Episodic brain disorders

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The hypothalamus in episodic brain disorders

Sebastiaan Overeem, Jorine A van Vliet, Gert J Lammers, Frans G Zitman, Dick F Swaab, and Michel D Ferrari

Episodic brain disorders (EBD) form an intriguing group of
neurological diseases in which at least some of the
symptoms occur in attacks. The hypothalamus integrates
many brain functions, including endocrine and autonomic
control, and governs various body rhythms. It seems a likely
site in which the initiation of attacks of EBD can be
modulated. Indeed, the hypothalamus has a crucial role in
EBD such as narcolepsy and cluster headache. The same
may be true for migraine and depression. Here we
summarise the evidence supporting an important role for the
hypothalamus in the initiation of disease episodes in various
EBD. Study of the various pathophysiological concepts of
EBD within the context of the hypothalamus may prove a
fruitful example of cross-fertilisation between various
research areas.
Lancet Neurology 2002; 1: 43744
Episodic brain disorders (EBD) are a fascinating group of
neurological disorders that share a recurrent paroxysmal
presentation or exacerbation of symptoms. Some of these
disorders, such as migraine and depression, are highly
prevalent and rank among the top 20 causes of disability in
the world.1 Others, such as narcolepsy and cluster
Maximum A Maximum B
Symptoms
headache, are much rarer but are by no means trivial to the
patient.
The term episodic usually refers to the occurrence of
symptoms in attacks separated by symptom-free intervals
(figure 1). However, episodic may also refer to the
exacerbation of continuously present mild symptoms (eg,
sleep attacks in narcoleptic patients with a continuously
low level of arousal; figure 1) or to the acute occurrence of
new symptoms superimposed on other chronic symptoms.
The duration of episodes can vary widely, from seconds
(eg, cataplexy) to months (eg, depression; figure 1).
Finally, attacks can occur regularly with attack-free
intervals of more or less regular duration (eg, migraine
attacks that occur only during the menstrual period), or
may be clustered in periods of many daily attacks
alternating with periods of months to years of complete
freedom from attacks (eg, episodic cluster headache,
figure 1).
Although the group of EBD includes clinically very
different syndromes, they seem to share some
pathophysiological mechanisms. Here, we propose that the
hypothalamus has a pivotal role in the modulation of
initiation of attacks in at least some EBD. We focus on the
clinical and mechanistic aspects of two EBD with
proven hypothalamic involvement
(narcolepsy and cluster headache)
and two with a likely involvement of
the hypothalamus (depression and

Symptoms

migraine). In addition, we briefly

discuss a few other disorders with
hypothalamic and (partly) episodic
symptom patterns, such as Prader-
None None Willi syndrome.
Time (days) Time (days)

Maximum C Maximum D
SO and GJL are members of the
Narcolepsy Research Group, MDF and
Symptoms

Symptoms

JAvV are from the Leiden Headache Group

at the Department of Neurology, and FGZ
is at the Department of Psychiatry, Leiden
University Medical Centre, Leiden,
None None Netherlands. DFS is at the University of
Amsterdam and the Netherlands Institute
Time (months) Time (days) for Brain Research, Amsterdam,
Weeks Months Netherlands.
to years
Correspondence: Prof Michel D Ferrari,
Department of Neurology, Leiden
Figure 1. Various ways in which the symptoms of episodic cerebral disorders present themselves University Medical Centre, PO Box 9600,
through time. A: Disease attacks with symptom-free intervals. B: Exacerbations superimposed on a 2300 RC Leiden, Netherlands. Tel +31 71
continous background of symptoms. C: Very long disease episodes. D: Paroxysmal symptoms 5262895; fax +31 71 5248253;
clustered in periods. email M.D.Ferrari@lumc.nl

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 Personal view
Figure 2. Midsaggital section through the hypothalamus and pituitary,
showing the various hypothalamic nuclei. AHA=anterior hypothalamic area;
ARC=arcuate nucleus (infundibular nucleus); DMN=dorsomedial nucleus;
LHA=lateral hypothalamic area; PHA=posterior hypothalamic area;
PON=preoptic nucleus; PVN=paraventricular nucleus;
SCN=suprachiasmatic nucleus; SON=supraoptic nucleus,
VMN=ventromedial nucleus.
The hypothalamus
The hypothalamus (figure 2) is the main centre for the
integration of endocrine functions, autonomic responses
and behaviour, and governs the rhythmicity and timing of
many body functions.2,3 Despite its small mass (4 g), no
other brain structure contains so many different
specialised cell groups.2,3
The endocrine system
The hypothalamus controls the endocrine system in three
different ways. First, there is direct secretion of
neurohormones into the systemic circulation from the
posterior pituitary gland. Second, regulatory hormones are
released in the local portal circulation and control
the production and systemic release of hormones
from the anterior pituitary. Third, all endocrine
organs, including adipose tissue, are innervated by
the autonomic nervous system, which is also influenced
by the hypothalamus.4,5 Most hormones are secreted
438 THE LANCET Neurology Vol 1 November 2002
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Episodic brain disorders
in a pulsatile way, with plasma concentrations
showing variations not only on a daily scale, but also
with periods of minutes to seasons.
Autonomic and behavioural functions
The hypothalamus influences behaviour through neuronal
connections with other areas of the brain and by
altering endocrine and autonomic function. Autonomic
functions controlled by the hypothalamus include
the regulation of body temperature, blood pressure,
bodyweight, vigilance states, and pain perception.
Together with the metabolic rate, the motivational drive
to feed is a cornerstone in the maintenance of energy
homoeostasis and consequently bodyweight. Although
the hypothalamus has long been known to be crucial
to the regulation of appetite and energy homoeostasis,
the unravelling of the cell groups involved
and their connections has particularly gathered speed in
the past decade.6,7 The feeding-related nuclei all act together,
using many neurotransmitters, to form a highly complicated
network, the properties of which are just beginning to be
elucidated.6,7 Several peripheral signals (such as leptin and
ghrelin) indicate the amount of stored energy and feeding
status to the hypothalamus.810
In 1930, von Economo11 predicted the role of
the hypothalamus in the regulation of sleep and arousal
on the basis of studies of patients with encephalitis lethargica.
