Epilepsy Research (2014) 108, 349—354
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
Parkinson’s disease: Less epileptic seizures more status epilepticus Berend Feddersen ∗,1, Jan Rémi, Marion Einhellig, Cordula Stoyke, Philipp Krauss, Soheyl Noachtar Epilepsy Center, Department of Neurology, University of Munich, Germany Received 2 April 2013; received in revised form 22 October 2013; accepted 12 November 2013 Available online 21 November 2013
KEYWORDS Epilepsy; Parkinson’s disease; Seizure; Status epilepticus; Dopamine
Summary We compared the rate of epilepsy and status epilepticus (SE) in patients with and without Parkinson’s disease (PD). Out of 1215 patients with idiopathic PD, 31 had epilepsy and 19 of these had at least one episode of SE (61.3%) compared to 298 of 2537 patients (11.7%; p < 0.001) with epilepsy and without concomitant PD. This clinical finding supports the hypothesis that the functional impairment of the basal ganglia in PD patients makes SE more likely. © 2013 Elsevier B.V. All rights reserved.
Introduction Epidemiologic studies suggest that the incidence of epilepsy in patients with idiopathic Parkinson’s disease (PD) compared to an age-matched normal population is remarkably low, consisting of only one or two cases for 100,000 individuals over the age of 60 (Vercueil, 2006). Additionally, epilepsy patients may have a seizure reduction or even attain seizure freedom, in case they develop PD (Vercueil, 2000). It has been hypothesized, that these influences may be due to increased intracortical inhibition which may result
∗ Corresponding author at: Epilepsy Center, Department of Neurology, University of Munich, Marchioninistr. 15, 81377 Muenchen, Germany. Tel.: +49 89 7095 0; fax: +49 89 7095 6691. E-mail address: [email protected] (B. Feddersen). 1 Current address: Department of Palliative Medicine, University of Munich, Marchioninistr. 15, 81377 Muenchen, Germany.
from changes in cortical excitability (Brown and Marsden, 1984), or that the associated dopaminergic drugs may suppress seizures. The latter has been demonstrated in selected epilepsy syndromes (Mervaala et al., 1990), but is not yet used in clinical practice. A decrease in dopaminergic tone may not always be beneficial, as demonstrated for patients with ring chromosome 20. These patients have a decreased bilateral striatal 18[F]fluoro-L-DOPA uptake (Biraben et al., 2004). They have long-lasting generalized seizures that often evolve into status epilepticus (SE) and it was suggested that the dysfunction of the striatal dopaminergic neurotransmission may impair seizure cessation (Biraben et al., 2004). Furthermore, in a genetic model of absence epilepsy, rats showed seizure aggravation following a decrease in dopaminergic tone, and seizure inhibition through dopaminergic stimulation (Deransart and Depaulis, 2002). These differential effects on the occurrence of single seizure on one hand and the possible failure in seizure termination on the other hand led us to hypothesize that PD
0920-1211/$ — see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2013.11.013
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patients, despite being known to have less seizures and a reduced incidence of epilepsy, may have a higher incidence to develop SE. We, therefore, studied the incidence of SE in patients with PD and without PD.
Methods The electronic medical reports for all in- and outpatients of the Department of Neurology, University of Munich of the years 2000—2006 were retrospectively searched for the terms ‘‘Parkinson’s disease’’, ‘‘dopaminergic deficit’’, ‘‘epilepsy’’, ‘‘epileptic seizure’’, and ‘‘status epilepticus’’. All resulting reports were reviewed and the diagnoses of PD and epilepsy were reviewed according to clinical criteria from the records. We included only PD patients with idiopathic Parkinson syndrome, which means that the PD arose spontaneously without a known cause. Convulsive SE was defined at that time as seizures with convulsions (clonic, tonic—clonic) lasting longer than 30 min, a non-convulsive SE lasting longer than 30 min, with continuous EEG status pattern, or when consciousness was not regained between two seizures. Patients were categorized according to the presence or absence of epilepsy, PD and SE. Additionally, the dopaminergic therapy was reviewed and categorized for the PD patients into present, absent or increased during SE. The differences in categorical values were tested for statistical significance with Fisher’s exact test. Statistical significance was assumed at p < 0.05. Multiple testing was accounted for by a Bonferroni—Holm review of the resulting p-values. The study was conducted according to the ethical standards committee from the University of Munich, Germany.
Results We identified 1215 patients with idiopathic PD, 31 with concomitant epilepsy (2.6%; mean age 67 ± 9.7) and 2537 patients with epilepsy that did not have concomitant PD (mean age 43 ± 17.7; p < 0.05). The main etiologies of the patients with epilepsy without concomitant PD were focal of unknown etiology (23%), idiopathic generalized (15%), cerebrovascular events (14%) and neoplasms (12%). Of the 31 PD patients 19 (11 male) had had a SE (61.3%), as compared to 298 patients (143 male) with SE of the epilepsy group without concomitant PD (11.7%; p < 0.001; Fig. 1A). There were no gender differences between both groups. Patients with SE and without PD had as main etiologies cerebrovascular events (34%), withdrawal of antiepileptic medication (18%) or neoplasms (12%). The 19 patients with idiopathic PD and SE were further characterized (Table 1). Nine of them (47%) had non-convulsive SE, compared to 59% in the SE group without concomitant PD, p = ns. Idiopathic PD had not been diagnosed in 5 patients before the development of SE (26%) and 8 presented a SE as their first epileptic event. Ten of the 19 patients (53%) did not have any dopaminergic medication when developing SE. The dopaminergic medication included L-Dopa in 5 patients, LDopa and Cabergolin in 2 patients and L-Dopa, cabergoline and amantadine in another 2 patients, see also Table 1. The SE was successfully terminated in 14/19 patients (74%). In all patients where the dopaminergic medication was initiated
Figure 1 (A) Status epilepticus is more frequent in patients with PD (61.3%) compared to patients without concomitant PD (11.7%; Fisher’s exact test, p < 0.001). (B) In patients older than 65 years, status epilepticus is more frequent in patients with PD (68.2%) compared to patients without concomitant PD (35.2%; Fisher’s exact test, p < 0.01).
