Regresja zespołu Downa (DSDD/URDS)

​Aller-Alvarez, J.S., Menéndez-González, M., Ribacoba-Montero, R., Salvado, M., Vega, V., Suárez-Moro, R., Sueiras, M., Toledo, M., Salas-Puig, J., & Alvarez-Sabin, J.  Neurologia. 2017 Mar, 32(2), 69-73. English, in Spanish. doi: 10.1016/j.nrl.2014.12.008.                
 

Patients with Down syndrome (DS) who exhibit Alzheimer disease (AD) are associated with age. Both diseases with a common neuropathological basis have been associated with late-onset myoclonic epilepsy (LOMEDS). This entity presents electroencephalogram features as generalized polyspike-wave discharges. Authors present a series of 11 patients with the diagnosis of DS or AD who developed myoclonic seizures or generalized tonic-clonic seizures. In all cases, clinical and neuroimaging studies and polygraph EEG monitoring was performed. In all cases, cognitive impairment progressed quickly after the onset of epilepsy causing an increase in the degree of dependence. The most common finding in the EEG was a slowing of brain activity with theta and delta rhythms, plus intercritical generalized polyspike-waves were objectified in eight patients. In neuroimaging studies was found cerebral cortical atrophy. The most effective drug in this series was the levetiracetam. The association of generalized epilepsy with elderly DS represents an epiphenomenon in evolution which is associated with a progressive deterioration of cognitive and motor functions. This epilepsy has some electroclinical characteristics and behaves as progressive myoclonic epilepsy, which is probably related to the structural changes that characterize the evolutionary similarity of DS with AD. Recognition of this syndrome is important, since it has prognostic implications and requires proper treatment.

Altuna, M., Giménez, S., & Fortea, J. Journal of Clinical Medicine, 2021 (June 24), 10(13). 2776- [e-print].  doi: 10.3390/jcm10132776.

Individuals with Down syndrome (DS) have an increased risk for epilepsy during the whole lifespan, but especially after age 40 years. The increase in the number of individuals with DS living into late middle age due to improved health care is resulting in an increase in epilepsy prevalence in this population. However, these epileptic seizures are probably underdiagnosed and inadequately treated. This late onset epilepsy is linked to the development of symptomatic Alzheimer's disease (AD), which is the main comorbidity in adults with DS with a cumulative incidence of more than 90% of adults by the seventh decade. More than 50% of patients with DS and AD dementia will most likely develop epilepsy, which in this context has a specific clinical presentation in the form of generalized myoclonic epilepsy. This epilepsy, named late onset myoclonic epilepsy (LOMEDS) affects the quality of life, might be associated with worse cognitive and functional outcomes in patients with AD dementia and has an impact on mortality. This review summarizes the current knowledge about the clinical and electrophysiological characteristics, diagnosis and treatment of epileptic seizures in the DS population, with a special emphasis on LOMEDS. Raised awareness and a better understanding of epilepsy in DS from families, caregivers and clinicians could enable earlier diagnoses and better treatments for individuals with DS.

Collacott R.A.  Journal of Intellectual Disability Research, 1993, 37( 2), 153-60.  doi: 10.1111/j.1365-2788.1993.tb00582.x. 

Widespread inquiry identified 378 adults with Down syndrome resident in Leicestershire, England. The immediate carer of 351 of these (92.8%) was interviewed for the purpose of establishing a past history of seizures, including the age at which the seizures began. The immediate carer was also invited to provide information to enable the completion of an Adaptive Behaviour Scale (A.B.S.) rating. Individuals with a history of seizures were divided into two groups on the basis of whether or not seizures commenced prior to or after age 35 years. Two control groups of individuals with Down syndrome, but without a history of seizures were selected. Adaptive Behavior Scale scores for those in whom seizures commenced at a younger age were similar to those who had no recorded history of seizures. However, in those in whom seizures began in later life, scores on all domains of the A.B.S. were significantly reduced compared to both young epileptic patients and their controls. Adaptive Behavior Scale scores for the older control group held an intermediate position, suggesting that late-onset epilepsy may be a late manifestation of a dementing process. A clinical diagnosis of dementia recorded in the case records was significantly associated with the presence of late-onset epilepsy. This is supportive of the hypothesis that late-onset epilepsy in individuals with Down's syndrome is associated with Alzheimer's disease.