He suggested that the region near the optic chiasm
would contain sleep-promoting neurons and the
posterior hypothalamus would harbour neurons
that promote wakefulness;11 the networks that integrate these
functions are also found in the hypothalamus.12
The regulation of pain perception is yet another function
in which the hypothalamus plays a part. Thermal destruction
of the ventromedial region of the posterior hypothalamus in
rats results in a transient hyperalgesia,13 whereas electrical
stimulation of the hypothalamus can relieve pain.14,15 Several
hypothalamic peptides have either antinociceptive effects (eg,
calcitonin and fragments of the opiomelanocortin family) or
nociceptive effects (substance P and cholecystokinin).1618
The biological clock
One important function of the hypothalamus is the initiation
of body rhythms. The most apparent expression of
rhythmicity in our lives is the alternation of sleep and
wakefulness. However, there are many body functions
that express variations in time, not only on a daily
(circadian) scale but also on a seasonal (circannual) scale.
Examples include the circadian variation in body
temperature and the changing plasma concentrations of
hormones. Although entrained by external factors, most
notably the lightdark cycle, body rhythms are generated by
the endogenous pacemaker, located in the suprachiasmatic
nucleus (SCN) of the hypothalamus.19 The SCN consists
of several neuronal subpopulations that use various
neurotransmitters including vasopressin and vasoactive
intestinal peptide. To exert its main function, the SCN
has extensive projections, mainly within the hypothalamus
and via a polysynaptic pathway to the pineal gland.19
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 Episodic brain disorders
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Narcolepsy
Clinical picture
Narcolepsy is characterised by various symptoms,
historically bundled into a tetradexcessive daytime
sleepiness, cataplexy, hypnagogic hallucinations, and sleep
paralysis.20 Daytime hypersomnolence is expressed by the
occurrence of irresistible sleep attacks throughout the day.
In other words, patients can be awake, but they cannot stay
awake. The sleep episodes are commonly superimposed on
a more continuous feeling of sleepiness. Cataplexy is a
sudden bilateral loss of muscle tone with preserved
consciousness, in response to strong emotions such as
mirth or laughter (figure 3). Most cataplectic attacks are
brief, lasting seconds to a few minutes. Hypnagogic
hallucinations are unusually vivid dream experiences Figure 3. Top: a cataplectic attack in a patient with narcolepsy, here
elicited by laughter. Note that the paralysis is not instantly complete; the
occurring at sleep onset. Sleep paralysis is a complete patient is able to reach out his arms to break the fall. Below: cataplectic
inability to move at sleep onset or awakening. Nowadays, attack in a hypocretin-receptor-2 mutated Doberman Pinscher. The
the narcoleptic tetrad is considered incomplete: attack was triggered by the excitement from receiving a piece of palatable
fragmented night-time sleep and obesity are important food. The attack is partial; the most obvious weakness is in the hindlimbs.
features in many patients as well.
corroborated by similar findings in hypocretin-deficient
Pathophysiology animals.35 We recently established a striking loss of the
The symptoms of narcolepsy are normally explained by a circadian fluctuation of plasma leptin concentrations and
loss of state boundary control, resulting in an inability to an overall lowering of the 24 h mean concentrations of this
maintain a state of vigilance, and a breakdown of the appetite-inhibiting peptide.36 Because the circadian
normal confinement of certain characteristics to a certain variation in leptin concentrations is governed by the SCN,37
state (eg, resulting in the occurrence of rapid-eye- these findings suggest that the hypocretin system is also
movement-sleep atonia during the day [cataplexy]).21,22 involved in relaying signals from the biological clock to
During the past 2 years, the fundamental pathological basis downstream hormonal and autonomic systems.
of narcolepsy has been elucidated, and a crucial role for the
hypocretin system has been identified. The hypocretins The hypothalamus and the sleep switch
(orexins) are neuropeptides that are exclusively produced How can a deficiency in hypothalamic hypocretin function
in the hypothalamus.23,24 The fast-paced sequence of result in the paroxysmal features of narcolepsy? Saper and
discoveries started with the findings that the well-
characterised canine model for narcolepsy (figure 3) results
Hypocretin
from mutations in the gene that encodes hypocretin
receptor 2,25 and that hypocretin knockout mice display the
narcoleptic phenotype.26 Subsequently Nishino and
TMN
colleagues27,28 showed that the vast majority of narcoleptic VLPO
LC/DR
patients lack hypocretin-1 in the CSF, in contrast to
healthy controls and patients with diverse neurological
disorders.29 The deficiency is generally not caused by
mutations in the hypocretin gene; to date only one patient
with atypical and very early onset of narcolepsy turned out
to have such a mutation.30 Post-mortem studies showing a Sleep Arousal
selective loss of hypocretin mRNA and immunoreactive
peptide in the lateral hypothalamus suggest an
autoimmune-mediated destruction of the hypocretin-
producing neurons;30,31 however, there is no direct evidence Flip-flop
for such a mechanism.
Figure 4. Highly simplified model, illustrating the capability of a
hypothalamic system to regulate other brain functions.12 This scheme
Other indicators of hypothalamic involvement
mainly applies to non-rapid-eye-movement (non-REM) sleep, although a
As already suggested by many anecdotal reports, a recent similar mechanism can be drawn for REM sleep. Also, note that other
systematic study showed that most patients with systems involved in sleep regulation, such as the cholinergic system, are
narcolepsy are obese, with a third having a body-mass not depicted in this figure. With the present knowledge, hypocretin seems
index of more than 30.32 Since patients with narcolepsy to stabilise the system, holding the switch in the wake position. Direct
projections from the SCN (shown in green) could bring about circadian
have normal locomotor activity33 and caloric intake,34 a low variations in the propensity to change vigilance states.
metabolic rate due to hypocretin deficiency is the likely VLPO=ventrolateral preoptic area; TMN=tuberomamillary nucleus;
cause of their high bodyweight. This theory is now LC=locus coeruleus; DR= dorsal raphae.

