ARTICLE
Auteur(s) : Masoud Sangani, Asim Shahid, Shahram Amina,
Mohamad
Koubeissi
Department of Neurology, University Hospitals
of Cleveland, Cleveland, USA
Article reçu le 5 Ao�t 2009, accepté le 22 F�vrier 2010
The percentage of people with Down Syndrome (DS) and Alzheimer's
disease (AD) varies in some of the epidemiologic studies presented.
A review of these studies showed that of patients with DS,
AD-type dementia was present in 10-25% aged 40-49 years, 20-50%
aged 50-59 years, and 60-75% older than 60 years
(Schweber, 1989). The incidence of dementia in Down syndrome (DS)
is estimated to be greater than 25% in individuals over
35 years of age. This number has been shown to increase with
advancing age (Schweber, 1989), presumably in relation to the
increased probability of triplication and over-expression of the
amyloid precursor gene on chromosome 21 (Schupf and Sergievsky,
2002). Descriptions of late-onset epilepsy in DS patients are
rare.
Nearly all patients with DS after the age of 40 years have
histopathological evidence of cerebral neurofibrillary proteins,
identical to those seen in AD (Sisodia and St George-Hyslop, 2002).
It is in this subset of patients with DS that late myoclonic
seizures have been reported, usually after the development of
dementia (De Simone et al., 2006; Möller et al., 2001;
Crespel, 2007).
Whether the neuropathological changes associated with AD
predispose to myoclonic seizures remains to be established.
Myoclonic seizures are more common in such disorders as
post-hypoxic and spongiform encephalopathy, as well as in juvenile
myoclonic epilepsy. For all kinds of myoclonic epilepsies,
levetiracetam has shown good efficacy in controlling seizures
(Van Zandijcke, 2003). We report two additional cases of myoclonic
epilepsy following cognitive decline in older individuals with DS
who experienced an optimal response to moderate doses of
levetiracetam as monotherapy.
Case 1
A 52-year-old left-handed man with DS presented with a six-month
history of cognitive decline, consistent with dementia. His
behavioural changes included a decline in previously marginal
language abilities and more dependence on caregivers for activities
of daily living, such as dressing and using public transportation.
Two to three months after the onset of his cognitive symptoms,
brief, intense, single extremity or whole body jerks were noted
that were occasionally accompanied by a loud scream. His whole-body
jerks resulted in falls and injury. There was no apparent loss of
consciousness and the patient resumed his activities after the
jerks. The jerks were more prominent in the morning or after a
mid-day nap. Phenytoin treatment was initiated by the primary care
physician with no change in the frequency or intensity of these
events.
He was admitted to our epilepsy monitoring unit and phenytoin
was discontinued. His EEG revealed a posterior basic rhythm of
5-6 Hz, with generalised intermittent slowing. Photic
stimulation did not elicit abnormal responses. More than
20 episodes of myoclonic seizures were recorded, ranging from
subtle, single extremity jerks to full-body violent jerks. All
seizures were associated with generalised spikes and
polyspike-and-wave discharges, which were maximum in the anterior
head regions (figure 1). The
duration ranged between 0.5 to 1 second and occurred every
5-10 minutes. Oral levetiracetam was then administered at a dose of
250 mg twice a day with complete resolution of myoclonic
seizures. Two days after initiation of levetiracetam treatment, the
patient's family noted some improvement in his cognition back to
what they estimated to be 50-60% of his pre-dementia baseline.
Case 2
A 44-year-old right-handed man with DS was diagnosed with dementia.
Eight months after he was diagnosed with dementia, he started to
have episodes of upper body and bilateral arm jerking.
Occasionally, the jerks involved the left arm alone. He experienced
falls secondary to severe and violent jerks. At times, his
myoclonic jerks would interfere with such daily activities as
eating and dressing.
On examination, he was not able to count beyond 10 or spell
any words. No formal neuropsychological evaluation was done. The
patient was placed on 10 mg per day memantine without any
clear improvement.
