Acta Neurol Scand DOI: 10.1111/ane.12304
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Seizures in E200K familial and sporadic Creutzfeldt-Jakob disease Appel S, Chapman J, Cohen OS, Rosenmann H, Nitsan Z, Blatt I. Seizures in E200K familial and sporadic Creutzfeldt-Jakob Disease. Acta Neurol Scand: DOI: 10.1111/ane.12304. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Although seizures (other than myoclonus) are frequently reported in Creutzfeldt-Jakob disease (CJD), their frequency, clinical manifestations, and effect on the disease course is unknown. Objectives – To characterize the frequency of seizures in E200K familial and sporadic CJD, to describe its semiology, EEG and MRI findings. Methods – In this retrospective study, we reviewed all patients with CJD who were seen in the Sheba Medical Center between the years 2003–2012 and underwent clinical evaluation, genetic testing, EEG and MRI studies. The diagnosis of seizures was carried out based on documentation of episodes consistent with seizures or episode of unresponsiveness correlated with ictal activity in EEG. Results – Sixty-four probable patients with CJD were included in the study, 57 (89%) with E200K familial (fCJD) and 7 (11%) with sporadic (sCJD). Seizures occurred in 8 patients: 3 of 7 (43%) in patients with sCJD compared to 5/57 (9%) in patients with E200K fCJD (P = 0.04, chi-square test). Two of E200K fCJD patients with seizures had other non-prion etiologies for seizures (brain metastasis, known history of temporal lobe epilepsy which started 44 years before the diagnosis of CJD). Seizures occurred late in the course of the disease with an average of 12 days between the onset of seizures and death. Conclusion – Seizures in E200K fCJD were infrequent and occurred late in the disease course. This difference suggests that E200K fCJD represents a separate subtype of the disease with distinct clinical characteristics.
Introduction
Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease caused by formation and deposition of the abnormal prion protein (PrPSc) in the central nervous system (1). Several clinical subtypes of the disease have been characterized including sporadic (sCJD), acquired, and familial (fCJD) forms (2). The largest cluster of fCJD exists in the North African Jewish community of Libyan and Tunisian ancestry linked to the E200K mutation in the prion protein gene (PRNP) (3). Seizures (other than myoclonus) have been described in patients with CJD including cases of status epilepticus (4). Few
S. Appel1, J. Chapman2,3, O. S. Cohen2,3, H. Rosenmann4, Z. Nitsan1, I. Blatt2,3 1 Department of Neurology, Barzilai Medical Center, affiliated to Ben Gurion University, Ashkelon, Israel; 2 Department of Neurology, Sheba Medical Center, Ramat-Gan, Israel; 3Sackler Faculty of medicine, TelAviv University, Tel Aviv, Israel; 4Department of Neurology, Hadassah University Hospital, Jerusalem, Israel
Key words: E200K familial Creutzfeldt-Jakob disease; sporadic Creutzfeldt-Jakob disease epilepsy; prion disease; seizures S. Appel, Barzilai Medical Center, Hahistadrut 2, Askelon, 78278, Israel Tel.: +972-53-8272784 Fax: +972-8-6745463 e-mail: [email protected] Accepted for publication August 4, 2014
published series of patients with sCJD specifically reported seizures with an incidence of around 20% (5, 6). This incidence is higher than the incidence reported in other neurodegenerative disorders like Alzheimer disease (7) but lower than the incidence of seizures in fulminant diseases such as Herpes encephalitis, where seizure incidence in the acute phase is higher and varies between 40 and 60% (8). EEG examinations of patients with CJD often reveal generalized periodic epileptiform discharges, periodic lateralized epileptiform discharges (PLEDs), and interictal spikes. (IIS) One of the main symptoms of the disease is myoclonus, implying that epileptic activity frequently occurs in CJD. The goal of this study 1
Appel et al. was to characterize the frequency of seizures in patients with E200K and sporadic CJD and to describe its semiology, EEG and MRI findings.