or increased during the treatment of SE (n = 6) status cessation could be obtained. In none of the 5 patients in whom the SE could not be interrupted, an initiation or increase of dopaminergic medication was attempted. The most frequent localization of the focal SE was the frontal lobe (10/19 patients, 53%). As it has been suggested that elderly patients (such as patients with PD) may have a tendency to present with SE or have prolonged non-convulsive seizures more often than younger individuals (DeLorenzo et al., 1996), we were assessing the rate of SE in the age group > 65 years. In that group we identified 22 patients with PD and concomitant epilepsy (mean age 75.7 ± 6.8 years), and 463 patients with epilepsy without concomitant PD (mean age 74.8 ± 6.7 years; p > 0.05). Of the 22 PD patients 15 had had a status epilepticus (68.2%), as compared to 163 patients with status epilepticus of the epilepsy group without concomitant PD (35.2%; p < 0.01; Fig. 1B).
Discussion Our study demonstrates a marked increase of the rate of SE in patients with idiopathic PD as compared to epilepsy patients. Concordant with previous reports, the prevalence
Characterization of the 19 patients with Parkinson’s disease (PD) and status epilepticus. Mean age was 73 years (SD 9.2 years), 10 males and 9 females.
Nr
Age
Gender
History of epilepsy
History of PD
Status epilepticus
Etiology
EEG localization
Dopaminergic Tx before SE?
Dopaminergic Tx increased during SE?
AED to treat SE
SE interrupted
1
89
M
No
No
NCSE
MA
No
Yes
LDOPA
BZD, CBZ
Yes
2
66
M
No
Yes
NCSE
MA
Left hemisphere Bifrontal
No
Yes
LDOPA
Yes
3
66
M
Yes
No
CSE + NCSE MA
Right frontal
No
Yes
4
55
M
No
Yes
NCSE
ICB
No
Yes
5
84
F
Yes
Yes
CSE
MA
No
No
BZD, PHT
No
6
65
F
Yes
Yes
NCSE
Unknown
Right hemisphere Right Frontal Bifrontal
LDOPA, AMANTADIN LDOPA
BZD, VPA, TPM BZD, PHT, LEV BZD, PHT
Yes
LDOPA
Yes
Yes
7
77
M
No
Yes
NCSE
SDH
Yes
LDOPA
No
8
84
F
Yes
Yes
CSE
Gliosis
Yes
BZD, PHT
No
72
M
Yes
Yes
CSE
Gliosis
No
BZD, PHT, VPA
Yes
10
78
M
Yes
Yes
CSE
Tumor
Yes
No
BZD, PHT
Yes
11 12
71 68
F F
No Yes
No Yes
NCSE CSE
SAH Unknown
Right temporal Left frontal Left frontal
LDOPA CABERGOLIN LDOPA, AMANTADIN, CABERGOLIN LDOPA
No
9
Left hemisphere Left hemisphere Bifrontal
BZD, PB, TPM BZD, PHT
No Yes
CBZ PHT,
Yes Yes
13
80
F
Yes
No
NCSE
MA
Left frontal
No
LTG,
Yes
14
82
F
No
Yes
NCSE
MA
Right frontal
Yes
BZD, BZD, GBP BZD, LEV BZD,
PHT
Yes
15
72
M
Yes
Yes
CSE
Gliosis
Bifrontal
Yes
No
16
74
F
No
No
CSE
Left frontal
No
No
17
65
F
Yes
Yes
NCSE
Ischemic stroke MA
BZD, PHT, OXC BZD, PHT
No
No
80
M
No
Yes
CSE + NCSE MA
No
No
19
58
M
Yes
Yes
CSE
BZD, VPA, TPM, LEV BZD, OXC, PROP BZD, CBZ
Yes
18
Right temporal Left hemisphere Right temporal
Tumor
Yes
Yes
LDOPA, CABERGOLIN
No Yes No
LDOPA, AMANTADIN, CABERGOLIN LDOPA
LDOPA
No
No
No
LDOPA
LDOPA
Parkinson’s disease
Table 1
Yes Yes
Yes
No
No Yes
351
Abbreviations: SE, status epilepticus; NCSE, non-convulsive status epilepticus; CSE, convulsive status epilepticus; MA, microangiopathy; ICB, intracerebral bleeding; SDH, subdural hemorrhage; SAH, subarachnoidal hemorrhage; Tx, therapy; AED, antiepileptic drug(s); BZD, benzodiazepine; CBZ, carbamazepine; PHT, phenytoin; TPM, topiramate; VPA, valproate; LEV, levetiracetam; PB, phenobarbital; GBP, gabapentin; LTG, lamotrigine; OXC, oxcarbazepine; PROP, disoprivan.
