Late onset epilepsy and dementia with Lewy bodies: Underestimated association?

Abstract

Relationship between Alzheimer's disease (AD) and late onset epilepsy (LOE) has been widely described leading to an expansion of the clinical spectrum of AD. Dementia with Lewy bodies (DLB) has scarce data detailing its association with epilepsy. We report 4 patients presenting DLB and LOE. Most of them developed LOE before the first symptoms of DLB, they all presented Parkinsonism and cognitive fluctuations, half of them presented status epilepticus and none had co-amyloid pathology, sv2a inhibitors were poorly tolerated and routine EEG were often inefficient to diagnose epileptiform abnormalities.

Keywords

Alzheimer's disease biomarkers dementia with Lewy bodies epilepsy

Introduction

It is now well established that bi-directional associations exist in the field of epilepsy and neurodegenerative disease.¹ It has been extensively described in Alzheimer's disease (AD),² late onset epilepsy (LOE) can be related to other neurodegenerative disease,³ such as dementia with Lewy bodies (DLB)^4,5 or fronto-temporal dementia,⁶ and represent a challenge in diagnosis and patient care.⁷ DLB is a neurodegenerative disease due to α-synuclein pathology, with a wide spectrum of symptoms ranging from Parkinsonism to cognitive impairment, multimodal hallucinations, autonomic dysfunction and REM sleep behavior disorder. Despite epidemiological studies,^8–11 few case reports have been published to describe the association between DLB and epilepsy as it has been widely done for AD, leading up to describe a new clinical variant of this disease.¹² Hence it is of special interest to describe natural history of epilepsy in patients with DLB in order to expand the knowledge and understanding of the association between epilepsy and DLB and to better treat those patients whose epilepsy causes augmentation of frailty and mortality.^8,13,14

In this paper, our objective was to highlight the association between DLB and epilepsy through 4 cases reports.

All cases were patients recruited in the epilepsy unit from the Neurology department, Lariboisière Hospital, France. They were assessed by one trained epileptologist with skills in LOE and neurodegenerative diseases. Epilepsy and epileptic syndromes diagnosis and classification were performed according to international criteria^15,16 including neurological exam, electroencephalograms, brain MRI interpretations. A multidisciplinary expert team (DLB Unit, Lariboisière Hospital, Paris, France, dedicated to the assessment and treatment of DLB) performed DLB diagnosis, including neurological exam, nuclear imaging, cerebrospinal fluid (CSF) biomarkers and neuropsychological testing. DLB diagnosis were performed according to McKeith et al.¹⁷

Table 1 summarizes the 4 cases.

Table 1.

Clinical, paraclinical and treatment of the 4 cases.

Patients	Case 1	Case 2	Case 3	Case 4
Medical history of interest	– 1 episode of Febrile seizure in childhood	– Depression-anxiety syndrome – Obstructive sleep apnea syndrome – atrial fibrillation	None	– Depression-anxiety syndrome – medullar aplasia
Age (y) at cognitive disorder	74	78	55	62
Age (y) at first seizure	73	69	58	59
Seizure type	– unknown onset, tonic-clonic – Status	– Focal onset with impaired awareness, aphasia and right upper limb dystonia – Status	– unknown onset, myoclonia of upper limbs	– diurnal focal onset with impaired awareness, aphasia, oroalimentary automatisms – nocturnal, unknown onset, tonic clonic
MMSE at X years old	24/30 at 74 and 76	28/30 at 79, 23/30 at 80	17/30 at 61	22/30 at 69
DLB clinical criteria Core clinical features	– fluctuating cognition – parkinsonism – recurrent visual hallucinations – REM sleep behavior disorder	– fluctuating cognition – parkinsonism – recurrent visual hallucinations	– fluctuating cognition – Parkinsonism – recurrent visual hallucinations – REM sleep behavior disorder	– fluctuating cognition – parkinsonism – REM sleep behavior disorder
Supportive clinical features	– auditive hallucinations	– constipation	– autonomic dysfunction – constipation – urinary incontinence – orthostatic hypotension – repeated falls – anosmia – delusions	– sensory hallucinations – autonomic dysfunction – constipation – anosmia
EEG	– slow wave posterior activity in theta range 7–8 Hz – no epileptiform activity	– slow wave posterior activity in theta range 7Hz – temporal and occipital delta activity slow waves	– slow wave posterior activity in theta range 6 Hz – bilateral spikes with right predominance of temporal and parietal areas	– Normal posterior activity – no epileptiform activity
MRI	– no epileptogenic lesion – Insular atrophy	– no epileptogenic lesion – bilateral hippocampal atrophy (Scheltens 3)	– no epileptogenic lesion – bilateral hippocampal atrophy (Scheltens 2)	– no epileptogenic lesion – diffuse cortical atrophy
CSF biomarkers/amyloid PET	Normal CSF biomarkers (amyloid, tau, ptau)	Negative amyloid PET	Normal CSF biomarkers (amyloid, tau, ptau)	Normal CSF biomarkers (amyloid, tau, ptau)
Neuropsychological assessment	Episodic memory dysfunction	Executive dysfunction Episodic memory dysfunction	Not done	Executive dysfunction Episodic memory dysfunction
Anti-seizure treatment, side effects	Levetiracetam :2000 mg/day, stopped for side effects. Then Lamotrigine : 150 mg/day, efficient	Levetiracetam: 1000 mg/day then 1500 mg/day, stopped for inefficiency and side effects Then Lamotrigine 150 mg/day, efficient	Lamotrigine: stopped for side effects during increasment. Then Valproate 1000 mg/day : stopped for side effects Then Briviact 25mgx2/j: inefficient	Levetiracetam 1000 mg/day: inefficient Lacosamide 200 mg/day: inefficient Then Lamotrigine 200/d + zonisamide 400/d : better efficiency
Epilepsy treatment response	Pharmaco sensitive	Pharmaco sensitive	Pharmaco resistant	Pharmaco resistant
DLB treatment	Melatonine	none	Melatonine DOPA Rivastigmine	Melatonine

