Seizure: European Journal of Epilepsy
Volume 19, Issue 7 , Pages 383-389, September 2010

Senile myoclonic epilepsy: Delineation of a common condition associated with Alzheimer's disease in Down syndrome

  • Roberto De Simone

      Affiliations

    • Centre Saint Paul - Hôpital Henri Gastaut, 300 Boulevard Sainte Marguerite, 13258 Marseille 09, France
    • Unità di Neurologia – Centro di diagnosi e cura delle epilessie, Ospedale Sant’Eugenio, Piazzale Umanesimo 10, 00144 Roma, Italy
    • ,
  • Xavier Salas Puig

      Affiliations

    • Servicio de Neurologia Hospital General de Asturias, Oviedo, Spain
    • ,
  • Philippe Gélisse

      Affiliations

    • Epilepsy Unit, Hopital Gui de Chauliac, 34295 Montpellier Cedex, France
    • ,
  • Arielle Crespel

      Affiliations

    • Epilepsy Unit, Hopital Gui de Chauliac, 34295 Montpellier Cedex, France
    • ,
  • Pierre Genton

      Affiliations

    • Centre Saint Paul - Hôpital Henri Gastaut, 300 Boulevard Sainte Marguerite, 13258 Marseille 09, France
    • Corresponding Author InformationCorresponding author. Tel.: +33 491 170 750; fax: +33 491 170 791.

Received 2 December 2009; accepted 9 April 2010. published online 05 July 2010.

Article Outline

Abstract 

In Down syndrome (DS), epilepsy is frequent in all age classes and is recognized as a significant cause of additional handicap and morbidity. Longer life expectancy has led to the recognition of the high incidence of both Alzheimer's disease and seizures in elderly persons with DS. Neuropathological markers of AD are found in all DS brains and clinical symptoms of AD become apparent by the age of 60 years and above in over 50% of DS subjects. Following preliminary description of myoclonic seizures and/or myoclonic epilepsy in isolated cases or small series, we wish to report the diagnostic criteria, treatment and prognosis of a specific and recognizable form of epilepsy associated with AD in a larger group of middle-aged to elderly DS patients. This markedly under-recognized entity may indeed concern an already large and steadily increasing number of patients. We reviewed all medical records of patients with DS referred to our centers (Centre Saint Paul-Gastaut, Marseille; Epilepsy Unit, Montpellier University Hospital; Department of Neurology, Hospital General de Asturias, Oviedo) since 1995. DS had been diagnosed in all at birth, and all presented with the typical morphological changes associated with DS. We selected all cases (18) referred as adults with new onset of myoclonic jerks (MJ) and/or behavioral or cognitive deterioration (CD).

Keywords: Epilepsy, Myoclonic, Down

 

In Down syndrome (DS), epilepsy is frequent in all age classes and is recognized as a significant cause of additional handicap and morbidity.1, 2, 3, 4, 5 Longer life expectancy has led to the recognition of the high incidence of both Alzheimer's disease (AD) and seizures in elderly persons with DS.6 Neuropathological markers of AD are found in all DS brains7 and clinical symptoms of AD become apparent by the age of 60 years and above in over 50% of DS subjects.8 Although nearly all elderly DS patients develop seizures,9, 10 little attention has been paid to the clinical characteristic of epilepsy in this special category. Following preliminary description of myoclonic seizures and/or myoclonic epilepsy in isolated cases or small series,11, 12, 13, 14, 15, 16 we wish to report the diagnostic criteria, treatment and prognosis of a specific and recognizable form of epilepsy associated with AD in a larger group of middle-aged to elderly DS patients. This markedly under-recognized entity may indeed concern an already large and steadily increasing number of patients.

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1. Patients and methods 

We reviewed all medical records of patients with DS referred to our centers (Centre Saint Paul-Gastaut, Marseille; Epilepsy Unit, Montpellier University Hospital; Department of Neurology, Hospital General de Asturias, Oviedo) since 1995. DS had been diagnosed in all at birth, and all presented with the typical morphological changes associated with DS. We selected all cases referred as adults with new onset of myoclonic jerks (MJ) and/or behavioral or cognitive deterioration (CD). We did not use a standardized test to evaluate CD, but had to rely on the observations of caregivers, and carefully inspected the notes collected in the institutions where most patients lived. We also collected all medical files, EEG tracings, video–EEG recordings and neuroimaging data concerning these patients. All patients were seen several times. Because of variable general health and social conditions, there was no regular or scheduled uptake of the patients who were followed according to the requests of their caretakers.