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 Personal view
Figure 5. Functional and corroborating structural hypothalamic changes
in cluster headache. A: areas of positron-emission tomography activation
in the ipsilateral inferior posterior hypothalamus, in nine patients with
chronic cluster headache during a nitric-oxide-induced acute attack. B:
voxel-based morphometry in 25 patients with cluster headache, showing
a significant structural difference in the hypothalamic grey matter
compared with 29 healthy controls. Reproduced with permission from
Nature Publishing Group.53 http://www.nature.com/medicalresearch/
colleagues12 recently presented a model that elegantly
describes the role of the hypothalamus in the control of the
sleep switch. In short, they propose that the sleep-
promoting function of the ventrolateral preoptic area, and
the wake-promoting function of several monoaminergic
nuclei, including the tuberomamillary nucleus, form a
reciprocal inhibitory relationship with the properties of a
flip-flop circuit (figure 4). This essentially means that
systems that promote wakening and sleep interact as an
inherently unstable system with the tendency to avoid
intermediate states, so that an organism is clearly waking or
clearly sleeping with only brief times spent in transitions.
The hypocretin system in this model forms a stabilising
finger on the switch12 or, in other words, acts as a state-
boundary controller.20 In narcolepsy, hypocretin deficiency
makes the patient more susceptible to sudden,
inappropriate vigilance-state transitions. In addition to this
model, the SCN may use the hypocretin system to
influence the propensity to fall asleep or to stay awake
(figure 4).38,39
Cluster headache
Clinical picture
Cluster headache is typically characterised by attacks of
excruciating unilateral retro-orbital or periorbital pain
lasting 15180 min. The pain is often described as if a
burning needle is pushed into the eye, causing patients to
walk around in agony during attacks or even consider
committing suicide. The attacks can occur up to eight
times a day and are associated with one or more features of
ipsilateral cranial autonomic activation such as miosis,
ptosis, lacrimation, conjunctival injection, rhinorrhoea, or
nasal congestion.40 The prevalence of cluster headache is
estimated to be between one in 1000 and one in 10 00041
and is three to seven times higher in men than women.42 In
about 80% of the patients, the attacks occur in clusters
periods of weeks to months with frequent attacks,
alternated by symptom-free periods of months to years
the remaining 20% of patients have chronic cluster
headache with no such attack-free periods. Several
440 THE LANCET Neurology Vol 1 November 2002
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Episodic brain disorders
retrospective studies suggest that the disorder follows a
seasonal rhythm.43,44 In addition to the circannual rhythm
of the cluster periods, the attacks within a cluster
commonly follow a striking circadian patternattacks
typically recur at the same time of day in individual
patients, and most patients frequently wake up at night
with attacks.42 Some shift-working patients report a
reverted attack pattern during their shifted daynight
rhythm (personal observation).
During cluster periods, several factors can trigger
cluster-headache attacks, for example alcohol, low partial
oxygen pressure, and nitric oxide donors such as glyceryl
trinitrate.45,46
The role of the hypothalamus
The seasonal rhythm of cluster periods, the circadian
rhythm of the attacks, their relation with sleep, and the
facial autonomic symptoms during the attacks all suggest a
role for the hypothalamus in the initiation of cluster
headache attacks and cluster periods. This idea is further
supported by endocrine studies in patients with cluster
headaches. Total production of melatonin and excretion of
its metabolites were lower in cluster headache patients than
in controls, and there was a significant phase advance in
the 24 h melatonin rhythm.47,48 Changes in production of
cortisol, prolactin, and sex hormone production have been
found, although differences in study design complicate
interpretation.47,4951
Recently, structural and functional abnormalities in the
hypothalamus of patients with cluster headaches have been
demonstrated by use of modern neuroimaging techniques.
Studies with positron emission tomography showed
activation of the ipsilateral hypothalamus during attacks of
cluster headache evoked by glyceryl trinitrate (figure 5).52
Voxel-based morphometry magnetic resonance imaging in
patients outside cluster periods revealed permanent
bilateral structural abnormalities in the hypothalamus,
matching the area of activation shown on positron
emission tomography during attacks (figure 5).53 These
findings prompted Leone and co-workers54 to use deep
brain stimulation of the posterior hypothalamic
grey matter in a patient with intractable chronic
cluster headache, resulting in a complete cessation of
the attacks.
The mechanism through which hypothalamic
abnormalities could result in cluster headache attacks is
unknown. On the basis of the circadian and circannual
timing of the attacks and cluster-periods respectively, the
hypothalamic abnormalities could result in a lowered
threshold for pain. The threshold could be further
modulated by the biological clock. The first part of this
hypothesis is supported by the observation that destruction
of the posterior hypothalamus in rats caused transient
hyperalgesia13 and that electrical stimulation of the
posterior hypothalamus alleviated cluster-headache attacks
in a patient unresponsive to drugs.54 Threshold modulation
by the SCN could explain not only the timing of attacks in
general, but also the fact that trigger factors such as alcohol
are effective only within a cluster period.
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 Episodic brain disorders
Depression
Clinical picture
A major depressive episode is characterised by a period of
at least 14 days with depressed mood or loss of interest or
pleasure combined with at least three of the following
symptoms: significant weight loss; insomnia or
hypersomnia; psychomotor agitation or retardation;
fatigue or loss of energy; feelings of worthlessness or
excessive or inappropriate guilt; diminished ability to
think, concentrate, or make decisions; and suicidal
tendency.55 Many depressed patients also suffer from
increased anxiety and decreased libido. Depression
frequently runs an episodic coursemultiple episodes
are found in 3040% of cases, and in psychiatric
settings recurrence rates of up to almost 90% have been
found.56 In some cases, depressive episodes follow a
seasonal pattern.57
Hypothalamic abnormalities
An essential feature of depression is the hyperactivity of the
stress system, reflected in a sustained activation of the
hypothalamuspituitaryadrenal axis. When challenged
with a combination of dexamethasone and corticotropin-
releasing hormone (CRH), about 80% of depressed
psychiatric in-patients show increased secretion of
corticotropin and cortisol, indicating a feedback resistance
at the level of the paraventricular nucleus and pituitary.58,59
In these patients, increased concentrations of cortisol in
plasma, urine, and CSF, an exaggerated response to
corticotropin, and an enlargement of both the pituitary
and the adrenal glands are found.59,60 Post-mortem studies
showed a higher than normal number of neurons that
express CRH61 and increased expression of CRH-mRNA62
in the paraventricular nucleus of patients with depression.
