ARTICLE
Auteur(s) : Nandini Mullatti
The Centre for Epilepsy and Dept. of Clinical Neurophysiology,
Kings College Hospital, UK
Presented at the International Symposium on Hypothalamic
Hamartoma and Epilepsy, Montreal Neurological Institute, Montreal,
Canada, November 29th 2001.
Hypothalamic hamartoma (HH) is often associated with a
catastrophic epilepsy syndrome associated with gelastic seizures
and refractory epilepsy. Sometimes, precocious puberty (PP),
behaviour problems and learning difficulties occur [1]. While most
of the literature on the subject describes the clinical
manifestations and treatment in children, there are recent reports
of adult patients with HH [2]. Generally, the manifestations of HH
in adults are poorly understood, since it is regarded as very rare.
However, with improvements in neuroimaging, it is inevitable that a
greater number of adults with HH, some without the typical
manifestations, will be detected. Recently we have had the
opportunity to evaluate a number of such patients with HH, and we
present our experience below.
Patient details
Fourteen adult patients were evaluated at King’s College
Hospital between 1999-2002. Some of them are part of a larger group
of patients, both children and adults with HH who have been
evaluated at our centre, and the details of which have been
published elsewhere [7]. All patients were evaluated with a
detailed history and examination, MRI scans, EEGs, video EEG (in
five patients) and neuropsychological assessment (six patients).
Their ages ranged from 16-56 years (mean 33.5 years).
Seven were female. All patients presented clinically with
refractory epilepsy. Only one patient presented with gelastic
seizures, although, on reviewing the seizure details, overt
gelastic seizures were present in six patients. In a further four
patients, the gelastic nature of the seizures existed only as mere
feelings of “a need to laugh”, and in another patient, although
gelastic seizures had been present in childhood, they had
subsequently stopped completely. Three patients never had gelastic
seizures. Two of these patients developed epilepsy in adult life,
and the third developed epilepsy at the age of 13, after presenting
with precocious puberty at the age of 7 years.
Eleven patients had epilepsy that began in childhood, but all of
these patients had been diagnosed as having HH only in adult life.
In three other patients with HH, the epilepsy only began in adult
life. Presenting seizure types were tonic seizures
(n = 5), complex partial seizures (n = 8), and
atonic seizures (n = 4). Atypical absences were
particularly frequent in one patient. Two patients had moderate
learning difficulties, and six had mild learning difficulties.
Seven of these adult HH patients were in employment and six were
married or in long term relationships. A history of precocious
puberty, although borderline, was present in two other
patients.
Two cases are illustrated below.
Case 1
This 35 year-old man works full time. Although only
diagnosed as having HH at the age of 30 years, his symptoms
probably began as a baby when it was noted that he had attacks of
inappropriate laughter. These subsided, only to recur at the age of
six, but they were not troublesome and were not recognized as
seizures. Early development was normal, and he went to normal
school, passed his secondary school examinations, and was able to
obtain a qualification in carpentry. More overt seizures with
giggling and confusion, and generalised tonic clonic seizures,
began in his teens but they did not significantly hamper his
education. Subsequently, he held down a number of jobs and is
presently working in a factory. He is married and has two
children.
He currently has seizures which begin with a nervous giggle, of
which he is aware, and which is not associated with mirth. This
progresses to swallowing and sometimes, oral and limb automatisms
develop. On occasions, more complex automatisms develop, such as
walking on to the road and directing traffic. During these
episodes, he speaks irrelevant but clear sentences. He has
post-ictal confusion lasting up to 30 min. Frequency of
complex partial seizures reduced on treatment with tiagabine and
carbamazepine. His main seizure type now comprises brief gelastic
attacks which occur several times a week. MRI scans show a 1cm
diameter HH in the third ventricle above the mamillary bodies. EEGs
show bilateral temporal sharp waves. Neuropsychological evaluation
shows a full scale IQ of 108, with a verbal IQ of 96 and a
performance IQ of 123, moderate impairment of verbal short term
memory and intact visuospatial memory.