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2. Results 

Eighteen observations (6 M, 12 F) fulfilled our criteria (Table 1). The cause of referral was the onset of myoclonic jerks, often associated with falls, in nine (pat. 1–3, 6, 7, 10, 14–16), a generalized tonic–clonic seizure (GTCS) in seven (pat. 5, 8, 9, 12, 13, 17, 18), while one patient (pat. 4) was already followed for preexisting epilepsy, and another patient was referred for suspected epilepsy in a context of CD, and MJ appeared only during follow-up (pat. 11).

Table 1.
BirthDeathSexFirst contactCaregiverCopathologiesOnset (years)MR/CTEEGVideo–EEG
DementiaJerksGTCSAge at death
1193272yearsF1993FamilyPhlebitis
Cataract		59596372Normal (CT)Generalized SW PPR 2 yrs before deathYes
21948 M2004InstitutionPhlebitis hypothyroidism525556 Subcortical atrophy (MRI)Generalized SW parcellar and axial myocloniaYes
31947 F2004InstitutionMitral insufficiency left eye blindness B hepatitis5257– NDDiffuse slowing; generalized slow SW, PPRNo
41966 M1995InstitutionHypothyroidism focal epilepsy at age 14, in remission363836 Normal (CT)Diffuse slowing; generalized SSWNo
51948 F1981InstitutionRetinal rupture, seizures at age 33 (in remission)525353 NDDiffuse slowing central SW and PSW PPRYes
61948 F2004InstitutionHypothyroidism
Hyperuricemia		5555– Diffuse atrophy (CT)Diffuse slowing generalized SWNo
71965 F2005FamilyHypothyroidism363940 NDGeneralized SW and polySW PPRYes
81955 F2006Institution 464745 NDDiffuse slowing generalized SWYes
91958 F2005InstitutionHypothyroidism454547 Diffuse atrophy (CT)Diffuse slowing bilateral frontal slow SWNo
101957 F2007InstitutionHypothyroidism475050 NDDiffuse slowing photic driving without PPRNo
111965 F2008InstitutionHypothyroidism3842– NDDiffuse slowingNo
121947 M1999Family 5257– Diffuse atrophy (CT)Generalized SW and polySWYes
131949 F2006InstitutionHypothyroidism475350 Diffuse atrophy (CT)Diffuse slowing generalized SW and polySW PPRYes
14194261yearsM1997FamilyLung tuberculosis55555561Diffuse atrophy (CT)Diffuse slowing generalized SW PPRNo
15195749yearsM2001Family 4444 49NDDiffuse slowingNo
161947 M1998Family 515152 NDDiffuse slowingNo
17195350yearsF2002Family 49484850Diffuse atrophy (CT)NANo
181955 F2008FamilyCataracts
Heart defect
Hypothyroidism		515253 Diffuse atrophy (CT))Diffuse slowing bilateral frontal slow SWNo

CT: computer tomography; MRI: magnetic resonance imaging; ND: not done; PPR: photoparoxysmal response; SW: spike-waves.

All patients showed signs of cognitive and behavioral deterioration with progressive loss of autonomy. Onset of cognitive deterioration occurred at a mean age of 48.2 years (median 49, SD 6.5, range 36–59). All had MJ with mean onset at 50 years (median 51, SD 6.3, range 38–59). Thirteen had GTCS: for these, average onset was at 49.8 years (median 50, SD 6.98, range 36–63); the earliest GTCS had occurred at age 36 in patient 4, who had experienced nocturnal focal seizures earlier in life.