Furthermore, the first clinical study of a CRH1-receptor
antagonist in major depression showed a significant
antidepressive effect.63 Antiglucocorticoids also have an
antidepressive effect.64 In addition to the activation of the
hypothalamuspituitaryadrenal axis, raised activity of
neurons expressing vasopressin and oxytocin has been
found in depression, possibly increasing the effects of CRH
on behaviour at a central level.65
Diurnal fluctuations of body temperature,
norepinephrine, thyroid-stimulating hormone, and
melatonin are lower in depressed patients than in non-
depressed individuals.66 In addition, depressed patients
have characteristic sleep abnormalitiesdysinhibition of
rapid-eye-movement sleep, suppressed slow-wave sleep,
and dysregulation of ultradian rhythms.67,68 These findings
suggest a role for both hypothalamic sleep-regulatory
centres (such as the hypocretin system) and the SCN in
depression. Furthermore, there may be a link between
disturbed SCN function and the CRH abnormalities found
in depression. Vasopressin produced by the SCN inhibits
CRH synthesis in the paraventricular nucleus. The recent
findings that depressed patients have lower than normal
synthesis and release of vasopressin in the SCN are one
possible explanation for the hyperactivity of the stress
system.69 In depressions with a seasonal pattern, an
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important role for the SCN is likely. Data on 24 h
melatonin secretion suggest that in patients with seasonal
depression, the SCN generates a biological signal similar to
the one that mammals use to regulate seasonal changes in
their behaviour, which is not the case in healthy
volunteers.70
Migraine
Clinical features
Migraine is a common neurovascular disorder, typically
characterised by attacks of severe, disabling, in most cases
unilateral, throbbing headache. The attacks last 472 h and
are accompanied by symptoms such as nausea, vomiting,
photophobia, and phonophobia.40 Up to a third of patients
may experience auras preceding or accompanying the
headache phase. Migraine auras are reversible focal
neurological symptoms, mostly visual, some sensory or
motor, which typically last 560 min and have an
expanding spreading nature. Many patients also
consistently experience pronounced well-recognised
predictable prodromal (or premonitory) symptoms 148 h
before an attack. These may include depression, irritation,
hyperactivation, hypersensitivity to sound or light,
hyperosmia, dysphasia, food cravings, anorexia, nausea,
vertigo, and fluid retention.71
Hypothalamic involvement
Several pathways involved in the pathophysiology of the
headache and aura phases of migraine attacks have been
identified and further characterised.72 Although where,
how, and why migraine attacks begin are unknown, the
hypothalamus may be the site of initiation.73 The
observation that premonitory symptoms may occur up to
48 h before the aura and headache phase of the attack seem
to point at a transient hypothalamic dysfunction in the
earliest phase of a pending attack. Other arguments for the
hypothalamic initiation of attacks are the circadian
rhythmicity of the onset of migraine attacks74,75 and the
remarkable temporal relation of hormonal fluctuations and
the onset of migraine in female patients (in whom migraine
preferentially begins around puberty and fades after the
menopause and attacks commonly occur around
menstruation).76 Several endocrinological and autonomic-
function studies suggest involvement of the hypothalamus
as well, although the interpretation of the results is not
straightforward. Changes have been found in melatonin
excretion, -endorphin and cortisol response to naloxone,
and activation of the hypothalamuspituitaryadrenal axis
in patients with migraine, both related and unrelated to the
menstrual cycle.7783 Cardiovascular reflex tests,8487
pupillometry,88,89 and sweating function90 suggest
autonomic dysfunction between attacks.
Other disorders
Prader-Willi syndrome is characterised by grossly
diminished fetal activity, hypotonia in infancy, mental
retardation, feeding problems in infancy, and later insatiable
hunger and gross obesity, hypogonadism, hypogenitalism,
and cryptorchism.91 Although these former symptoms are
441
 Personal view
Search strategy and selection criteria
Data for this review were identified by searches of Medline with
the search term hypothalamus combined with narcolepsy, necessarily mean that the primary pathophysiological
cluster headache, depression, migraine and Prader-Willi abnormalities have to reside in the hypothalamus, or that
syndrome. Additional references were selected from relevant
articles; several articles were also iden tified through searches
of the extensive files of the authors. Only references published
in English were used.
not episodic, depressive episodes, excessive daytime
sleepiness, and, in some cases, cataplexy are common in
patients with Prader-Willi syndrome. Dysfunction of various
hypothalamic systems may be the basis of several symptoms,
including abnormal function of neurons expressing
luteinising-hormone-releasing hormone and growth-
hormone.3,92 No significant changes were observed in
feeding-regulating neurotransmitters, agouti-related
protein, and neuropeptide Y.93 However, the paraventricular
nucleus (which is innervated by neuropeptide-Y neurons) is
28% smaller than normal in patients with Prader-Willi
syndrome and there is a 42% decrease in the number of
oxytocin-expressing neurons.94 These findings support the
hypothesis that oxytocin-expressing neurons of the
paraventricular nucleus could be candidates for a
physiological role as satiety neurons in ingestive
behaviour.95 The combination of obesity, sleepiness, and, in
some cases, cataplexy (all found in narcolepsy as well)
suggests that the hypocretin system may be compromised in
Prader-Willi syndrome, a hypothesis that is being tested.