The patient was admitted to the epilepsy monitoring unit for two
days. His posterior basic rhythm was of medium-amplitude and
symmetric at 7-8 Hz. Photic stimulation and hyperventilation
did not induce abnormal clinical or electrographic responses. More
than 50 myoclonic jerks were recorded which appeared most
prominent in the left arm, but clearly affected both arms and the
head at other times. Nearly all of the myoclonic jerks correlated
with generalised spike-and-wave complexes (figure 1). These
myoclonic jerks occurred every 10-30 minutes and were more frequent
during sleep and when he was tired. The myoclonus was eliminated
both clinically and electrographically after starting levetiracetam
treatment and the patient was discharged with a course of
500 mg twice a day of levetiracetam. Upon follow-up six months
later, the family reported recurrence of some subtle, occasional
jerks. The jerks abated after increasing his levetiracetam dosage
to 750 mg twice a day for a follow-up period of five
months.
Discussion
Trisomy 21, or Down syndrome, is a relatively common genetic
condition with an incidence that is dependent on maternal age. DS
occurs in one in every 725 term pregnancies in mothers aged
32 years, and one in every 12 in mothers aged
49 years (Schweber, 1989). The prevalence of dementia in DS
patients older than 35 years has been reported to be greater
than 25% (Bartolomei et al., 1995). Previously reported cases
share remarkable similarities with our cases in the presentation of
dementia, that preceded myoclonic jerks by months to years. In the
report of Crespel et al. (2007), similarities are apparent
both in terms of age of onset and precedence of dementia, as well
as similar seizure semiological and electrographic manifestations.
Levetiracetam was instituted for both patients. Myoclonic jerks
as well as EEG abnormalities resolved one to two days after
treatment. The patient of the first case study remained seizure
free until the last follow-up about four months later. His
cognition remained poor with one to two-word sentences, and
difficulty following commands. He continues to take levetiracetam,
250 mg twice a day. The second patient required a higher dose
for optimal seizure control.
Levetiracetam has been shown in open-label trials and multiple
case reports to have anti-myoclonic activity (Van Zandijcke, 2003).
Levetiracetam is well tolerated, has no interaction with other
drugs, does not require titration, and is excreted unchanged in the
urine. It has been shown to be useful in patients with myoclonus,
including juvenile myoclonic epilepsy (for which it is
FDA-approved), severe post-anoxic myoclonus (Krauss et al.,
2001) and Unverricht-Lundborg disease (Genton and Gélisse, 2000).
The mechanism of action of levetiracetam is unknown, but does not
appear to be based on any inhibitory or excitatory
neurotransmission (Striano et al., 2005). Use of levetiracetam
in myoclonic epilepsies is based on past experience with piracetam,
a structurally related compound that has shown effective
anti-myoclonic activity at high doses (Noachtar et al.,
2008).
Electrophysiological studies report that myoclonic seizures are
produced through a cortical generator via a polysynaptic mechanism
acting on the muscles (Auvin et al., 2008). Apparently, the
epileptiform discharges stimulate the motor cortex resulting in
myoclonic jerks (Auvin et al., 2008). The specific mechanisms
underlying myoclonus in DS are not yet fully understood.
Late Onset Myoclonic epilepsy in Down Syndrome (LOMEDS), as
described by Möller et al. (2001), should be suspected, or at
least anticipated in individuals with Down syndrome over the age of
35 years. Dementia may precede the onset of myoclonic jerks by
months to years. The semiology, time of day, and electrographic
findings are similar to those of juvenile myoclonic epilepsy.
De Simone et al. (2006) reported a clear improvement of
jerks after starting levetiracetam treatment in a similar case of
LOMEDS. The patients in our study responded well to low doses of
levetiracetam with complete seizure freedom, although cognition
continued to decline. This may suggest that a decline in cognition
is independent of seizure frequency, however this was based on
subjective reporting and formal neuropsychological testing before
and after the treatment of epilepsy may be warranted for a more
accurate report. Although low dose levetiracetam was very effective
in the two cases reported here, as well as a case of LOMDES
reported by De Simone et al. (2006), definite conclusions can
not be made from small numbers of case reports. We suggest that
long-term efficacy of levetiracetam should be verified in larger
controlled studies.
Disclosure
None of the authors has any conflict of interest to disclose.
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