Patients were first seen at various stages of their condition: patient 5 had been evaluated at age 33 for seizures 19 years prior to the onset of CD, and patient 12 was seen for CD 5 years before the onset of MJ. Among the other 16 patients, five were seen within 1 year of onset of cognitive deterioration (pat. 6, 14–17), although the precise onset of CD was difficult to ascertain in pat. 14–17; four between 1 and 3 years after onset (patients 1, 9, 10, 18); seven, 4 or more year after the onset (patients 2, 3, 4, 7, 8, 11, 13). Two patients had prior epilepsy, and among the 16 others, 11 were first seen within 1 year after the onset of MJ or GTCS.

Cognitive deterioration was present in all. It was marked clinically by loss of interests and social interactions, forgetfulness, disorientation in space and time. In 14 it was the initial symptom, alone or associated with myoclonus (six patients) or CGTS (one patient). In all cases, it was progressive with a final bedridden situation. All patients exhibited some type of behavioral disorder after the onset of CD. Four patients died, all were bedridden with severe dementia:

•Pat. 1, at age 72, 13 years after the onset of CD and of MJ.

•Pat. 14, 15 and 17 died at age 61, 49 and 50, respectively 6, 5 and 2 years after the onset of symptoms, which occurred in close succession, over less than a year (although CD may have preceded the occurrence of seizures in these three patients, but this could not be adequately assessed from our files; they had been referred at a late stage of their condition).

All patients exhibited MJ, which were prominent at or soon after awakening in all in the early stages of their condition, except in pat. 5 and 17, in whom the data were not reliable, and in pat. 6, in whom MJ occurred somewhat later in the morning. Myoclonic jerks appeared sometimes as asymmetrical to clinical observers and were always associated with generalized discharges on the EEG when documented. At a later stage, with progression of dementia, MJ occurred diffusely over the daytime and appeared as parcellar and less easily recognizable. Falls due to massive MJ were the main reason for referral in six patients. MJ occurred simultaneously or apparently simultaneously with the first symptoms of CD in seven (with unsatisfactory documentation of CD onset in five of these), within 2 years in four, within 3–6 years in seven.

GTCS were reported in 14 patients, including in recently evaluated pat. 10, who had her first GTCS a few weeks after her first evaluation for MJ in 2007. Patient 4 had had a series of GTCS 20 years before the onset of CD and MJ, and had been considered to be in remission of earlier epilepsy. The onset of GTCS had apparently preceded CD in 2 patients, was simultaneous with CD in two, and occurred 1–4 years after CD in the others.

EEG was performed in 17 patients (no documentation in patient 17) according to the 10–20 international system with one or more channels for EMG polygraphy and showed diffuse slowing in 13 patients, generalized spike-wave (SW) and polySW in 10, generalized and parcellar myoclonus (seven patients); in pat. 18, no MJ were recorded on the video–EEG in spite of positive history, possibly because the patient had been treated with LEV 1000mg/d prior to the first EEG recording. Video–EEG documentation of MJ was obtained in seven cases. In patient 9, EEG transiently showed also a massive diffused slowing concomitant with valproate-induced encephalopathy, after the resolution of which there was still diffuse irregular slowing and numerous isolated interictal spikes and SW. Six patients showed a photoparoxysmal response (PPR) on intermittent photic stimulation (IPS) consisting in brief myoclonic jerks, although no patient exhibited signs of photosensitivity in daily life. In patient 13, PPR was evident a 11–21Hz, appearing only 9 years after the start of CD. Successive EEG recordings showed that background activity tended to remain normal during the first years following the onset of dementia, and that sharp interictal and ictal changes increased progressively over the years, parallel to the slowing of background. Neuroimaging was performed in nine patients, showing in eight mild to moderate diffuse cortical and subcortical cerebral atrophy.

Valproate (VPA) was used at 500–1000mg/d, alone (six patients) or with levetiracetam (LEV) 1000mg/d (five patients), topiramate (TPM) 100mg/d (one patient), or lamotrigine (LTG) 50mg/d (one patient). A clear suppression of seizures was seen in five cases (two with VPA alone). LEV was used alone at the dosage of 1000mg/d (two patients) with a documented good effect on MJ (but recurrence of GTCS in one), or with VPA (five patients) or LTG 100mg/d (one patient) or piracetam (PIR) (one patient) with a documented good effect in four cases. In patient 12, the association of VPA 1000mg/d and LEV 1000mg/d appeared efficacious on MJ, whereas VPA and LEV used separately were inefficacious. TPM, LTG and PIR were used only in combination with LEV, VPA, or phenobarbital (PB) (five patients) with a documented good effect in three cases. In addition to anticonvulsants, nine patients received either antidepressants or neuroleptics or both. Hypothyroidism was compensated in all those affected. All associated conditions were considered stable.