Recurrent episodes of hypersomnia, hyperphagia, and
abnormal behaviour (including euphoria, irritability, and
hypersexuality) are the clinical hallmarks of the Kleine-Levin
syndrome.96,97 This rare disorder typically occurs in male
adolescents and resolves in early adulthood. The clinical
features strongly suggest that an episodic hypothalamic
dysfunction underlies Kleine-Levin syndrome. In several
case reports, neuroendocrinological changes (mainly low
cortisol concentrations and high thyroid-stimulating-
hormone concentrations) were found, although these
findings have not been substantiated in systematic studies.96
Hypothalamic hamartomas are commonly associated
with precocious puberty and gelastic epilepsy. These gelastic
seizures originate from the hypothalamic abnormality and
may resolve after removal of the hamartoma.98 Several
mechanisms have been proposed for the mechanism of
epileptogenesis in hypothalamic hamartomas, including
intrinsically epileptogenic activity of dysplastic cells or
abnormal neuropeptide production.98 The hypothalamus
and surrounding structures form a subcortical pathway for
seizure propagation,99 which could be involved in another
presumably hypothalamic epileptic phenomenonthe
epigastric aura in complex partial seizures.
Discussion
The hypothalamus serves as a crucial centre for the
integration and coordination of various brain functions.
The wide range of tasks controlled by a very small part of
the brain makes the hypothalamic region particularly
442 THE LANCET Neurology Vol 1 November 2002
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Episodic brain disorders
prone to involvement in several disorders. We hypothesise
that in EBD, the onset of the disease episodes is modulated
within the hypothalamus. An initiating function does not
the hypothalamus is the only brain region affected.
Several mechanisms could explain a relation between a
structural hypothalamic abnormality and the various
paroxysmal disorders. First, hypothalamic systems could
stabilise interactive brain networks that are inherently
unstable. When these systems become compromised, the
result can be an uncontrolled switching from one state to
another: a paroxysmal symptom pattern. The hypocretin
system is thought to stabilise the sleepwake flip-flop
(figure 4), and the narcoleptic phenotype is thought to be
the consequence of destabilisation of the switch because of
hypocretin deficiency. Second, the hypothalamus could be
involved in the modulation of other brain functions, for
example acting as a filter in neuronal transmission. If the
input to the filter changes over time (eg, owing to external
inputs), alterations in filter thresholds could result in
symptoms. An example is the hypothalamic involvement
in nociceptive transmission. Structural hypothalamic
changes in cluster headache could make patients more
likely to have an attack; and, conversely, external
stimulation of the hypothalamus improves symptoms.
Third, disease episodes could be directly triggered by
the hypothalamus, particularly by the SCN. This
would typically lead to symptoms following a circadian
or circannual pattern. Possible examples include
seasonal depressive periods and monthly menstrual or
early-morning migraines. In both these disorders the
events triggered by the SCN are likely to be superimposed
on other hypothalamic abnormalities, reflected for
example in continuous endocrine dysfunction, and
perhaps leading to threshold changes. Fourth, dysfunction
of hypothalamic systems (as opposed to diminished or
inappropriately enhanced function) could cause specific
symptom patterns. Hamartomas consist of different
abnormal cell types, some of which have intrinsic epileptic
activity. When located in or connected with the
hypothalamus, they result in a very typical phenotype.
Last, a combination of the mechanisms mentioned above
could be involved in certain disorders. In Prader-Willi
syndrome, there are many hypothalamic abnormalities,
resulting in an array of symptoms, both continuous
and paroxysmal.
Various experimental approaches may shed more light
on the precise role of the hypothalamus in EBD.
Obviously, monitoring of hypothalamic function around
the onset of disease attacks (with or without possible
trigger factors) could prove rewarding. Another approach
would be to study disorders that share symptoms (such as
daytime sleepiness in narcolepsy and Prader-Willi
syndrome), to identify common brain abnormalities.
Study of the mechanisms underlying such common
features within the context of the hypothalamus may prove
a fruitful example of cross-fertilisation between research
efforts in various disease areas.
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 Episodic brain disorders
Acknowledgments
We thank Nobu Fujiki and Seiji Nishino from Stanford University,
California for the pictures used in the lower part of figure 3.
Authors contributions
MDF contributed to the original concept of the review and took overall
responsibility. GJL contributed to the original concept of the paper and
co-drafted the narcolepsy section and the discussion. SO drafted the
introduction and co-drafted the sections on narcolepsy and other
disorders, and the discussion. JAvV drafted the cluster headache and
migraine sections. FGZ drafted the depression section. DFS drafted the
hypothalamus form and function section and co-drafted the other
disorders section.
References
1 World Health Organization. The world health report
2001. Mental health: new understanding, new hope.
Geneva: WHO, 2001.
2 Saper CB. The hypothalamus. In: Paxinos G, ed. The 22
human nervous system. San Diego: Academic Press,
1990: 389413.
3 Swaab DF. Neurobiology and neuropathology of the 23
human hypothalamus. In: Bloom FE, Hkfelt T, eds.
The primate nervous system, part I. Amsterdam:
Elsevier, 1997: 39137.
4 Bartness TJ, Song CK, Demas GE. SCN efferents to 24
peripheral tissues: implications for biological
rhythms. J Biol Rhythms 2001; 16: 196204.
5 Buijs RM, Kalsbeek A. Hypothalamic integration of
central and peripheral clocks. Nat Rev Neurosci 2001; 25
2: 52126.
6 Kalra SP, Dube MG, Pu S, Xu B, Horvath TL,
Kalra PS. Interacting appetite-regulating pathways in 26
the hypothalamic regulation of body weight. Endocr
Rev 1999; 20: 68100.
7 Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, 27
Baskin DG. Central nervous system control of food
intake. Nature 2000; 404: 66171.
28
8 Baile CA, Della-Fera MA, Martin RJ. Regulation of
metabolism and body fat mass by leptin. Annu Rev
Nutr 2000; 20: 10527.
9 Elmquist JK. Hypothalamic pathways underlying the
endocrine, autonomic, and behavioral effects of 29
leptin. Int J Obes Relat Metab Disord 2001; 25
(suppl 5): S7882.
10 Ariyasu H, Takaya K, Tagami T, et al. Stomach is a
major source of circulating ghrelin, and feeding state 30
determines plasma ghrelin-like immunoreactivity
levels in humans. J Clin Endocrinol Metab 2001; 86:
475358.
31
11 von Economo C. Sleep as a problem of localization.
J Nerv Ment Dis 1930; 71: 24959.
12 Saper CB, Chou TC, Scammell TE. The sleep switch: 32
hypothalamic control of sleep and wakefulness.