Case 2
This 33 year-old musician presented with a two year history
of infrequent, abrupt falls to the ground and episodes of
blankness. The attacks of falling occurred without warning and, on
occasions, he has injured himself. Falls were followed by a brief
period of unresponsiveness occuring once every few months, but
tonic clonic jerks have never been noted. The episodes of blankness
were brief and occurred in clusters, resulting in days when he was
not able to do much, and these occurred once every few weeks. He
was treated with lamotrigine, with some benefit. He is able to work
full-time, as the front manager of a theatre and has a long-term
girlfriend. His early development was normal, and he went to normal
school. On review, it became apparent that puberty probably was
precocious and began around the age of eight years. His partner
abnormal interictal sleeping pattern. As far as he can remember, he
has never slept much. He normally goes to bed between 11 pm
and midnight and will take about an hour to fall asleep. He will
then wake two or three times in the night, toss and turn and then
get up to watch television or do some work. He then returns to
sleep and awakens around 7 am. He is not “a morning person”,
but does not feel sleepy during the day. This has been his normal
sleep pattern all his life. He reports that on occasions when he
does fall asleep, he has very vivid dreams, which he can recall on
awakening. Sometimes he has hypnagogic hallucinations. He has never
had sleep paralysis, nor does he have irresistible urges to sleep
in the daytime. He is not troubled by his sleep pattern and is
surprised that other people seem to sleep 7-8 hours every
night.
The MRI scan revealed a small, 4 mm diameter HH arising from
the left mammillary body. An EEG showed occasional temporal sharp
transients. Video EEG telemetry performed over five days with
reduction of lamotrigine, showed no interictal abnormalities and
there were no attacks of blankness or falling. On the
3rd and 4th night of this study,
polysomnography was performed. On both nights, it was confirmed
that the patient slept very little, between four to five hours in
bed, with frequent arousals every few minutes. Total sleep time was
about three and a half hours. The maximum period of stage two/three
sleep was one and a half hours: he had little slow wave sleep and
no REM sleep.
Discussion
The epilepsy syndrome noted in adult patients with HH appears to
be different from the catastrophic epilepsy noted in children, and
this is particularly the case when the epilepsy begins in later
life. The differences are highlighted below.
Differences between adults and children with hypothalamic
hamartoma
Milder epilepsy with later onset
Our findings suggest that the later onset of epilepsy in
patients with HH is associated with a milder epilepsy syndrome. The
epilepsy syndrome is usually restricted to one or two partial
seizure types, commonly complex partial (“pseudotemporal”)
seizures, or tonic seizures, with a variable expression of gelastic
seizures, and occasional generalized seizures. This is different
from children with early onset epilepsy, which begins with gelastic
and other partial seizures at the onset and progresses to multiple
refractory seizure types and, on occasions, symptomatic generalized
epilepsy develops [1, 2].
Gelastic seizures are less prominent with later onset of
epilepsy
Gelastic seizures appear to occur less frequently when the
epilepsy begins later in life. All three patients with HH who did
not have gelastic seizures had developed epilepsy later in life,
after the age of 10 in one patient, and in two others, at the
age of 26 and 31 respectively. When the epilepsy begins
early in association with HH, gelastic seizures almost always
occur. Eleven of our patients with HH had the onset of epilepsy
before five years of age, and all had gelastic seizures. Gelastic
seizures became either less prominent and were reduced to “mere
feelings of an urge to laugh” or completely disappeared as the
patient entered into teenage and adult life, in five of our
14 patients. Sturm et al. [1] who describe it as
“pressure to laugh”, have also reported this feature in two adult
patients with HH and mild epilepsy.
Learning difficulties are less common
Thirdly, the later onset of the epilepsy (and the absence of the
symptomatic generalized epilepsy) appears to be associated with
significantly fewer learning difficulties. Half of the patients in
this series were in employment and all, except two patients who
were in residential care, were independent in Activities of Daily
Living but living with family members. This is in contrast to the
early onset epilepsy in children with HH, where up to two thirds
had moderate or severe learning difficulties [5]. Deonna and
Ziegler reviewed the literature for documented cases of HH with
normal cognition [6]. Of 67 cases in the literature with
details of cognition and behavior, 10 were reported to be of
normal intelligence. Six of these involved late onset (one patient
with adult onset), but four patients had early onset epilepsy,
similar to our patient described above as case 1. At the present
time, there are no definitive data to indicate exactly how
epileptic pathology interferes with development, cognition and
behaviour in HH. Suggested mechanisms are excitotoxic damage to the
mamillary bodies and the medial thalamus from the frequent
epileptiform discharges from the HH [7]. It is also postulated that
frequent epileptic discharges in the hypothalamic amygdala and
frontal systems at an early developmental age interfere with the
processing of life experiences and result in aberrant personality
or behavioural changes [6]. Six of our patients with HH who have a
normal IQ have been shown, on neuropsychological testing, to have
specific and disproportionate memory deficits.