The two following cases illustrate the progression of this condition, which was slow in patient 1 and rapid in patient 8.

Patient 1: This woman, born in 1932 was referred in 1993, at age 61 years, because of repeated falls in the morning after awakening. Bilateral MJ, evident while the patient was lying in her bed or in the early morning, had been increasingly noted for the past year. She lived with two unmarried siblings, and had neither a family history of epilepsy nor other organic complications of DS. At age of 59 she had phlebitis, at age of 60 she was operated for cataracts. A progressive cognitive decline had occurred over the past 2 years, particularly involving short-term memory and praxis, as shown by the deterioration of her marked drawing abilities (Fig. 1a and b). At awakening from nocturnal sleep, the EEG shows normal background with generalized SW and polySW associated with MJ (Fig. 2). She was given PIR 25g/d and VPA 500mg/d, but MJ, involving both arms and legs, slowly increased. A first GTCS occurred in 1995. VPA was increased to 1000mg/d. Repeated sleep EEG showed increased slowing of background. Clobazam and LEV were added to VPA and PIR, resulting in abatement of myoclonus. In 2000, a video–EEG showed erratic myoclonus, more evident in the early morning after awakening, asynchronous and predominant in the upper limbs, infrequently associated with generalized isolated spikes. IPS evoked MJ, while it had been negative in 1993. GTCS persisted (one to several per year). Cognitive impairment and dependency progressed, and the patient, bedridden for her last 2 years, died of pneumonia in March, 2005, 14 years after the onset of cognitive decline and 12 years after the onset of MJ.

  • View full-size image.
  • Fig. 2. 

    Patient 1: Polygraphic EEG performed at awakening 2 years after the onset of myoclonic jerks and before the onset of GTCS; (a and b) no slowing of background activity, generalized spike- and polyspike-and-wave complexes associated with bilateral myoclonic jerks; (c) enlargement of (b) showing the relationship between EEG discharge and jerk. Recording speed: 15mm/s.

Patient 8: This woman, born in 1955, had no family history of epilepsy and no significant personal history. In 2000, she had an isolated generalized tonic–clonic seizure, and was given phenobarbital 100mg/d. The same year, her caregivers noted progressive memory problems, confusion, and spatial and temporal disorientation. During 2002, massive myoclonus appeared, mainly in the early morning, after awakening. In 2004 she was totally dependent, unable to walk and to recognize her family. The patient was given LEV 1000mg/d with a good effect on myoclonus. In 2006, the EEG showed diffuse slowing, generalized SW associated with axial myoclonus and parcellar myoclonus without apparent EEG anomalies (Fig. 3), as well as increased subclinical SW discharges during ILS. In 2006, after several falls, VPA 1500mg/d was added. A CT was performed in 2004 and showed mild diffuse subcortical and cortical cerebral atrophy. The patient is now bedridden.

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  • Fig. 3. 

    Patient 8: Polygraphic EEG performed in the late morning 6 years after the onset of cognitive decline and GTCS, and 4 years after the onset of myoclonic jerks. The patient was already severely demented with permanent myoclonus. Note the marked slowing of the background activity and frequent diffuse bursts of spike and wave complexes, generally coupled with myoclonic jerks; also note the presence of unilateral myoclonias that are not associated with EEG activities (EMG1: right deltoid; EMG2: left deltoid). Recording speed: 15mm/s.

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3. Discussion 

In our centers, no DS patient aged more than 50 years was referred for epilepsy or cognitive deterioration who did not present with the clinical features of this “senile” myoclonic epilepsy. No patient exhibited new onset of focal seizures. Although recruitment bias is possible, this entity appears as the typical, perhaps obligate presentation of middle-aged or elderly DS subjects who experience the symptoms of AD.