Trends Neurosci 2001; 24: 72631.
13 Millan MJ, Przewlocki R, Millan MH, Herz A.
Evidence for a role of the ventro-medial posterior 33
hypothalamus in nociceptive processes in the rat.
Pharmcol Biochem Behav 1982; 18: 90107.
14 Richardson DE, Akil H. Long term results of
periventricular gray self-stimulation. Neurosurgery
1977; 1: 199202.
15 Leone M, Franzini A, Bussone G. Stereotactic 34
stimulation of posterior hypothalamic gray matter in
a patient with intractable cluster headache. N Engl J
Med 2001; 345: 142829. 35
16 Faris PL, Komisaruk BR, Watkins LR, Mayer DJ.
Evidence for the neuropeptide cholecystokinin as an
antagonist of opiate analgesia. Science 1983; 219:
31012. 36
17 Braga PC, Dal Sasso M, Bernini A, Bartucci F,
Pollo A, Carbone E. Antinociceptive activity of
salmon calcitonin: electrophysiological correlates in
a rat chronic pain model. Neurosci Lett 1993; 151:
8588. 37
18 Hokfelt T, Ljungdahl A, Terenius L, Elde R,
Nilsson G. Immunohistochemical analysis of peptide
pathways possibly related to pain and analgesia:
enkephalin and substance P. Proc Natl Acad Sci USA 38
1977; 74: 308185.
19 Swaab DF. Biological rhythms in health and disease:
the suprachiasmatic nucleus and the autonomic
system. In: Appenzeller O, ed. The autonomic 39
nervous system: part I, normal functions.
Amsterdam: Elsevier, 1999: 467521.
20 Overeem S, Mignot E, van Dijk JG, Lammers GJ. 40
Narcolepsy: clinical features, new pathophysiologic
insights, and future perspectives. J Clin Neurophysiol
2001; 18: 78105.
21 Broughton R, Valley V, Aguirre M, Roberts J,
THE LANCET Neurology Vol 1 November 2002
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Conflict of interest
None of the authors has a conflict of interest.
Role of the funding source
SO is supported in part by the LUMC Fellowship 2000. JAvV is
sponsored by the Asclepiade foundation. Part of the research by DFS
was supported by the Research Institute for Diseases in the Elderly,
funded by the Ministry of Education and Science and the Ministry of
Health, Welfare and Sports, through the Netherlands Organisation
for Scientific Research (NWO), and by Merck & Co. Inc. None of
these organisations had a role in the writing of this paper or in the
decision to submit it for publication.
Suwalski W, Dunham W. Excessive daytime
sleepiness and the pathophysiology of narcolepsy-
cataplexy: a laboratory perspective. Sleep 1986; 9:
20515.
Overeem S, Lammers GJ, van Dijk JG. Cataplexy:
tonic immobility rather than REM-sleep atonia?
Sleep Med (in press).
de Lecea L, Kilduff TS, Peyron C, et al. The
hypocretins: hypothalamus-specific peptides with
neuroexcitatory activity. Proc Natl Acad Sci USA
1998; 95: 32227.
Sakurai T, Amemiya A, Ishii M, et al. Orexins and
orexin receptors: a family of hypothalamic
neuropeptides and G protein-coupled receptors that
regulate feeding behavior. Cell 1998; 92: 57385.
Lin L, Faraco J, Li R, et al. The sleep disorder canine
narcolepsy is caused by a mutation in the hypocretin
(orexin) receptor 2 gene. Cell 1999; 98: 36576.
Chemelli RM, Willie JT, Sinton CM, et al.
Narcolepsy in orexin knockout mice: molecular
genetics of sleep regulation. Cell 1999; 98: 43751.
Nishino S, Ripley B, Overeem S, Lammers GJ,
Mignot E. Hypocretin (orexin) deficiency in human
narcolepsy. Lancet 2000; 355: 3940.
Nishino S, Ripley B, Overeem S, et al. Low
cerebrospinal fluid hypocretin (orexin) and altered
energy homeostasis in human narcolepsy.
Ann Neurol 2001; 50: 38188.
Ripley B, Overeem S, Fujiki N, et al. CSF
hypocretin/orexin levels in narcolepsy and other
neurological conditions. Neurology 2001; 57:
225358.
Peyron C, Faraco J, Rogers W, et al. A mutation in a
case of early onset narcolepsy and a generalized
absence of hypocretin peptides in human narcoleptic
brains. Nat Med 2000; 6: 99197.
Thannickal TC, Moore RY, Nienhuis R, et al.
Reduced number of hypocretin neurons in human
narcolepsy. Neuron 2000; 27: 46974.
Dahmen N, Bierbrauer J, Kasten M. Increased
prevalence of obesity in narcoleptic patients and
relatives. Eur Arch Psychiatry Clin Neurosci 2001;
251: 8589.
Middelkoop HA, Lammers GJ, Van Hilten BJ,
Ruwhof C, Pijl H, Kamphuisen HA. Circadian
distribution of motor activity and immobility in
narcolepsy: assessment with continuous motor
activity monitoring. Psychophysiology 1995; 32:
28691.
Lammers GJ, Pijl H, Iestra J, Langius JA, Buunk G,
Meinders AE. Spontaneous food choice in
narcolepsy. Sleep 1996; 19: 7576.
Hara J, Beuckmann CT, Nambu T, et al. Genetic
ablation of orexin neurons in mice results in
narcolepsy, hypophagia, and obesity. Neuron 2001;
30: 34554.
Kok SW, Meinders AE, Overeem S, et al. Reduction
of plasma leptin levels and loss of its circadian
rhythmicity in Hypocretin (Orexin)-deficient
narcoleptic humans. J Clin Endocrinol Metab 2002;
87: 80509.
Kalsbeek A, Fliers E, Romijn JA, et al. The
suprachiasmatic nucleus generates the diurnal
changes in plasma leptin levels. Endocrinology 2001;
142: 267785.
Abrahamson EE, Leak RK, Moore RY. The
suprachiasmatic nucleus projects to posterior
hypothalamic arousal systems. Neuroreport 2001; 12:
43540.
