic, hypothalamic and caudate
nuclei, putamen, globus pallidus and locus ceruleus caused by poliovirus
infection (63). Role of basal ganglia in fat igue mechanism is also
supported by the observation of fatigue in patients with idiopathic
Parkinson’s disease (PD) that is characterised by the loss of
melanin-containing neurones in the substantia nigra pars compacta. Fatigue
in PD is extremely common and is often considered a “warning sign” of
oncoming PD since it may antedate the development of motor symptoms by
several months. Patients symptomatic of the Parkinsonian triad (rigidity,
bradykinesia and tremor) demonstrate rapid fatiguability of motor tasks
(64).

We believe that basal ganglia pathways are involved in the mechanism of
the chronic fatigue symptoms that comprise of both physical and mental
fatigue. This is not identical with the brain-fatigue generator model in
PPS proposed by Bruno et al. (65) but shares the similar view that the
central fatigue is due to a failure of normal cortical and brainstem
activation process. Given the complexity of the basal ganglia circuitry
and neurotransmission, it would be naive to suggest that a single
neurotransmitter abnormality or loss of a single projection system in the
basal ganglia would be responsible for central fatigue (comprising
symptoms of both physical and mental fatigue).

The interaction between ion channels, neurotransmitters and specific
neuroanatomical network: Paroxysmal disorders like idiopathic epilepsy and
common migraine provide important models for CFS where fatigue symptoms
fluctuate on a day to day basis. In common migraine, paroxyms of headache
are produced by an interaction between altered ion channel (calcium)
excitability and neurotransmitter (serotonin) sensitivity acting on a
specific anatomic pathway (trigeminovasscular and hypothalamic). In
idiopathic epilepsy, both voltage-gated (potassium and sodium) and
ligand-gated (nicotinic acetylcholine and NMDA-subtype) ion channels are
considered responsible; the neurotransmitters involved are either an
excess of glutamate (excito-toxic) or deficiency of GABA (inhibitory). The
neuranatomic pathways are cortical foci, thalamus and cortical projection
system to the other brain areas and the reticular activating system.

We propose that a similar model of pathogenic mechanism is responsible for
the symptoms in epidemic neuromyasthenia, myalgic encephalomyelitis and
the sporadic form of the same illness currently known as CFS. Throughout
this review, we have emphasised the nature of paroxysmal changes in the
severity of symptoms, both physical and mental fatigue and the
neuropsychiatric changes, that were well recognised in the epidemic
outbreaks of the illness (5) and are commonly experienced in the sporadic
form (61) of CFS. Based on our previous work, we suspected potassium ion
channels to be the key players and the alteration of the neuronal
excitability caused by potassium channelopathy as the basis of the
fluctuating nature of CFS symptoms (61). An ion channel dysfunction in CFS
will also explain the phenomenon of increased jitter in SFEMG that was
postulated to be due to the abnormal muscle membrane function in the
original study (21). We, however, acknowledge the role of basal ganglia as
the neural integrator for the motor and motivational aspects of higher
cortical and limbic activities (66) and we believe that a failure of this
function, induced by an interaction between the ion channels and
neurotransmitters, will cause CFS while the fluctuations in the symptom
severity are caused by ion channelopathy altering the neurotransmitter
signals to the excitable tissues. The neurotransmitters that are directly
involved are serotonin, dopamine and acetylcholine or more appropriately,
a balance between these three neurotransmitters within the basal ganglia
network. The final result is a shift in the neuronal excitability of the
cortical, limbic and brainstem areas giving rise to the characteristic
constellation of symptoms seen in CFS. Downregulation of the
hypothalamic-piltuitary-adrenal (HPA) axis in CFS is probably a secondary
phenomenon and an adaptive response to the changes in the neurotransmitter
system rather than the primary event responsible for the fatigue symptoms.
Immunological dysfunction and aberrant cytokine responses in CFS (18) are
likely to be the consequences of this alteration in the HPA axis (59).

CONCLUSION
The anatomical pathways and the chemical substrate for fatigue in the
disorders of central nervous system are not fully understood. There is
extensive, bidirectional linkage between the basal ganglia and cerebral
cortex that includes several functional and anatomically distinct circuits
regulating motor activity and more complex cognitive bahaviours. Basal
ganglia are involved in the higher order, cognitive aspects of motor
control and these neurons also influence many other functions through
their extensive connections with the association cortex, hypothalamus and
limbic structures (66).

Alteration in the normal flow of sequential activation within the basal
ganglia system affecting the neural integrator will cause central fatigue.
This would probably the result of a combination of events that may include
structural damage to basal ganglia (e.g., in encephalitis lethargica), ion
channel dysfunction (chronic ciguatera poisoning) or altered
neurotransmitter balance (Parkinson’s disease), acting either singly or in
combination. Central-type fatigue may occur transiently in the setting of
an inherited ion channel disease (channelopathy), as in paroxysmal
dyskinesias and more persistently, in acquired neurodegenerative diseases
like PD.

In this paper, we are proposing a complex interaction between ion
channels, neurotransmitters and specific neuroanatomic areas in the brain
to be responsible for central fatigue in CFS comprising the symptoms of
both physical and mental fatigue. This is not a new model since comparable
mechanisms of pathogenesis are currently accepted for common migraine and
idiopathic epilepsy, the latter thought to be a psychiatric illness until
the second half of the twentieth century. A better understanding of the
anatomy and neurotransmission of the basal ganglia pathways would be
extremely important in the therapeutic management of central fatigue.
Unraveling the neurobiology of basal ganglia and their interaction with
ion channels and neurotransmitters integrating motivation, motor and
emotional activities will have important connotation not only in the
treatment of CFS but also in PD, PPS and MS.

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