Corniello, C., Dono, F., Evangelista, G., Consoli, S., De Angelis, S., Cipollone, S., Liviello, D., Polito, G., Melchiorre, S., Russo, M., Granzotto, A., Anzellotti, F., Onofrj, M., Thomas, A., & Sensi, S.L. Seizure, 2023 Jul, 109, 62-67. doi: 10.1016/j.seizure.2023.05.017.

Late onset myoclonic epilepsy in Down Syndrome (LOMEDS) is a peculiar epilepsy type characterized by cortical myoclonus and generalized tonic-clonic seizures (GTCS), in people suffering from cognitive decline in Down syndrome (DS). In this review, we analyzed available data on the diagnostic and therapeutic management of individuals with LOMEDS.  We performed a systematic search of the literature to identify the diagnostic and therapeutic management of patients with LOMEDS. The following databases were used: PubMed, Google Scholar, EMBASE, CrossRef. Data from 46 patients were included. DS was diagnosed according to the patient's clinical and genetic characteristics. Diagnosis of Alzheimer's dementia (AD) preceded the onset of epilepsy in all cases. Both myoclonic seizures (MS) and generalized tonic-clonic seizures (GTCS) were reported, the latter preceding the onset of MS in 28 cases. EEG was performed in 45 patients, showing diffuse theta/delta slowing with superimposed generalized spike-and-wave or polyspike-and-wave. A diffuse cortical atrophy was detected in 34 patients on neuroimaging. Twenty-seven patients were treated with antiseizure medication (ASM) monotherapy, with reduced seizure frequency in 17 patients. Levetiracetam and valproic acid were the most used ASMs. Up to 41% of patients were unresponsive to first-line treatment and needed adjunctive therapy for seizure control. AD-related pathological changes in the brain may play a role in LOMEDS onset, although the mechanism underlying this phenomenon is still unknown. EEG remains the most relevant investigation to be performed. A significant percentage of patients developed a first-line ASM refractory epilepsy. ASMs which modulate the glutamatergic system may represent a good therapeutic option.

Devinsky, O. Lancet Neurology, 2026 Jan 26. https://doi.org/10.1016/S1474-4422(25)00496-X

Epilepsy and Alzheimer's disease are bidirectionally related. Epilepsy is often complicated by progressive cognitive impairments, and late-onset epilepsy (onset generally after 55-65 years of age) is a strong risk factor (≥2-fold) for dementia and Alzheimer's disease. Conversely, people with Alzheimer's disease have a 2-fold or higher increased risk of seizures or epilepsy than the age-matched general population. Risk factors for dementia among people with epilepsy include late-onset epilepsy, treatment resistance, high seizure burden, long duration of epilepsy, structural brain lesions, APOE ε4 alleles carriership, and vascular risk factors. In turn, risk factors for epilepsy among people with Alzheimer's disease include early-onset Alzheimer's disease, greater tau or amyloid burden, more severe cognitive impairment or advanced Alzheimer's disease stage, APOE ε4 alleles carriership, structural brain lesions, and coexisting psychiatric disorders. The mechanisms underlying this bidirectional relationship are poorly understood. The contribution of seizures and epileptiform activity to the clinical course of dementia remains unclear. The association of epileptic activity with rapid cognitive decline in Alzheimer's disease might either reflect that epileptic activity drives cognitive decline or that greater burden of Alzheimer's disease pathology independently drives both epileptic activity and cognitive decline, or that a combination of these factors is responsible. Whether cognitive decline drives epileptic activity or not is unknown.

Gholipour., T, Mitchell, S., Sarkis, R.A., & Chemali, Z.  Epilepsy & Behavior, 2017 Mar; 68, 11-16. doi: 10.1016/j.yebeh.2016.12.014. Epub 2017 Feb 10.