Aston-Jones G, Chen S, Zhu Y, Oshinsky ML. A
neural circuit for circadian regulation of arousal.
Nat Neurosci 2001; 4: 73238.
Headache Classification Committee of the
International Headache Society. Classification and
diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalalgia 1988; 8
(suppl 7): 196.
http://neurology.thelancet.com
Personal view
41 DAlessandro R, Gamberini G, Benassi G,
Morganti G, Cortelli P, Lugaresi E. Cluster headache
in the republic of San Marino. Cephalalgia 1986; 6:
15962.
42 Bahra A, May A, Goadsby PJ. Cluster headache: a
prospective clinical study with diagnostic
implications. Neurology 2002; 58: 35461.
43 Kudrow L. The cyclic relationship of natural
illumination to cluster period frequency. Cephalalgia
1987; 7 (suppl 6): 7678.
44 Nappi A, Cavallini G, Micieli F, Granella G,
Manzoni C, Sandrini G. Temporal pattern and
accompanying symptoms in the international
headache society diagnostic criteria for cluster
headache. In: Olesen J, ed. Headache classification
and epidemiology. New York: Raven Press, 1994:
10712.
45 Dodick DW, Rozen TD, Goadsby PJ, Silberstein SD.
Cluster headache. Cephalalgia 2000; 20: 787803.
46 Ekbom K. Nitrolglycerin as a provocative agent in
cluster headache. Arch Neurol 1968; 19: 48793.
47 Chazot G, Claustrat B, Brun J, Jordan D, Sassolas G,
Schott B. A chronobiological study of melatonin,
cortisol, growth hormone and prolactin secretion in
cluster headache. Cephalalgia 1984; 4: 21320.
48 Leone M, Lucini V, D Amico D, et al. Abnormal 24-
hour urinary excretory pattern of 6-
sulphatoxymelatonin in both phases of cluster
headache. Cephalalgia 1998; 18: 66467.
49 Waldenlind E, Gustafsson SA. Prolactin in cluster
headache: diurnal secretion, response to
thyrotropin-releasing hormone, and relation to sex
steroids and gonadotropins. Cephalalgia 1987; 7:
4354.
50 Leone M, Lucini V, DAmico D, et al. Twenty-four-
hour melatonin and cortisol plasma levels in relation
to timing of cluster headache. Cephalalgia 1995; 15:
22429.
51 Strittmatter M, Hamann GF, Grauer M, et al.
Altered activity of the sympathetic nervous system
and changes in the balance of hypophyseal, pituitary
and adrenal hormones in patients with cluster
headache. Neuroreport 1996; 7: 122934.
52 May A, Bahra A, Bchel C, Frackowiak RSJ, Goadsby
PJ. Hypothalamic activation in cluster headache
attacks. Lancet 1998; 352: 27578.
53 May A, Ashburner J, Bchel C, et al. Correlation
between structural and functional changes in brain
in an idiopathic headache syndrome. Nat Med 1999;
5: 83638.
54 Leone M, Franzini A, Bussone G. Stereotactic
stimulation of posterior hypothalamic gray matter in
a patient with intractable cluster headache.
N Engl J Med 2001; 345: 142829.
55 American Psychiatric Association. Quick reference to
the diagnostic criteria from DSM-IV-TR.
Washington: American Psychiatric Association, 2000.
56 Weel-Baumgarten EM, Schers HJ,
van den Bosch WJ, van den Hoogen HJ, Zitman FG.
Long-term follow-up of depression among patients
in the community and in family practice settings: a
systematic review. J Fam Pract 2000; 49: 111320.
57 Harmatz MG, Well AD, Overtree CE,
Kawamura KY, Rosal M, Ockene IS. Seasonal
variation of depression and other moods: a
longitudinal approach. J Biol Rhythms 2000; 15:
34450.
58 Heuser I, Yassouridis A, Holsboer F. The combined
dexamethasone/CRH test: a refined laboratory test
for psychiatric disorders. J Psychiatr Res 1994; 28:
34156.
59 Holsboer F, Barden N. Antidepressants and
hypothalamic-pituitary-adrenocortical regulation.
Endocr Rev 1996; 17: 187205.
60 Nemeroff CB. The corticotropin-releasing factor
(CRF) hypothesis of depression: new findings and
new directions. Mol Psychiatry 1996; 1: 33642.
443
 Personal view
61 Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ,
Swaab DF. Increased numbers of corticotropin-
releasing hormone expressing neurons in the
hypothalamic paraventricular nucleus of depressed
patients. Neuroendocrinology 1994; 60: 43644.
62 Raadsheer FC, van Heerikhuize JJ, Lucassen PJ,
Hoogendijk WJ, Tilders FJ, Swaab DF.
Corticotropin-releasing hormone mRNA levels in
the paraventricular nucleus of patients with
Alzheimers disease and depression. Am J Psychiatry
1995; 152: 137276.
63 Zobel AW, Nickel T, Kunzel HE, et al. Effects of the
high-affinity corticotropin-releasing hormone
receptor 1 antagonist R121919 in major depression:
the first 20 patients treated. J Psychiatr Res 2000; 34:
17181.
64 Wolkowitz OM, Reus VI, Chan T, et al.
Antiglucocorticoid treatment of depression: double-
blind ketoconazole. Biol Psychiatry 1999; 45:
107074.
65 Purba JS, Hoogendijk WJ, Hofman MA, Swaab DF.
Increased number of vasopressin- and oxytocin-
expressing neurons in the paraventricular nucleus of
the hypothalamus in depression. Arch Gen Psychiatry
1996; 53: 13743.
66 Swaab DF, Fliers E, Hoogendijk WJ, Veltman DJ,
Zhou JN. Interaction of prefrontal cortical and
hypothalamic systems in the pathogenesis of
depression. Prog Brain Res 2000; 126: 36996.
67 Seifritz E. Contribution of sleep physiology to
depressive pathophysiology.
Neuropsychopharmacology 2001; 25: S8588.
68 Armitage R, Hoffmann RF, Rush AJ. Biological
rhythm disturbance in depression: temporal
coherence of ultradian sleep EEG rhythms. Psychol
Med 1999; 29: 143548.