352 of epileptic seizures itself in PD patients was lower than expected for that age group. In our study 2.6% of PD patients had epilepsy which is in the same range as the 2.4% reported previously (Bodenmann et al., 2001). Vercueil described a cross calculation of the prevalence of each disorder resulting in a figure of only one or two cases for 100,000 individuals over the age of 60, which might explain why co-morbidity studies do not detect this association (Vercueil, 2006). It is known that that the prevalence of epilepsy (general population 5.15 per 1000 people) increases with age (65—69 years 6.01; 70—74 years 6.53; 75—79 years 7.39; 80—84 years 7.54 and 85 years and older 7.73)(Wallace et al., 1998). Furthermore the risk of developing SE is also increased with age. The annual incidence rate of SE, in the epidemiological study of Richmond, VA, USA, was 86 per 100,000 in the 60 years and older age group, almost twice that of the general population (de Assis et al., 2012; DeLorenzo et al., 1996). Since the risk of SE increases with age and our PD patients were older (67 yrs.) than the epilepsy patients (43 yrs.), we separately analyzed the elderly (age > 65 years) which corroborated the results of a higher rate of SE in PD patients. One has to keep in mind, though, that comorbidities associated with epilepsy and typical for elderly population like Alzheimer’s disease (Friedman et al., 2012) or stroke (Gilad, 2012), might be possible confounding factors. Since cortical degeneration is more prevalent in atypical parkinsonian disorders like Lewy Body Disease, Multiple System Atrophy and Cortical Basal Degeneration, which might be related to a higher incidence of SE, these patients were not included in the study. However we are aware, that the retrospective nature of the investigation might be biased by the fact, that some of the patients with PD might be diagnosed during disease progression to one of the atypical PD disorders. Recent studies using nuclear imaging unveil alterations of different components of the dopaminergic system, in a variety of epileptic syndromes. Changes have been reported in ring chromosome 20 epilepsy (Biraben et al., 2004), refractory temporal lobe epilepsy (Bouilleret et al., 2008) and juvenile myoclonic epilepsy (Odano et al., 2012). Even though these studies do not allow an unambiguous conclusion about the dopaminergic system in epileptic patients, it seems likely that these alterations are disease related. These results suggest an involvement of the dopaminergic system within the basal ganglia of epileptic patients even though it remains unclear, if alterations precede seizures or are their consequence. On the level of a single seizure, it has been shown that presumed seizure spread into the basal ganglia — semiologically expressed by ictal dystonia — is associated with a reduced rate of secondary seizure generalization compared to seizure spread to the frontal lobe (Feddersen et al., 2012). However, dysfunction of the dopaminergic transmission and, more generally, the basal ganglia, is unlikely to be the cause of epilepsy (Deransart and Depaulis, 2002). It is more likely, that they influence seizure severity and are involved in the termination of seizures by modulating thalamic nuclei involved in seizure maintenance. Investigations in a rat model of genetic absence epilepsy (GAERS) showed, that cortical spike and wave discharges (SWDs) influence the firing pattern in the basal ganglia, eventually
B. Feddersen et al. leading to an activation of the substatia nigra pars reticulata (SNr) (Deransart et al., 2003). This changes the activity of their thalamic targets, which in turn could affect cortical neurons excitability and, consequently, the generation of cortical epileptic discharges. Thus, the nigro-thalamocortical pathway may provide an on-line system control of absence seizures (Paz et al., 2007). It as been demonstrated in vivo that cortical paroxysms were accompanied by rhythmic bursts of action potentials in ventro medial thalamic neurons. Pharmacological blockade of excitatory inputs of nigrothalamic neurons led to a transient interruption of spike-and-wave-discharges, correlated with a change in the activity of thalamic cells, which was increased in frequency and converted into a sustained arrhythmic firing pattern. Simultaneously, cortical neurons exhibited a decrease in their firing rate that was associated with an increase in membrane polarization and a decrease in input resistance (Paz et al., 2007). During absence seizures in GAERS neurons in the SNr show an increased firing and synchronization to cortical SWD’s that decreases before or with seizure termination (Deransart et al., 2003). Additionally, the involvement of the SN is not limited to generalized epilepsies, as a magnetic resonance imaging study showed a decreased volume of the SN in patients with TLE ipsilateral to the epileptic focus (Keihaninejad et al., 2012). The loss of SN pars compacta neurons observed in PD can affect widespread brain networks, including motor and cognitive networks. In a study using functional MRI in PD patients it has been shown that the SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons compared to controls (Wu et al., 2012). In PD there is a loss of SNr neurons as well, which might influence cortical activity through the projections to the thalamus (especially ventromedial thalamus) and pontomesencephalic structures like the superior colliculus, and the pedunculopontine nucleus of the tegmentum (Deransart and Depaulis, 2002). Altogether the thalamic nuclei targeted by the basal ganglia open this system onto a large portion of the frontal pole of the cortex, including motor, premotor, prefrontal and limbic areas (Chevalier and Deniau, 1990). As a side finding, dopaminergic therapy seemed to have a beneficial influence on the outcome of status epilepticus in our PD patients, but the design of this study as a retrospective analysis does not allow definite judgment. Nevertheless, it may be one more reason to continue or initiate dopaminergic treatment in PD patients with SE. Pharmacological manipulations of the basal ganglia showed modulation of seizures in several animal models of seizures or epilepsy. The common endpoint of all these antiepileptic effects appears to result from an inhibition of the SN which could lead in turn to a disinhibition of the thalamus or the superior colliculus and then to an inhibition of cortical excitability. Because the striatum receives important dopaminergic projections (Nauta and Domesick, 1984) and activation of such neurotransmission was shown to generally result in seizure suppression (Al-Tajir and Starr, 1991; Ogren and Pakh, 1993), several authors have tested the effects of dopaminergic agonist directly into the striatum. Turski
Parkinson’s disease et al. (1988) presented evidence that bilateral application of picomole amounts of apomorphine (a dopamine agonist) into the striatum confers protection against seizures produced by pilocarpine (a cholinergic agonist) in rats. Bilateral application of nanomolar amounts of haloperidol (a dopamine antagonist) into the striatum or systemic application of haloperidol both lower the threshold for pilocarpine-induced seizures. It is possible that also other systems may have an effect on the development of PD and SE as several neurotransmitters are implicated in both diseases, which leads to novel pharmacological strategies in PD by: (i) targeting disturbances of the serotonergic, noradrenergic, glutamatergic, GABAergic, and cholinergic systems in addition to the dopaminergic system, and (ii) characterizing alterations in the levels of neurotransmitter receptors and transporters that are associated with the various manifestations of the disease (Brichta et al., 2013). It has been discussed recently that the loss of locus coeruleus noradrenergic neurons, may play not only a role in Alzheimer’s disease and PD but also in epilepsy (Szot, 2012). Neuroplasticity may be another overlapping mechanism of PD and SE, as it has been shown that in human Parkinson’s disease, primary motor cortex plasticity is severely impaired in de novo patients (Kishore et al., 2012), as is the corticostriatal plasticity in parkinsonian rodents (Calabresi et al., 2007). Furthermore we cannot rule out the influence of our data by gender issues, as it is known that the incidence of PD is much higher in men and it has been reported that the incidence for SE in general is higher in men (McHugh and Delanty, 2008), even if more women over 50 have absence status (Szucs et al., 2008). We speculate from our data, that the functional impairment of the basal ganglia in PD patients makes SE more likely, because the termination of seizures is impaired lastly due to a dopaminergic deficit. Further studies should address the relationship of PD and epilepsy, especially in the light of dopaminergic treatment.
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353 Calabresi, P., Picconi, B., Parnetti, A., Mercuri, N.B., Bernanrd, G., 2007. Dopamine-mediated regulation of corticostriatal synaptic plasticity. Trends Neurosci. 30, 211—219. Chevalier, G., Deniau, J.M., 1990. Disinhibition as a basic process in the expression of striatal functions. Trends Neurosci. 13, 277—280. de Assis, T.M., Costa, G., Bacellar, A., Orsini, M., Nascimento, O.J., 2012. Status epilepticus in the elderly: epidemiology, clinical aspects and treatment. Neurol. Int. 4 (e17), 78—84. DeLorenzo, R.J., Hauser, W.A., Towne, A.R., Boggs, J.G., Pellock, J.M., Penberthy, L., Garnett, L., Fortner, C.A., Ko, D., 1996. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 46, 1029—1035. Deransart, C., Depaulis, A., 2002. The control of seizures by the basal ganglia? A review of experimental data. Epileptic Disord. 4 (Suppl. 3), S61—S72. Deransart, C., Hellwig, B., Heupel-Reuter, M., Leger, J.F., Heck, D., Lucking, C.H., 2003. Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy. Epilepsia 44, 1513—1520. Feddersen, B., Remi, J., Kilian, M., Vercueil, L., Deransart, C., Depaulis, A., Noachtar, S., 2012. Is ictal dystonia associated with an inhibitory effect on seizure propagation in focal epilepsies? Epilepsy Res. 99, 274—280. Friedman, D., Honig, L.S., Scarmeas, N., 2012. Seizures and epilepsy in Alzheimer’s disease. CNS Neurosci. Ther. 18, 285—294. Gilad, R., 2012. Management of seizures following a stroke: what are the options? Drugs Aging 29, 533—538. Keihaninejad, S., Heckemann, R.A., Gousias, I.S., Hajnal, J.V., Duncan, J.S., Aljabar, P., Rueckert, D., Hammers, A., 2012. Classification and lateralization of temporal lobe epilepsies with and without hippocampal atrophy based on whole-brain automatic MRI segmentation. PLoS ONE 7, e33096 (Epub 2012, April 16). Kishore, A., Joseph, T., Velayudhan, B., Popa, T., Meunier, S., 2012. Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease. Clin. Neurophysiol. 123, 822—828. McHugh, J.C., Delanty, N., 2008. Epidemiology and classification of epilepsy: gender comparisons. Int. Rev. Neurobiol. 