were compared to the CJD patients without seizures. Statistics
Methods
In this retrospective study, we reviewed the medical records of all patients with CJD who were evaluated in the CJD Clinic or hospitalized in the Department of Neurology of the Sheba Medical Center during the years 2003–2012. The diagnosis of probable CJD was established according to the 1998 WHO criteria (9) with the modification of using CSF Tau protein level instead of the 14-3-3 level. Tau concentrations were measured by an ELISA (Innotest hTau-Ag, Innogenetics, Ghent, Belgium). Using a cutoff value of 1000 pg/ml, our sensitivity was 72% for patients with fCJDE200K and 83.3% for patients with sCJD, with a specificity of 93.1%, as published by us previously (10). The study was approved by the Institutional review Board of the Sheba Medical Center, and all patients signed an informed consent prior to inclusion in this study. The evaluation included personal and family history review, physical examination, DNA testing for PRNP gene mutations, CSF analysis for Tau protein, EEG and MRI studies. The diagnosis of seizures was carried out based on documentation of episodes consistent with seizures or episode of unresponsiveness correlated with ictal activity in EEG. Patients were classified as ‘E200K familial CJD’ (fCJD) if they had a positive family history and/or were positive for E200K mutation in the PRNP gene. Cutoff level of Tau protein above 1000 was considered as consistent with the diagnosis of CJD. MRI was conducted using a 1.5 Tesla system and included T1, T2, DTI, and DWI sequences. Digital EEG was performed with an electrode array according to the international 10–20 method. The demographic data, genetic, EEG and MRI findings, and the clinical course
ANOVA or chi-square test was used to compare the groups. Significance was set at P < 0.05. Results
Sixty-four probable patients with CJD were included in the study (for demographic and clinical data see Table 1). Thirty-five (55%) were men, and the average age was 59.5 8.3 years. Fifty-seven patients (89%) who were of LibyanJewish ancestry and positive for the typical mutation of E200K in the PRNP gene were classified as E200K familial CJD (fCJD). Seven patients (11%) were negative for the E200K mutation, had no family history of CJD and were classified as sporadic CJD (sCJD). Eight patients (14%) had seizures. Six patients had generalized tonic–clonic seizures (most likely secondarily generalized) and 2 patients (one with E200K fCJD and one with sCJD) presented with acute alerted mental status and unresponsiveness correlated with ictal activity per EEG consistent with the diagnosis of non-convulsive status epilepticus. Seizures were more common in patients with sCJD (3/7 in patients with sCJD vs. 5/57 in patients with E200K fCJD (P = 0.04 chi-square test)). The seizures were related to the diagnosis of CJD in all patients with sCJD but in only 3 of the patients with E200K fCJD. One patient with E200K fCJD (case 38) had been diagnosed with epilepsy at the age of 12, 44 years before the diagnosis of CJD. Her seizures consisted of episodes of unresponsiveness and secondarily generalized tonic–clonic seizures. Another patient E200K fCJD (case 44) was diagnosed with brain metastasis from lung adenocarcinoma which presented with seizures 12 months before the presentation of CJD. The seizures related to CJD
Table 1 Demographic and clinical features CJD patients without history of seizures
Number Gender (male) Average age (years) Clinical presentation
2
CJD patients with history of seizures
sCJD
fCJD
sCJD
fCJD
4 2 61.25 9.09 Gait imbalance-2, cognitive decline-1, vertigo-1
52 28 59.3 8.3 Cognitive decline-14, gait imbalance-11, insomnia-8, hemiparesis-2 illusions-3, headache-3, neuropathy-3, behavioral change-1, weight loss-1, pruritus-1, tiredness-1, depression-1, low back pain-1, hearing loss-1, focal dystonia-1
3 2 44.65 4.6 Illusions-1, behavioral change-1, hemiparesis 1
5 3 61.8 9.9 Gait imbalance-2, illusions-1, cognitive-1, numbness-1
Seizures in CJD (excluding the 2 cases with other etiologies mentioned above) occurred late in the course of the disease with an average period of 12 days between the onset of the seizures and death. No correlation was found between the demographic characteristics (gender, age of onset, first clinical presentation) and the occurrence of seizures (data is not shown). In 4 other patients, anti-epileptic treatment was started without any history of established seizures. Two patients were started on treatment due to myoclonic jerks and 2 others patients due to PLEDs on their EEG. No clinical improvement was noticed in any of these patients with AED treatment. EEG findings
EEG records were available for 52 patients. (see Table 2) EEG was normal in 4 patients (8%). In
those patients with abnormal EEG, the most frequent findings were non-specific slowing (focal or diffuse), seen in 28 (54%) patients, and the typical finding of Periodic Sharp Wave Complexes (PSWCs) which was seen in 20 patients (38%) (See Figs 1 and 2). Epileptiform abnormalities were seen in 11 patients (21%): Three (4%) had isolated focal interictal spikes (IIS), 6 had PLEDs, 1 had BiPLEDs, and 1 had a pattern of Generalized Periodic Epileptiform Discharges (GPEDs). An EEG study of one of the patients who presented with altered mental status showed non-convulsive focal status epilepticus. Another patient presented to another hospital with decreased mental status and his EEG was consistent with non-convulsive focal status epilepticus. However, his EEG was not available to us. Seizures were not associated with epileptiform activity on interictal EEG (P = 0.6, chi-square), and
Table 2 EEG finding CJD patients with history of seizures
CJD patients without history of seizures fCJD** Number Background Slow activity: diffuse/focal Periodic Sharp Wave Complex: diffuse/focal Normal Epileptiform abnormalities Individual abnormalities
sCJD
fCJD*
sCJD
41
4
4
3
21/5 9/4 2
0 2/1 1
1/0 0/2 1
1/0 1/1 0
1 NCSE
1 PLED
5 PLEDs, 3 IIS, 1 BiPLEDs, 1GPED
0
*EEG of 1 patient was not available. **EEG of 13 patients was not available. PLEDs, periodic lateralized epileptiform discharges; NCSE, non-convulsive status epilepticus; IIS, interictal spike; BiPLEDs, bilateral periodic lateralized epileptiform discharges, GPEDs, generalized periodic epileptiform discharges.