Behaviour problems are fewer with later onset
Finally, behavioural problems occur in children with HH.
Weissenberger et al. reported on 12 children with HH
and gelastic seizures [8]. When compared to their unaffected
siblings, children with HH had a statistically higher rate of
psychiatric conditions, including oppositional defiant disorder
(83%), attention deficit/hyperactivity disorder (75%), aggression
(89%), conduct disorder (33%), speech retardation/learning
impairment (33%), and anxiety and mood disorders (17%). In another
study, Fratelli et al. reported on eight children, six of
whom had rage attacks with kicking, screaming and biting behaviour
[9]. The same six also had poor relationships with peers,
characterized by tendencies towards self-isolation and
self-directed play. The adults in our series have not been formally
psychiatrically tested, since they do not have any significant
psychiatric symptoms. No history of aggressive and defiant
behaviour in childhood was noted. However, they all appeared to be
loners, with poor peer relationships. The majority of the adults
(n = 10) were introverted, placid, shy individuals. Two
were rather disinhibited and chatty individuals. Two patients in
residential care also appeared rather placid, except when seizures
occurred.
Sleep problems in HH
Von Economo studied the brains of people affected by
encephalitis lethargica, a presumed viral illness which causes
profound sleepiness. He noted the relationship between lesions of
the posterior hypothalamus and profound sleepiness [10]. He also
recognised patients with the opposite problem i.e. those patients
who had a prolonged state of insomnia and had a lesion of the
preoptic area and basal forebrain. It is now established that sleep
active neurons occur in the preoptic area (POA) of the hypothalamus
and the basal forebrain, and sleep results because of the increased
activity of these neurons. The posterior hypothalamus, which
facilitates the awake state, contains hypocretin neurons. The
different stages of sleep occur as a consequence of the interaction
between different monoaminergic nuclei, the POA and the
peduculopontine, lateral tegmental nuclei. REM sleep occurs due to
increased firing of the extended venterolateral POA nuclei (VLPOA)
[11, 12]. It is possible that in our patient, described above as
Case 2, the HH has produced an impairment of function of the POA
and VLPOA nuclei.
Severe epilepsy, frequent antiepileptic discharges and behavioural
problems have usually complicated the evaluation of sleep in
patients with HH. The patient described above is of normal
intelligence, having infrequent seizures and gave a clear account
of his sleep difficulties. The absence of REM sleep was striking on
the hypnogram, on the two nights studied. In addition, there were
very frequent arousals, and reduction of slow wave sleep. Most
strikingly, the lack of night-time sleep was not associated with
any day-time sleepiness: this patient’s overall sleep clock and
sleep requirements appeared to have been altered. Although the
scalp EEG showed no abnormality during the polysomnography, a
possible explanation for the sleep problems would be that the
frequent HH discharges, unrecordable on the surface EEG, disturb
the function of the POA/ PPT, LDT systems.
Dunn et al. evaluated 6 patients with HH and gelastic
seizures, and refractory epilepsy, and noted sleep difficulties,
and in particular, a reduction in REM sleep in patients with HH
[13]. The reduction in REM sleep was related to the severity of the
seizures. They have therefore suggested that the reduction in REM
sleep contributed to the increased severity of seizures. Our
impression is that increased seizures and epileptiform discharges
from the HH interfere with generation of REM and slow wave sleep,
or that both effects operate in a circular fashion, each
exacerbating the other.
Management aspects - medical or minimally invasive
All of the 14 adult patients are receiving treatment with
AEDs. Two of the patients have considerable learning difficulties
and may not be able to make a fully informed decision about
surgical therapy. Two other adults have had stereotactic
thermocoagulation, with significant benefit to their seizures and
no side effects. Ten other patients, of whom seven are in
employment, are reasonably satisfied with the AED treatment and do
not wish to consider surgery. Indeed, given their high level of
functioning, it would be difficult to justify a surgical procedure
which carries the risk of a considerable degree of morbidity. For
such patients, we believe that either minimally invasive
procedures, such as stereotactic thermocoagulation should be
performed, or the best possible epilepsy control achieved with
AEDs. In patients with symptomatic, generalized EEG discharges,
broad spectrum AEDs appear to confer additional benefit. n
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