83, 11—26. Mervaala, E., Andermann, F., Quesney, L.F., Krelina, M., 1990. Common dopaminergic mechanism for epileptic photosensitivity in progressive myoclonus epilepsies. Neurology 40, 53—56. Nauta, W.J., Domesick, V.B., 1984. Afferent and efferent relationships of the basal ganglia. Ciba Found. Symp. 107, 23—29. Odano, I., Varrone, A., Savic, I., Ciumas, C., Karlsson, P., Jucaite, A., Halldin, C., Farde, L., 2012. Quantitative PET analyses of regional [11C]PE2I binding to the dopamine transporter — application to juvenile myoclonic epilepsy. Neuroimage 59, 3582—3593. Ogren, S.O., Pakh, B., 1993. Effects of dopamine D1 and D2 receptor agonists and antagonists on seizures induced by chemoconvulsants in mice. Pharmacol. Toxicol. 72, 213—220. Paz, J.T., Chavez, M., Saillet, S., Deniau, J.M., Charpier, S., 2007. Activity of ventral medial thalamic neurons during absence seizures and modulation of cortical paroxysms by the nigrothalamic pathway. J. Neurosci. 27, 929—941. Szucs, A., Barcs, G., Jakus, R., Rásonyi, G., Lalit, N., Holló, A., Kelemen, A., Janszky, J., Halász, P., 2008. Late-life absence status epilepticus: a female disorder? Epileptic Disord. 10, 156—161. Szot, P., 2012. Common factors among Alzheimer’s disease, Parkinson’s disease, and epilepsy: possible role of the noradrenergic nervous system. Epilepsia 53 (Suppl. 1), S61—S66. Turski, L., Cavalheiro, E.A., Bortolotto, Z.A., Ikonomidou-Turski, C., Kleinrok, Z., Turski, W.A., 1988. Dopamine-sensitive anticonvulsant site in the rat striatum. J. Neurosci. 8, 4027—4037.
354 Vercueil, L., 2000. Parkinsonism and epilepsy: case report and reappraisal of an old question. Epilepsy Behav. 1, 128—130. Vercueil, L., 2006. Epilepsy and neurodegenerative diseases in adults: a clinical review. Epileptic Disord. 8 (S1), S44—S54. Wallace, H., Shorvon, S., Tallis, R., 1998. Age-specific incidence and prevalence rates of treated epilepsy in an unselected
B. Feddersen et al. population of 2,052,922 and age-specific fertility rates of women with epilepsy. Lancet 352, 1970—1973. Wu, T., Wang, J., Wang, C., Hallett, M., Zang, Y., Wu, X., Chan, P., 2012. Basal ganglia circuits changes in Parkinson’s disease patients. Neurosci. Lett. 524, 55—59.
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
Parkinson’s disease: Less epileptic seizures more status epilepticus Berend Feddersen ∗,1, Jan Rémi, Marion Einhellig, Cordula Stoyke, Philipp Krauss, Soheyl Noachtar Epilepsy Center, Department of Neurology, University of Munich, Germany Received 2 April 2013; received in revised form 22 October 2013; accepted 12 November 2013 Available online 21 November 2013
KEYWORDS Epilepsy; Parkinson’s disease; Seizure; Status epilepticus; Dopamine
Summary We compared the rate of epilepsy and status epilepticus (SE) in patients with and without Parkinson’s disease (PD). Out of 1215 patients with idiopathic PD, 31 had epilepsy and 19 of these had at least one episode of SE (61.3%) compared to 298 of 2537 patients (11.7%; p < 0.001) with epilepsy and without concomitant PD. This clinical finding supports the hypothesis that the functional impairment of the basal ganglia in PD patients makes SE more likely. © 2013 Elsevier B.V. All rights reserved.
Introduction Epidemiologic studies suggest that the incidence of epilepsy in patients with idiopathic Parkinson’s disease (PD) compared to an age-matched normal population is remarkably low, consisting of only one or two cases for 100,000 individuals over the age of 60 (Vercueil, 2006). Additionally, epilepsy patients may have a seizure reduction or even attain seizure freedom, in case they develop PD (Vercueil, 2000). It has been hypothesized, that these influences may be due to increased intracortical inhibition which may result
∗ Corresponding author at: Epilepsy Center, Department of Neurology, University of Munich, Marchioninistr. 15, 81377 Muenchen, Germany. Tel.: +49 89 7095 0; fax: +49 89 7095 6691. E-mail address: [email protected] (B. Feddersen). 1 Current address: Department of Palliative Medicine, University of Munich, Marchioninistr. 15, 81377 Muenchen, Germany.
from changes in cortical excitability (Brown and Marsden, 1984), or that the associated dopaminergic drugs may suppress seizures. The latter has been demonstrated in selected epilepsy syndromes (Mervaala et al., 1990), but is not yet used in clinical practice. A decrease in dopaminergic tone may not always be beneficial, as demonstrated for patients with ring chromosome 20. These patients have a decreased bilateral striatal 18[F]fluoro-L-DOPA uptake (Biraben et al., 2004). They have long-lasting generalized seizures that often evolve into status epilepticus (SE) and it was suggested that the dysfunction of the striatal dopaminergic neurotransmission may impair seizure cessation (Biraben et al., 2004). Furthermore, in a genetic model of absence epilepsy, rats showed seizure aggravation following a decrease in dopaminergic tone, and seizure inhibition through dopaminergic stimulation (Deransart and Depaulis, 2002). These differential effects on the occurrence of single seizure on one hand and the possible failure in seizure termination on the other hand led us to hypothesize that PD
0920-1211/$ — see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2013.11.013
350
B. Feddersen et al.
patients, despite being known to have less seizures and a reduced incidence of epilepsy, may have a higher incidence to develop SE. We, therefore, studied the incidence of SE in patients with PD and without PD.