Adults with Down syndrome (DS) are at higher risk of developing Alzheimer-type dementia and epilepsy. The relationship between developing dementia and the risk of developing seizures in DS is poorly characterized to date. In addition, treatment response and medication tolerability have not been rigorously studied.  We identified 220 patients with a diagnosis of DS and dementia. Those without a history of developing seizures (DD) were compared to patients with new-onset seizures (DD+S) after the age of 35. Electronic records were reviewed for demographics, seizure characteristics, cognitive status, and psychiatric comorbidities.  Of the patients included for analysis, twenty-six out of 60 patients had new-onset seizures or developed seizures during the follow-up period (the DD+S group) with a median onset of 2.0years after the dementia diagnosis. Generalized tonic-clonic seizures were the most common seizure type (61.5% of DD+S). Sixteen (61.5%) patients were reported to have myoclonus. Levetiracetam was the most commonly used initial medication, with the majority (73%) of patients treated achieving partial or complete seizure control. The DD+S patients tended to have a similar burden of new-onset neuropsychiatric symptoms compared to the DD group.  New-onset epilepsy seems to occur early in the course of dementia in DS patients. Patients generally respond to treatment. A great burden of neuropsychiatric symptoms is seen. Future studies need to explore the relationship between ß-amyloid accumulation and epileptiform activity and attend to the care and needs of DS patients with dementia and seizures.

Lott, I.Y., Doran, E., Nguyen, V.Q., Tournay, A., Movsesyan, N., & Gillenc, D.L.  Journal of Alzheimer’s Disease, 2012,  29(1),177-185. doi:10.3233/JAD-2012-111613

The objective of this study was to determine the association of seizures and cognitive decline in adults with Down syndrome (DS) and Alzheimer's-type dementia. A retrospective data analysis was carried out following a controlled study of antioxidant supplementation for dementia in DS. Observations were made at baseline and every 6 months for 2 years. Seizure history was obtained from study records. The primary outcome measures comprised the performance-based Severe Impairment Battery (SIB) and Brief Praxis Test (BPT). Secondary outcome measures comprised the informant-based Dementia Questionnaire for Mentally Retarded Persons and Vineland Adaptive Behavior Scales. Because a large proportion of patients with seizures had such severe cognitive decline as to become untestable on the performance measures, time to “first inability to test” was measured. Adjustments were made for the potentially confounding co-variates of age, gender, APOE44 status, baseline cognitive impairment, years since dementia onset at baseline, and treatment assignment. The estimated odds ratio for the time to “first inability to test” on the SIB comparing those with seizures to those without is 11.02 (95% CI: 1.59, 76.27), a ratio that is significantly different from 1 (p = 0.015). Similarly, we estimated an odds ratio of 9.02 (95% CI: 1.90, 42.85) on the BPT, a ratio also significantly different than 1 (p = 0.006). Results from a secondary analysis of the informant measures showed significant decline related to seizures. We conclude that there is a strong association of seizures with cognitive decline in demented individuals with DS. Prospective studies exploring this relationship in DS are indicated.

Möller, J,C,, Hamer, H,M,, Oertel, W,H,, & Rosenow, F.   Seizure, 2001 Jun,10(4) 303-306. doi: 10.1053/seiz.2000.0500. 

The authors report about a patient with late-onset myoclonic epilepsy in Down's syndrome (LOMEDS) as a differential diagnosis of adult-onset progressive myoclonic epilepsies. A 55-year-old male with Down's syndrome (DS) is described who developed progressively frequent myoclonus and generalized myoclonic-tonic seizures (GMTSs) at the age of 52. EEG recordings demonstrated background slowing and generalized polyspike-wave discharges occasionally associated with myoclonic jerks, leading to the classification of primary generalized epileptic myoclonus. Descriptions of late-onset epilepsy in DS patients are rare. However, a review of the pertinent literature revealed at least two other cases of elderly DS patients developing progressive myoclonic epilepsy after the onset of dementia. We suggest that late-onset myoclonic epilepsy in Down's syndrome as characterized here should be considered in the differential diagnosis of adult-onset myoclonic epilepsies. LOMEDS apparently shares features with myoclonic epilepsy in Alzheimer's disease (AD) and Unverricht-Lundborg disease (ULD) caused by a mutation on chromosome 21. Since life expectation of DS patients has markedly increased, LOMEDS may be more frequent than currently acknowledged.