The first clinical description of late-onset myoclonus in patients with DS appeared in abstract form.17 In a series of 14 patients, the EEG recordings showed no specific change. The author mentioned the use of VPA, without specifying the results. In 1994, Genton and Paglia11 described the case of a 61-year-old patient (our pat. 1). In 1995 Li et al.12 described a 51-year-old man with a first GTCS at age 50, followed by myoclonic jerks occurring either at or soon after awakening. In 2001 Mőller et al.13 described a 55-year-old patient with a first generalized myoclonic–tonic seizure; myoclonic jerks of the upper extremities had begun 3 years earlier, usually in the morning; they improved on VPA and TPM. The EEG showed generalized continuous slowing as well as generalized SW, occasionally associated with generalized MJ occurring 180–250ms after the onset of the polyspike component. Our group recently described four further cases of the syndrome (pat. 2, 5, 12, 13).15, 16 We have thus now collected 12 more cases.

Veall1 showed an increased prevalence of epilepsy in DS with increasing age (1.9% under 20 years and 12.2% over 55 years) in 1654 patients with DS, and underlined the absence of evident causes of epilepsy. This rate becomes greater after a long-term monitoring of patients: in a study covering 12 years of observation, 36.8% of DS patients had epilepsy.18 The ethnic background is important: Eastern studies, from Japan19 and China,20 showed a low rate of epilepsy in DS patients. Veall1 suggested a bimodal distribution in the age of onset of seizures, while Pueschel,5 in 405 patients with DS, aged from 0.5 to 45 years, reported a triphasic distribution of epilepsy with peaks in infancy, early adulthood, and in patients over 50–55 years. In 1994, McVicker et al.21 reported a prevalence of 9.4% in a population of 191 patients with DS, increasing with age, being particularly high (46%) in those over the age of 50; the age of distribution of epilepsy showed an early peak in the third decade; a second peak was observed in the fifth and sixth decades. The clinical features of epilepsy in DS are variable, depending on age: infantile spasms,4, 19 childhood-onset myoclonic epilepsies, reflex epilepsy22, 23 and anecdotal forms like benign myoclonic epilepsy.24 All types of seizures are represented but GTCS seem to be the most common.3

The cause of higher prevalence of epilepsy in DS is not clear: structural abnormalities and biochemical disorders of CNS may be responsible, but copathologies, e.g. cardiovascular diseases and infections, may play a part. The brain of DS patients is small and globular, with a relative paucity of cells in the cortex. Kemper25 observed a lower neural density and abnormal neuronal distribution, in particular in cortical layers 2 and 4. Dysgenesis of dendritic spines in the form of longer and thinner necks has been reported,26 and linked to epileptogenesis. Scott27 observed hyperexcitable membrane properties in cultured dorsal root ganglion neurons from fetuses with DS. A defect in serotonin uptake in platelets of DS patients and a defect in cholinergic transmission sensible to age in particular regions as the superior colliculus and substantia nigra were reported28, 29 A significant role may be played by a defect in a gene coding for a subunit of glutamatergic receptor, the GluR5, coded in distal arm of chromosome 21, a critical region for DS.30 More recently, Thiel and Fowkes31 have suggested a nutritional factor of seizure development in DS. The triple chromosome 21 results in overexpression of many enzymes that are encoded on it, with consequent over-consumption of enzymatic substrates and overproduction of metabolic end-products. For example, the overexpression of the SOD-1 gene decreases the levels of hydrogen peroxide and causes metabolic changes, with impairment of neurotransmitter synthesis and possible alterations of membrane oxidative mechanisms. The lack of many nutritional factors like vitamins, oligoelements and amino acids, and the high amount of other substances, like cysteine and phenylalanine, typical of DS patients, could also play a major role in epileptogenesis.32 Finally, epilepsy can result from a mix of several factors that could drive to the final pathway of hyper-excitability, i.e. modifications of cellular membranes, structural modification, and alteration of inhibitory transmission.