69 Zhou JN, Riemersma RF, et al. Alterations in
arginine vasopressin neurons in the suprachiasmatic
nucleus in depression. Arch Gen Psychiatry 2001; 58:
65562.
70 Wehr TA, Duncan WC Jr, Sher L, et al. A circadian
signal of change of season in patients with seasonal
affective disorder. Arch Gen Psychiatry 2001; 58:
110814.
71 Silberstein SD. Migraine symptoms: results of a
survey of self-reported migraineurs. Headache 1995;
35: 38796.
72 Goadsby PJ, Lipton RB, Ferrari MD. Migraine:
current understanding and treatment. N Engl J Med
2002; 346: 25770.
444
For personal use. Only reproduce with permission from The Lancet Publishing Group.
73 Blau JN. Migraine pathogenesis: the neural
hypothesis reexamined. J Neurol Neurosurg
Psychiatry 1984; 47: 43742.
74 Fox AW, Davis RL. Migraine chronobiology.
Headache 1998; 38: 43641. 88
75 Solomon GD. Circadian rhythms and migraine.
Cleve Clin J Med 1992; 59: 32629.
76 MacGregor A. Gynaecological aspects of migraine.
Rev Contemp Pharmacother 2000; 11: 7590. 89
77 Brun J, Claustrat B, Saddier P, Chazot G. Nocturnal
melatonin excretion is decreased in patients with
migraine without aura attacks associated with
90
menses. Cephalalgia 1995; 15: 13639.
78 Murialdo G, Fonzi S, Costelli P, et al. Urinary
melatonin excretion throughout the ovarian cycle in
menstrually related migraine. Cephalalgia 1994; 14: 91
20509.
79 Nagel-Leiby S, Welch KM, DAndrea G, Grunfeld S,
Brown E. Event-related slow potentials and 92
associated catecholamine function in migraine.
Cephalalgia 1990; 10: 31729.
80 Facchinetti F, Martignoni E, Fioroni L, Sances G,
Genazzani AR. Opioid control of the hypothalamus-
pituitary-adrenal axis cyclically fails in menstrual 93
migraine. Cephalalgia 1990; 10: 5156.
81 Claustrat B, Loisy C, Brun J, Beorchia S, Arnaud JL,
Chazot G. Nocturnal plasma melatonin levels in
migraine: a preliminary report. Headache 1989; 29:
24245.
94
82 Facchinetti F, DAttoma G, Petraglia F, Pini LA,
Sternieri E, Genazzani AR. Circadian variations of
proopiocortin-related peptides in children with
migraine. Cephalalgia 1983; 3 (suppl 1): 9497.
83 Shaw SW, Johnson RH, Keogh HJ. Metabolic
changes during glucose tolerance tests in migraine 95
attacks. J Neurol Sci 1977; 33: 5159.
84 Shechter A, Stewart FW, Silberstein SD, Lipton RB.
Migraine and autonomic nervous system function: a 96
population-based, case-control study. Neurology
2002; 58: 42227.
85 Martin R, Ribera C, Molto JM, Ruiz C, Galiano L, 97
Matias-Guiu J. Cardiovascular reflexes in patients
with vascular headache. Cephalalgia 1992; 12:
36064.
86 Mikamo K, Takeshima T, Takahashi K. 98
Cardiovascular sympathetic hypofunction in muscle
contraction headache and migraine. Headache 1989;
29: 8689. 99
87 Boiardi A, Munari L, Milanesi I, Paggetta C,
THE LANCET Neurology Vol 1 November 2002
Episodic brain disorders
Lamperti E, Bussone G. Impaired cardiovascular
reflexes in cluster headache and migraine patients:
evidence for an autonomic dysfunction. Headache
1988; 28: 41722.
Micieli G, Tassorelli C, Magri M, Sandrini G,
Cavallini A, Nappi G. Vegetative imbalance in
migraine: a dynamic TV pupillometric evaluation.
Funct Neurol 1989; 4: 10511.
Rubin LS, Graham D, Pasker R, Calhoun W.
Autonomic nervous system dysfunction in common
migraine. Headache 1985; 25: 4048.
Gomi S, Gotoh F, Komatsumoto S, Ishikawa Y,
Araki N, Hamada J. Sweating function and retinal
vasomotor reactivity in migraine. Cephalalgia 1989;
9: 17985.
Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi
syndrome: consensus diagnostic criteria. Pediatrics
1993; 91: 398402.
Eiholzer U, Bachmann S, lAllemand D. Is there
growth hormone deficiency in Prader-Willi
syndrome? Six arguments to support the presence of
hypothalamic growth hormone deficiency in Prader-
Willi syndrome. Horm Res 2000; 53 (suppl 3): 4452.
Goldstone AP, Unmehopa UA, Bloom SR,
Swaab DF. Hypothalamic NPY and Agouti-related
protein are increased in human illness but not in
Prader-Willi syndrome and other obese subjects.
J Clin Endocrinol Metab 2002; 87: 92737.
Swaab DF, Purba JS, Hofman MA. Alterations in the
hypothalamic paraventricular nucleus and its
oxytocin neurons (putative satiety cells) in Prader-
Willi syndrome: a study of five cases. J Clin
Endocrinol Metab 1995; 80: 57379.
Arletti R, Benelli A, Bertolini A. Influence of
oxytocin on feeding behavior in the rat. Peptides
1989; 10: 8993.
Papacostas SS, Hadjivasilis V. The Kleine-Levin
syndrome: report of a case and review of the
literature. Eur Psychiatry 2000; 15: 23135.
Gadoth N, Kesler A, Vainstein G, Peled R, Lavie P.
Clinical and polysomnographic characteristics of 34
patients with Kleine-Levin syndrome. J Sleep Res
2001; 10: 33741.
Kuzniecky R, Guthrie B, Mountz J, et al. Intrinsic
epileptogenesis of hypothalamic hamartomas in
gelastic epilepsy. Ann Neurol 1997; 42: 6067.
Mirsky MA. Unraveling the neuroanatomy of
epilepsy. Am J Neuroradiol 1993; 14: 133642.
http://neurology.thelancet.com