DLB: dementia with Lewy bodies; REM: roll eye movement; EEG: electroencephalogram; CSF: cerebrospinal fluid; MMSE, Mini-Mental State Examination.

Case 1

A 73-year-old man developed a LOE by presenting status epilepticus with bilateral tonic-clonic seizures of unknown cause. Brain MRI showed insular atrophy and white matter hyperintensities (grade Fazekas 2). Post status standard and sleep Electroencephalogram (EEG) showed no epileptic activity but a slowing of the dominant rhythm between 6–8 Hz. He was initially treated by LEVETIRACETAM 2000 mg per day, treatment was switched to LAMOTRIGINE 150 mg per day due to side effect (irritability). Epilepsy was pharmaco-sensitive and he did not experience other seizures. One year later at the age of 74 his wife noticed cognitive difficulties associated with cognitive fluctuations and the patient reported to have visual and auditory hallucinations, REM sleep behavior disorder (RBD, he was fighting in his bed). Complete physical examination showed a parkinsonian rigidity in the right upper limb. Complete neuropsychological assessment showed episodic memory deficit, MMSE score was 24/30 (same score was performed at age 76). CSF biomarkers were normal (Aβ_{1–42/1–40}= 0.11 (N > 0.07), Tau 155 pg/mL (N < 220) and phosphorylated tau 11.8 pg/mL (N < 22)). We concluded to the diagnosis of DLB with mild cognitive impairment and epilepsy. After 4 years of follow-up the patient had a slight loss of autonomy in instrumental activities of daily living.

Case 2

A 69-year-old man with a medical history of stable depression-anxiety syndrome treated with mirtazapine and sertraline, stable obstructive sleep apnea treated with continuous positive airway pressure with and stable atrial fibrillation treated with oral anticoagulation developed a LOE of unknown cause with focal seizures with impaired awareness associating dystonic posture of the right upper limb and aphasia. Brain MRI showed global cortical atrophy, bilateral hippocampal atrophy (grade Scheltens 3) and white matter hyperintensities (grade Fazekas 2). Standard and sleep EEG showed no epileptic activity but a slowing of the dominant rhythm at 7 Hz and left temporal-occipital slow waves. He was initially treated by LEVETIRACETAM 1000 mg per day. Starting age 74 he reported a resting tremor of the right upper limb then in the following years visual hallucinations, constipation and cognitive complaint with fluctuations. Complete physical examination showed bilateral parkinsonian rigidity of upper limbs. A first neuropsychological assessment at age 78 showed mild executive dysfunction, MMSE was 28/30. He experienced a focal status epilepticus at age 79 (no cause was found, per-critic brain MRI showed DWI hyperintensities in the left pulvinar and temporal lobe) with aphasia, and dystonic posture of the right upper limb lasting 1 h 30 min, then transient motor deficit of the right limb and aphasia lasting 48 h. Treatment was then switched to LAMOTRIGINE 150 mg per day because of side effect (increased depression and anxiety). Epilepsy was pharmaco-sensitive and he did not experience any other seizures. He then noticed more cognitive difficulties, the second neuropsychological assessment (at age 80) showed a persistent executive dysfunction associated with verbal episodic memory deficit and the MMSE decreased to 23/30. PET-amyloid imaging (CSF Aβ and tau biomarkers were contraindicated because of curative anticoagulation) was normal, FDG-PET showed hypofixation in precuneus, posterior cingulum, and left intern and lateral temporal cortex. We concluded to the diagnosis of DLB with mild cognitive impairment and epilepsy. After 2 years of follow-up the patient had a slight loss of autonomy.