Methods The electronic medical reports for all in- and outpatients of the Department of Neurology, University of Munich of the years 2000—2006 were retrospectively searched for the terms ‘‘Parkinson’s disease’’, ‘‘dopaminergic deficit’’, ‘‘epilepsy’’, ‘‘epileptic seizure’’, and ‘‘status epilepticus’’. All resulting reports were reviewed and the diagnoses of PD and epilepsy were reviewed according to clinical criteria from the records. We included only PD patients with idiopathic Parkinson syndrome, which means that the PD arose spontaneously without a known cause. Convulsive SE was defined at that time as seizures with convulsions (clonic, tonic—clonic) lasting longer than 30 min, a non-convulsive SE lasting longer than 30 min, with continuous EEG status pattern, or when consciousness was not regained between two seizures. Patients were categorized according to the presence or absence of epilepsy, PD and SE. Additionally, the dopaminergic therapy was reviewed and categorized for the PD patients into present, absent or increased during SE. The differences in categorical values were tested for statistical significance with Fisher’s exact test. Statistical significance was assumed at p < 0.05. Multiple testing was accounted for by a Bonferroni—Holm review of the resulting p-values. The study was conducted according to the ethical standards committee from the University of Munich, Germany.
Results We identified 1215 patients with idiopathic PD, 31 with concomitant epilepsy (2.6%; mean age 67 ± 9.7) and 2537 patients with epilepsy that did not have concomitant PD (mean age 43 ± 17.7; p < 0.05). The main etiologies of the patients with epilepsy without concomitant PD were focal of unknown etiology (23%), idiopathic generalized (15%), cerebrovascular events (14%) and neoplasms (12%). Of the 31 PD patients 19 (11 male) had had a SE (61.3%), as compared to 298 patients (143 male) with SE of the epilepsy group without concomitant PD (11.7%; p < 0.001; Fig. 1A). There were no gender differences between both groups. Patients with SE and without PD had as main etiologies cerebrovascular events (34%), withdrawal of antiepileptic medication (18%) or neoplasms (12%). The 19 patients with idiopathic PD and SE were further characterized (Table 1). Nine of them (47%) had non-convulsive SE, compared to 59% in the SE group without concomitant PD, p = ns. Idiopathic PD had not been diagnosed in 5 patients before the development of SE (26%) and 8 presented a SE as their first epileptic event. Ten of the 19 patients (53%) did not have any dopaminergic medication when developing SE. The dopaminergic medication included L-Dopa in 5 patients, LDopa and Cabergolin in 2 patients and L-Dopa, cabergoline and amantadine in another 2 patients, see also Table 1. The SE was successfully terminated in 14/19 patients (74%). In all patients where the dopaminergic medication was initiated
Figure 1 (A) Status epilepticus is more frequent in patients with PD (61.3%) compared to patients without concomitant PD (11.7%; Fisher’s exact test, p < 0.001). (B) In patients older than 65 years, status epilepticus is more frequent in patients with PD (68.2%) compared to patients without concomitant PD (35.2%; Fisher’s exact test, p < 0.01).
or increased during the treatment of SE (n = 6) status cessation could be obtained. In none of the 5 patients in whom the SE could not be interrupted, an initiation or increase of dopaminergic medication was attempted. The most frequent localization of the focal SE was the frontal lobe (10/19 patients, 53%). As it has been suggested that elderly patients (such as patients with PD) may have a tendency to present with SE or have prolonged non-convulsive seizures more often than younger individuals (DeLorenzo et al., 1996), we were assessing the rate of SE in the age group > 65 years. In that group we identified 22 patients with PD and concomitant epilepsy (mean age 75.7 ± 6.8 years), and 463 patients with epilepsy without concomitant PD (mean age 74.8 ± 6.7 years; p > 0.05). Of the 22 PD patients 15 had had a status epilepticus (68.2%), as compared to 163 patients with status epilepticus of the epilepsy group without concomitant PD (35.2%; p < 0.01; Fig. 1B).
Discussion Our study demonstrates a marked increase of the rate of SE in patients with idiopathic PD as compared to epilepsy patients. Concordant with previous reports, the prevalence
Characterization of the 19 patients with Parkinson’s disease (PD) and status epilepticus. Mean age was 73 years (SD 9.2 years), 10 males and 9 females.
Nr
Age
Gender
History of epilepsy
History of PD
Status epilepticus
Etiology
EEG localization
Dopaminergic Tx before SE?
Dopaminergic Tx increased during SE?