Puri, B.K., Ho, K.W., & Singh, I.  International Journal of Clinical Practice, 2001, 55(7), 442-444.  https://pubmed.ncbi.nlm.nih.gov/11594252/

In a cohort of 68 adults (35 males and 33 females) with Down syndrome aged 29-83 years, a history of seizures was found in 26.5%. The overall mean age of onset of seizures was 37 years, males (22 years) being significantly younger than females (51 years). The age of onset was bimodally distributed, with the first peak occurring in the first two decades, and a late-onset peak occurring in the fifth and sixth decades. A strong association between Alzheimer's disease and seizures was confirmed. Of those with a history of seizures, those aged over 45 years were significantly more likely to develop Alzheimer's disease than those younger than 45. It is suggested that late-onset epilepsy in Down syndrome is associated with Alzheimer's disease, while early-onset epilepsy is associated with an absence of dementia.

Queder, N., McMillan, L., Sathishkumar, M., Taylor, L., Keator, D., Doran, E., Hom, C., & Mchale, S., Petersen, M., O'Bryant, S.,, Brickman, A., Head, E., Mapstone, M., Silverman, W., Lott, I., & Yassa, M.  Alzheimer's & Dementia, 2025, 20. 10.1002/alz.094071. 

There is an increased risk of epilepsy in Down syndrome (DS), especially after the age of 40. The onset of this co-occurring disease is closely associated with Alzheimer's disease (AD) related cognitive deterioration. Therefore, understanding the impact of late-onset epilepsy on AD biomarkers in people with DS is crucial. Here, we aim to test the difference in tau levels and hippocampal volume in people with late-onset seizures, childhood-onset seizures, and no seizures. We analyzed data from 54 participants (52 +/- 6.5 years, 66% females) with DS enrolled in the Alzheimer's disease Down syndrome study. A total of 18 participants had a history of seizures: 9 participants had recent onset of seizures in the last 5 years and 9 participants had childhood-onset of seizures. A 2-to-1 match method was used to identify 36 control match participants based on age, sex, and dementia status. Magnetic resonance imaging (MRI) and flortaucipir (FTP) positron emission tomography (PET) were used to assess atrophy and tau accumulation respectively. Plasma ptau181 levels were assessed using the ultra-sensitive single molecule array (Simoa) technology platform HDX imager. ANOVA was used to assess group differences. The results showed significant differences in ptau181 levels between individuals with late-onset seizure disorder, individuals with childhood-onset of seizures, and controls (F(2,51)= 9.649; p<.001). Post-hoc analysis revealed that individuals with late-onset seizure disorder had significantly higher levels of ptau181 compared to individuals with childhood-onset (p<.001) and controls (p = 0.002), with no differences between childhood-onset seizures and controls. No differences were observed in the hippocampus volume among the three groups. Differences in the temporal meta-ROI tau SUVR were assessed in a subset of our sample. We observed a trend in individuals with history of seizures showing higher tau SUVR in the temporal meta-ROI compared to controls. Our findings suggest that the levels of ptau181 could be impacted by late-onset seizure disorder. These results shed the light on the importance of assessing the impact of co-occurring disorder on AD related biomarkers. Future research will explore the impact of late-onset seizure disorder on AD-related brain biomarkers longitudinally.

Vossel, K., Johnson, E.L., Cretin, B., Matsumoto, R.  Lancet Neurology, 2026 Jan 29. doi: 10.1016/S1474-4422(25)00425-9 

An estimated 60% of patients with Alzheimer's disease develop epilepsy or subclinical epileptiform activity over the course of the disease. New-onset seizures in cognitively healthy adults also increase the risk of developing dementia. Epileptic activity, including both seizures and subclinical epileptiform discharges, can hasten the onset of Alzheimer's disease and accelerate cognitive decline. Studies are investigating whether antiseizure medications could improve cognitive outcomes, particularly in patients with Alzheimer's disease with epileptic activity. Detection of epileptic activity in people with Alzheimer's disease requires high clinical vigilance and neurophysiological monitoring. Evaluation and treatment of late-onset epilepsy or Alzheimer's disease-associated epileptic activity should be informed by clinical advances. Epilepsy management is especially important in patients receiving anti-amyloid monoclonal antibodies, which can increase seizure risk. Recent insights support the concept of an epileptic subtype of Alzheimer's disease, position epileptic activity as a modifiable risk factor in Alzheimer's disease, highlight innovations for earlier identification of epileptic activity, and provide evidence supporting the need for early detection and targeted treatment across the stages of Alzheimer's disease.