Case 3

A 55-year-old man with no medical history progressively developed a parkinsonian syndrome consisting in tremor of the left upper limb, rigidity of the 4 limbs, RBD, hyposmia, occasional constipation, visual hallucinations, delusional ideas, frequent falls and dysautonomia with orthostatic hypotension and urinary incontinence. He was treated with LEVODOPA 62.5 mg x3 per day, rivastigmine and melatonin without efficacy. At age 58 he started having cognitive complaint with MMSE score 17/30. He developed simultaneously intermittent myoclonus of the 4 limbs prevailing on the right upper limb. He completed paraclinic assessment with brain MRI showing bilateral hippocampal atrophy (grade Scheltens 2), an EEG with a slowing of the dominant rhythm to 6 Hz with bilateral temporal-parietal spikes prevailing on the right side, and CSF Aβ and tau biomarkers (performed in another center than ours) were normal and genetic testing on SNCA gene was negative. Treatment for myoclonus was initiated with LAMOTRIGINE but he had to stop because of a skin rash, then VALPROATE was used and stopped because of side effects, then he was treated with BRIVARACETAM up to 100 mg per day with a better efficacy on myoclonus, which were still persistent nevertheless. It was concluded to a DLB with pharmaco resistant myoclonic epilepsy. At age 61 he was dependent for all daily-living activities.

Case 4

A 59-year-old man with a history of cured medullar aplasia and depression anxiety syndrome progressively developed a LOE with focal seizures with impaired awareness, aphasia, oro-alimentary automatisms, and developed 2 years later tonic-clonic seizures during sleep. One year after developing focal seizures he developed a cognitive complaint with, isolated right upper limb rest tremor, RBD, hyposmia, constipation, cognitive fluctuations, as well as sensory hallucinations and sense of presence. He had no dysautonomia (no orthostatic hypotension). Brain MRI showed slight cortical atrophy without lobar predominance and repeated EEG were all considered as normal without focal slowing or interictal epileptic discharges. Neuropsychological assessment showed executive dysfunction and episodic memory impairment, MMSE was 22/30. CSF biomarkers were normal (Aβ_{1–42/1–40}= 0.16 (N > 0.07), tau 170 pg/mL (N < 220) and phosphorylated tau 15.9 pg/mL (N < 22)). It was concluded he had DLB with impaired awareness focal seizures and focal to bilateral seizures. He was initially treated with LEVETIRACETAM up to 500 mg x2/d, which was poorly tolerated (increased depression). Treatment was switched to LAMOTRIGINE up to 200 mg/d and LACOSAMIDE 200 mg/d but he had side effects (dizziness) and LACOSAMIDE was discontinued and replaced by ZONISAMIDE up to 400 mg/d, which improved seizures with absence of bilateralized seizures but persistence of focal seizures. Its epilepsy was considered pharmacoresistant. At age 69, he was still independent in daily-living activities.

Discussion

This paper assesses the epileptic and cognitive features in patients presenting LOE and DLB.

Time period between development of late onset epilepsy and DLB symptoms

In our study, we describe one classical case of myoclonic epilepsy developing 3 years after first DLB symptoms (case 3) and 3 patients (case 1-2-4) developing LOE before the first reported symptoms of DLB (between 1 and 9 years). Based on cases 1, 2, and 4 it is early to make the hypothesis that epilepsy should be part of the DLB clinical spectrum as well as Alzheimer's disease,^18–20 but some work should be done to untangle the relationship between epilepsy and DLB.

Parkinsonism and cognitive fluctuations in late onset epilepsy: key points to diagnose DLB?

All patients of our cases reports presented parkinsonism. Cretin described this feature in late onset epilepsy associated with neurodegenerative disease.²¹ The presence of this feature in the clinical exam should bring neurologists to complete neurological clinical and paraclinic assessment in those patients, thus they may find diagnosis criteria of DLB. All patients reported cognitive fluctuations too, which can be challenging to differentiate from focal seizures with impaired awareness, nevertheless and despite no EEG recording during cognitive fluctuations, they were well established by careful history taking¹⁸ and not misdiagnosed as focal seizures. Those two symptoms should be well sought in LOE.