AED to treat SE
SE interrupted
1
89
M
No
No
NCSE
MA
No
Yes
LDOPA
BZD, CBZ
Yes
2
66
M
No
Yes
NCSE
MA
Left hemisphere Bifrontal
No
Yes
LDOPA
Yes
3
66
M
Yes
No
CSE + NCSE MA
Right frontal
No
Yes
4
55
M
No
Yes
NCSE
ICB
No
Yes
5
84
F
Yes
Yes
CSE
MA
No
No
BZD, PHT
No
6
65
F
Yes
Yes
NCSE
Unknown
Right hemisphere Right Frontal Bifrontal
LDOPA, AMANTADIN LDOPA
BZD, VPA, TPM BZD, PHT, LEV BZD, PHT
Yes
LDOPA
Yes
Yes
7
77
M
No
Yes
NCSE
SDH
Yes
LDOPA
No
8
84
F
Yes
Yes
CSE
Gliosis
Yes
BZD, PHT
No
72
M
Yes
Yes
CSE
Gliosis
No
BZD, PHT, VPA
Yes
10
78
M
Yes
Yes
CSE
Tumor
Yes
No
BZD, PHT
Yes
11 12
71 68
F F
No Yes
No Yes
NCSE CSE
SAH Unknown
Right temporal Left frontal Left frontal
LDOPA CABERGOLIN LDOPA, AMANTADIN, CABERGOLIN LDOPA
No
9
Left hemisphere Left hemisphere Bifrontal
BZD, PB, TPM BZD, PHT
No Yes
CBZ PHT,
Yes Yes
13
80
F
Yes
No
NCSE
MA
Left frontal
No
LTG,
Yes
14
82
F
No
Yes
NCSE
MA
Right frontal
Yes
BZD, BZD, GBP BZD, LEV BZD,
PHT
Yes
15
72
M
Yes
Yes
CSE
Gliosis
Bifrontal
Yes
No
16
74
F
No
No
CSE
Left frontal
No
No
17
65
F
Yes
Yes
NCSE
Ischemic stroke MA
BZD, PHT, OXC BZD, PHT
No
No
80
M
No
Yes
CSE + NCSE MA
No
No
19
58
M
Yes
Yes
CSE
BZD, VPA, TPM, LEV BZD, OXC, PROP BZD, CBZ
Yes
18
Right temporal Left hemisphere Right temporal
Tumor
Yes
Yes
LDOPA, CABERGOLIN
No Yes No
LDOPA, AMANTADIN, CABERGOLIN LDOPA
LDOPA
No
No
No
LDOPA
LDOPA
Parkinson’s disease
Table 1
Yes Yes
Yes
No
No Yes
351
Abbreviations: SE, status epilepticus; NCSE, non-convulsive status epilepticus; CSE, convulsive status epilepticus; MA, microangiopathy; ICB, intracerebral bleeding; SDH, subdural hemorrhage; SAH, subarachnoidal hemorrhage; Tx, therapy; AED, antiepileptic drug(s); BZD, benzodiazepine; CBZ, carbamazepine; PHT, phenytoin; TPM, topiramate; VPA, valproate; LEV, levetiracetam; PB, phenobarbital; GBP, gabapentin; LTG, lamotrigine; OXC, oxcarbazepine; PROP, disoprivan.
352 of epileptic seizures itself in PD patients was lower than expected for that age group. In our study 2.6% of PD patients had epilepsy which is in the same range as the 2.4% reported previously (Bodenmann et al., 2001). Vercueil described a cross calculation of the prevalence of each disorder resulting in a figure of only one or two cases for 100,000 individuals over the age of 60, which might explain why co-morbidity studies do not detect this association (Vercueil, 2006). It is known that that the prevalence of epilepsy (general population 5.15 per 1000 people) increases with age (65—69 years 6.01; 70—74 years 6.53; 75—79 years 7.39; 80—84 years 7.54 and 85 years and older 7.73)(Wallace et al., 1998). Furthermore the risk of developing SE is also increased with age. The annual incidence rate of SE, in the epidemiological study of Richmond, VA, USA, was 86 per 100,000 in the 60 years and older age group, almost twice that of the general population (de Assis et al., 2012; DeLorenzo et al., 1996). Since the risk of SE increases with age and our PD patients were older (67 yrs.) than the epilepsy patients (43 yrs.), we separately analyzed the elderly (age > 65 years) which corroborated the results of a higher rate of SE in PD patients. One has to keep in mind, though, that comorbidities associated with epilepsy and typical for elderly population like Alzheimer’s disease (Friedman et al., 2012) or stroke (Gilad, 2012), might be possible confounding factors. Since cortical degeneration is more prevalent in atypical parkinsonian disorders like Lewy Body Disease, Multiple System Atrophy and Cortical Basal Degeneration, which might be related to a higher incidence of SE, these patients were not included in the study. However we are aware, that the retrospective nature of the investigation might be biased by the fact, that some of the patients with PD might be diagnosed during disease progression to one of the atypical PD disorders. Recent studies using nuclear imaging unveil alterations of different components of the dopaminergic system, in a variety of epileptic syndromes. Changes have been reported in ring chromosome 20 epilepsy (Biraben et al., 2004), refractory temporal lobe epilepsy (Bouilleret et al., 2008) and juvenile myoclonic epilepsy (Odano et al., 2012). Even though these studies do not allow an unambiguous conclusion about the dopaminergic system in epileptic patients, it seems likely that these alterations are disease related. These results suggest an involvement of the dopaminergic system within the basal ganglia of epileptic patients even though it remains unclear, if alterations precede seizures or are their consequence. On the level of a single seizure, it has been shown that presumed seizure spread into the basal ganglia — semiologically expressed by ictal dystonia — is associated with a reduced rate of secondary seizure generalization compared to seizure spread to the frontal lobe (Feddersen et al., 2012). However, dysfunction of the dopaminergic transmission and, more generally, the basal ganglia, is unlikely to be the cause of epilepsy (Deransart and Depaulis, 2002). It is more likely, that they influence seizure severity and are involved in the termination of seizures by modulating thalamic nuclei involved in seizure maintenance. Investigations in a rat model of genetic absence epilepsy (GAERS) showed, that cortical spike and wave discharges (SWDs) influence the firing pattern in the basal ganglia, eventually