Several authors have noted that late-onset epilepsy was associated with the neuropathological changes of AD.9, 10 The high frequency of myoclonus in DS, especially in elderly patients,33 has been explained by the frequent and early onset of dementia in DS. Nevertheless, myoclonus is also a symptom of AD. In a population of 83 AD cases, Hauser et al.34 found a cumulative risk of myoclonus of 12% by 10 years after onset of AD symptoms, and 17% by 16 years. Therefore, myoclonus is an accepted symptom of AD, with a physiologic basis that is not clearly understood: Wilkins et al.35 suggested a cortical origin, thus linking seizures (also present in AD patients with a 10-fold increase of risk) and myoclonus.

DS patients over the age of 40 show neuropathological changes characteristic of AD, including neurofibrillary tangles, neuritic plaques, and neuron cell loss.36 In an extensive survey of autopsy data for adults with DS, Schweber7 found that brain pathology of AD was universal in those aged 37 and over. While increases of diffuse plaques are not associated with dementia and neuronal degenerations, increases in the numbers of neuritic plaques, containing substantial amounts of fibrillised Aβ peptides, are observed in adults with DS predominantly after 50 years of age and are associated with neuronal degeneration and loss of function.37 The clinical manifestations of AD in DS could be closely associated with the development of these neuritic plaques. A further consequence of increasing longevity of DS patients has been the increasing number of reports of AD cases. Most studies have shown that the average age at onset of dementia is between 50 and 55 years, with a range from 38 to 70 years.9, 38 Lai and Williams9 identified in 96 patients with DS and dementia three phases of clinical deterioration. Seizures, mostly tonic–clonic, emerged in 84% of the patients. The dementia associated with DS generally follows a rapidly progressive course: death typically occurs within 3–5 years from the onset. In a recent study,8 a total of 92 hospitalized persons with DS were followed from 1985 to 2000. Eighteen (21%) patients developed dementia during follow-up, with a median age of onset 55.5 years (range 45–74). Dementia was associated with neuropathological features of Alzheimer's disease, and correlated with neocortical neurofibrillary tangle densities. At the age of 60 years and above, more than 50% of patients still alive had clinical evidence of dementia. The presence of great rates of AD in DS has been explained by a dose effect of the amyloidal precursor protein (APP).39 APP on chromosome 21 appears not to be up-regulated in adult DS brains by microarray or QPCR analysis, but numerous other genes functionally linked to APP processing are dysregulated: these are involved in development (notably notch signaling and Dlx family genes), lipid transport, and cellular proliferation.40

Chromosome 21 contains several genes that have been implicated in neurodegenerative mechanisms. These include Cu/Zn superoxide dismutase (SOD-1), Ets-2 transcription factors, Down syndrome Critical Region 1 (DSCR1) stress-inducible factor, and the amyloid precursor protein (APP).41 A key component of the senile plaques is the amyloid beta-peptide which is generated from the amyloid precursor protein (APP) by sequential action of beta-secretases (BACE1 and BACE2) and gamma-secretase. While BACE1 maps to chromosome 11, APP and BACE2 are located on chromosome 21.42 Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene on chromosome 21 is overexpressed in DS, resulting in increased amounts of phospho-Ser-202-Tau and phospho-Ser-404-Tau.43

Overexpression of APP in the obligate region for DS is associated with abundant Abeta plaques and tangles consistent with Braak stages V–VI. Intraneuronal Abeta in DS appears to trigger a pathological cascade leading to oxidative stress and a neurodegeneration typical of AD. There are suggestions that an increase in subcellular processing of APP and factors related to membrane APP cleavage favor the secretion of Abeta with age in DS. A misbalance between SOD-1 and glutathione perioxidase activity in DS has been linked to free radical generation. Ets-2 and DSCR1 overexpression in DS has been linked to cell degeneration. Age-related accumulation of somatic DNA mutations in both DS and AD contribute to oxidative stress that exacerbates the imbalance in gene expression. This leads to enhanced Abeta deposition and further neuronal vulnerability.41 Factors that influence the formation of deposits of beta-amyloid in neuritic plaques and neurofibrillary tangles, such as apolipoprotein E (APOE) ɛ4 allele, oestrogen deficiency, high levels of Aβ1–42 peptides, elevated expression of BACE2, and valine polymorphism of prion protein gene, are important in the pathogenesis of AD, and in earlier onset of dementia in DS.44 DS patients with APOE ɛ4 allele had significantly higher risk of developing AD (HR=1.8, 95% CI: 1.12–2.79), had an earlier onset of AD (55.0 years vs. 57.0 years; p=0.0027) and a more rapid progression to death compared with participants with ɛ3 allele (4.2 years vs. 5.4 years, respectively, p=0.048).45 Conversely, factors that decrease the formation of Aβ, such as the APOE ɛ2 allele or atypical karyotypes (as translocations, partial trisomies or disomies, and varying degrees of mosaicism) that reduce APP gene dose, are associated with lower mortality and reduced risk of dementia.46