Seizure and status epilepticus in DLB patients

In accordance with the literature of LOE, the patients with DLB presented various types of seizures²² including status epilepticus in half cases. Status epilepticus can be challenging in epilepsy of the elderly and can sometimes be confounded with cognitive fluctuations in DLB, nevertheless it is of particular importance to make the diagnosis because of its consequences on morbidity including future cognitive impairment,²³ in our cases, patient no.2 experienced a worsening of its cognition after a status. In line with cognition, patient no.3 who had pharmaco-resistant myoclonic epilepsy had a worse cognitive outcome.

Cognitive outcome and mechanisms of epileptogenesis in DLB

In AD uncontrolled epilepsy could be the cause of cognitive worsening in connection with the spreading of amyloid deposition due to seizures,²⁴ numerous mechanisms of epileptogenesis have been proposed in AD.²² In DLB mechanisms by which α-synuclein contributes to epilepsy could be activation of astrocytes and microglia, enhancing glial pro-inflammatory activity cytokines, nitric oxide, and reactive oxygen species. More investigations are warranted to determine whether lowering α-synuclein levels or inhibiting its aggregation in the brain modulates epilepsy,⁴ and thus cognitive outcome.

EEG reports in DLB

Routine and 1 h sleep EEG were not efficient to bring out epileptiform abnormalities except for patient 3 who experienced uncontrolled myoclonic epilepsy. They showed mostly slowing of the dominant rhythm, which has been lately described in DLB^25,26 and which is not specific of epilepsy, long term EEG should be recommended for those patients as ear-EEG to detect epileptiform activity in late onset epileptic patients with DLB.^10,27 Nevertheless, gold standard exams to detect epileptiform activity are 24-h EEG monitoring and setereotactic EEG (SEEG), which are poorly available for those patients in clinical practice.

Amyloid assessment in late onset epilepsy

All patients underwent AD biomarkers assessment, and no one had amyloid pathology. The presence of the sole α-synucleinopathy without amyloid deposition consolidate our diagnosis of DLB and that epilepsy could not be linked to a co-pathology with AD. Nevertheless, it should be interesting too to assess the clinical course of patients with co-pathology and epilepsy as it has never been explored before.

Anti-seizure medications outcome

In our cases reports LAMOTRIGINE was better tolerated and effective than SV2A inhibitors (LEVETIRACETAM and BRIVARACETAM). It is a point of interest since sv2a inhibitors are quite recommended in patients with neurodegenerative disease and late onset epilepsy.²⁸ Our experience on 4 patients indicates that sv2a inhibitors should be cautiously assessed in more DLB patients in further studies.

Our study is of particular interest since it points out that patients with LOE referred in epilepsy unit can develop in few years DLB (in our report: cases 1-2-4). One patient developed a more severe phenotype in cognitive and epileptic feature (case 3), it is the youngest and only patient who developed DLB before epilepsy, actually we could not assess why this patient had a worse cognitive and seizure control outcome than the others. DLB can be challenging to diagnose,¹⁷ there is actually no direct biomarker allowing to make a rapid diagnosis of α-synucleinopathy despite the development of real time quaking induced conversion test to detect α-synuclein, not available in large-scale clinical practice.^29,30 Focus should be made on diagnosing DLB in patients with late onset epilepsy given that treatment of epilepsy could change the course of the neurodegenerative disease, as well as AD.¹⁸ Unfortunately, and despite our high involvement in patient care, it was not possible to unify and standardize the clinical follow up (high interval between cognitive disorder and MMSE in cases 3 and 4, and between first seizure and MMSE in case 2 and between first seizure and MMSE in cases 2 and 4) and paraclinical examination (genetic assessment available only for case 3) for all patients. Further studies should be appropriate to compare the course of LOE evolving to DLB and conversely DLB developing epilepsy, to describe epileptic syndromes, cerebral pathology (α-synuclein associated or not with amyloid pathology), and antiseizure medication response in order to find predictive factors and better understand and treat those patients as it has been done previously in AD.

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

ORCID iD

Maximilien Porché

Ethical considerations

This case series was approved by the local ethic committee of Bichat University, Paris, France (CEERB GHU Nord n°10–037).

Consent to participate

Informed consent was obtained from the patients.

Consent for publication

Participants provided informed consent for allowing the publication of data.

Author contributions

Maximilien Porché (Conceptualization; Investigation; Writing – original draft); Julien Dumurgier (Writing – review & editing); Claire Hourrègue (Writing – review & editing); Claire Paquet (Supervision; Writing – review & editing).

Funding statement

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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