B. Feddersen et al. leading to an activation of the substatia nigra pars reticulata (SNr) (Deransart et al., 2003). This changes the activity of their thalamic targets, which in turn could affect cortical neurons excitability and, consequently, the generation of cortical epileptic discharges. Thus, the nigro-thalamocortical pathway may provide an on-line system control of absence seizures (Paz et al., 2007). It as been demonstrated in vivo that cortical paroxysms were accompanied by rhythmic bursts of action potentials in ventro medial thalamic neurons. Pharmacological blockade of excitatory inputs of nigrothalamic neurons led to a transient interruption of spike-and-wave-discharges, correlated with a change in the activity of thalamic cells, which was increased in frequency and converted into a sustained arrhythmic firing pattern. Simultaneously, cortical neurons exhibited a decrease in their firing rate that was associated with an increase in membrane polarization and a decrease in input resistance (Paz et al., 2007). During absence seizures in GAERS neurons in the SNr show an increased firing and synchronization to cortical SWD’s that decreases before or with seizure termination (Deransart et al., 2003). Additionally, the involvement of the SN is not limited to generalized epilepsies, as a magnetic resonance imaging study showed a decreased volume of the SN in patients with TLE ipsilateral to the epileptic focus (Keihaninejad et al., 2012). The loss of SN pars compacta neurons observed in PD can affect widespread brain networks, including motor and cognitive networks. In a study using functional MRI in PD patients it has been shown that the SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons compared to controls (Wu et al., 2012). In PD there is a loss of SNr neurons as well, which might influence cortical activity through the projections to the thalamus (especially ventromedial thalamus) and pontomesencephalic structures like the superior colliculus, and the pedunculopontine nucleus of the tegmentum (Deransart and Depaulis, 2002). Altogether the thalamic nuclei targeted by the basal ganglia open this system onto a large portion of the frontal pole of the cortex, including motor, premotor, prefrontal and limbic areas (Chevalier and Deniau, 1990). As a side finding, dopaminergic therapy seemed to have a beneficial influence on the outcome of status epilepticus in our PD patients, but the design of this study as a retrospective analysis does not allow definite judgment. Nevertheless, it may be one more reason to continue or initiate dopaminergic treatment in PD patients with SE. Pharmacological manipulations of the basal ganglia showed modulation of seizures in several animal models of seizures or epilepsy. The common endpoint of all these antiepileptic effects appears to result from an inhibition of the SN which could lead in turn to a disinhibition of the thalamus or the superior colliculus and then to an inhibition of cortical excitability. Because the striatum receives important dopaminergic projections (Nauta and Domesick, 1984) and activation of such neurotransmission was shown to generally result in seizure suppression (Al-Tajir and Starr, 1991; Ogren and Pakh, 1993), several authors have tested the effects of dopaminergic agonist directly into the striatum. Turski
Parkinson’s disease et al. (1988) presented evidence that bilateral application of picomole amounts of apomorphine (a dopamine agonist) into the striatum confers protection against seizures produced by pilocarpine (a cholinergic agonist) in rats. Bilateral application of nanomolar amounts of haloperidol (a dopamine antagonist) into the striatum or systemic application of haloperidol both lower the threshold for pilocarpine-induced seizures. It is possible that also other systems may have an effect on the development of PD and SE as several neurotransmitters are implicated in both diseases, which leads to novel pharmacological strategies in PD by: (i) targeting disturbances of the serotonergic, noradrenergic, glutamatergic, GABAergic, and cholinergic systems in addition to the dopaminergic system, and (ii) characterizing alterations in the levels of neurotransmitter receptors and transporters that are associated with the various manifestations of the disease (Brichta et al., 2013). It has been discussed recently that the loss of locus coeruleus noradrenergic neurons, may play not only a role in Alzheimer’s disease and PD but also in epilepsy (Szot, 2012). Neuroplasticity may be another overlapping mechanism of PD and SE, as it has been shown that in human Parkinson’s disease, primary motor cortex plasticity is severely impaired in de novo patients (Kishore et al., 2012), as is the corticostriatal plasticity in parkinsonian rodents (Calabresi et al., 2007). Furthermore we cannot rule out the influence of our data by gender issues, as it is known that the incidence of PD is much higher in men and it has been reported that the incidence for SE in general is higher in men (McHugh and Delanty, 2008), even if more women over 50 have absence status (Szucs et al., 2008). We speculate from our data, that the functional impairment of the basal ganglia in PD patients makes SE more likely, because the termination of seizures is impaired lastly due to a dopaminergic deficit. Further studies should address the relationship of PD and epilepsy, especially in the light of dopaminergic treatment.
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