This entity was diagnosed after a certain delay, because of the patients’ background and social position. Indeed, the earliest referrals of our patients were due to their families, soon after the onset of MJ or GTCS. However, CD and behavioral disorders have a very gradual, progressive onset in these patients, and failed to be recognized early because of the background disability. MJ may not be perceived until they lead to falls, or the patient may be referred only after the first GTCS.

In all descriptions, dementia appears as regularly progressive, as witnessed by caregivers and/or shown by neuropsychological assessment. It is described as the first symptom of the syndrome9, 10, 11, 47; precise assessment of cognitive deterioration may be difficult in a mentally handicapped population. Specific neuropsychological testing48 is available, but we did not employ these in our patients, relying instead on clinical observations performed in the family or by caregivers in institutions. In most cases, we were able to date with fair precision the onset of the cognitive decline.

Massive, bilateral MJ, sometimes leading to falls, are the major initial feature of the epilepsy and were present in all. They occur initially and characteristically at awakening. Whenever it was possible to record them on polygraphic video–EEG, they were associated with generalized SW discharges. In a later stage, they occur more diffusely over the day, and there are also erratic, fragmentary myoclonias that are not associated with evident changes on the EEG except overall slowing. Photoparoxysmal EEG responses were found in five patients, usually at a late stage of the evolution. GTCS were not present in all, but they may occur at a later stage and had been seen in all the patients who were followed until death. In our series, three had a GTCS as the first recorded epileptic event. Treatment may prevent myoclonus and seizures, and VPA and LEV, alone or associated, appear to be the most efficacious. However, not unexpectedly, symptomatic treatment did not influence the progressive course of the condition.

The characteristics of epilepsy associated with ageing and Alzheimer-type dementia in DS appear unequivocal, and justify the term of “senile myoclonic epilepsy”, as this condition mimics, at onset, the classical syndrome of “juvenile” myoclonic epilepsy.49 Typically, this truly progressive myoclonic epilepsy follows a sequence of dementia, awakening MJ and GTCS and progresses towards erratic myoclonus, full dependency and death within years. The EEG is not very informative at onset, and sleep EEG polygraphy may be necessary to record the significant features at awakening. The EEG progressively deteriorates with slowing of background and increase of paroxysmal changes. Senile myoclonic epilepsy apparently results from the combination of a background of DS and the progressive changes associated with AD.

Down syndrome represents 1–3 per 1000 births,50 or 37.6 per 10,000 births in Paris,51 i.e. at least 1000 new cases per year in France (present population around 63 millions, with around 800,000 births per year). Given (1) the markedly increased life expectancy of DS patients, (2) the fact that all ageing DS patients are exposed to AD, and (3) that all those presenting with clinical signs of dementia are very likely to develop this type of epilepsy, senile myoclonic epilepsy will probably soon become a common epilepsy syndrome. It is already frequent, although still under-recognized. Early recognition and therapy may avoid traumatic falls and GTCS. The particular context opens wide possibilities for studies on the prevention of both AD and epilepsy. As comparatively little attention has been devoted to the characterization of epilepsy and myoclonus in non-DS AD patients, the scope of senile myoclonic epilepsy might indeed be enlarged to a much wider population at risk. At present, senile myoclonic epilepsy probably already represents the commonest form of progressive myoclonic epilepsy.

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Conflicts of interest 

The authors declare that there are no conflicts of interest.

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PII: S1059-1311(10)00083-X

doi:10.1016/j.seizure.2010.04.008

Seizure: European Journal of Epilepsy
Volume 19, Issue 7 , Pages 383-389, September 2010

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