Figure. 1. Diffuse Periodic Sharp Wave Complexes in EEG of patient with fCJD.
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Figure. 2. Focal Periodic Sharp Wave Complexes in EEG of patient with fCJD.
epileptiform activity did not predict clinical seizures (P = 0.5, chi-square). Epileptiform activity was not correlated with any of the demographic and clinical features as well (data not shown). The epileptiform activity was frequently associated with PSWC activity elsewhere in the same record (epileptiform abnormalities in 8/20 patients with PSWC vs. 3/32 patients with no PSWC, P < 0.01 chi-square). PSWC was more common in patients with sCJD. (5/7 vs. 14/45, P = 0.04 chi-square).
CJD. Fifty patients (86%) had basal ganglia MRI involvement, 14 patients (24%) had thalamic involvement, and 35 patients (60%) had cortical involvement. No association was found between cortical involvement and history of seizures (P = 0.19, chi-square) or epileptiform activity on the EEG (P = 0.5, chi-square). No significant difference was found between demographic characters, EEG and MRI findings of patients with E200KfCJD and with sCJD.
MRI findings
MRI records of 58 patients were available (for details see Table 3). In 51 patients (88%), MRI showed the typical hyperintense signals from the basal ganglia (See Fig. 3), thalamus and/or cortex (see Fig. 4). In 2 patients, MRI was normal and in 5 patients MRI showed non-specific ischemic/ hyperintense lesions, unrelated to the diagnosis of Table 3 MRI finding
Number Deep gray matter involvement Cortical involvement Cortical and deep matter involvement Non-specific finding** Normal
CJD patients without history of seizures
CJD patients with history of seizures
fCJD
sCJD
fCJD
sCJD
46* 15 1 24 4 2
4 1 0 3 0 0
5 0 0 4 1 0
3 0 0 3 0 0
*MRI of 6 patients were not found. **Non-specific/ischemic white matter changes.
4
Figure. 3. MRI images of patient with CJD (including FLAIR, DWI, and ADC squences) showing hyperintense signals from the basal ganglia.
Seizures in CJD
Figure. 4. MRI images of patient with CJD (including FLAIR, DWI, and ADC squences) showing hyperintense signals from the basal ganglia and right frontal cortex.
Discussion
The incidence of seizures in our cohort was 14%. This incidence is similar to the one reported in chronic dementia (7) and previous CJD series (5, 6) unlike the significantly higher incidence of seizures seen in fulminant diseases such as herpes encephalitis (8). The seizures in our patients tended to occur later in the disease course and might be related to critical conditions with unstable metabolic/electrolyte imbalance or sepsis, rather than epileptogenicity directly caused by CJD pathology. A possible explanation may be found in the histopathological characteristics of these entities. Herpes encephalitis is characterized by well-demarcated necrotizing lesions and hemorrhages with meningeal cell exudates and perivascular cuffing with neuronophagia, in contrast to spongiform changes, neuronal loss and reactive gliosis with no significant inflammatory infiltrate seen in CJD. The typical brain area involved may offer an alternative explanation. Herpes encephalitis typically involves highly epileptogenic regions of the temporal lobe and orbitofrontal gyrus versus frontal regions and deep gray matter as seen in patients with CJD. The incidence of seizures in our cohort is lower than the figures seen in previous series (5, 6) reporting on incidence of 20% of seizures in patients with CJD. Due to the limited numbers of patients included in the series, the difference is non-significant and may be incidental.
However, it may reflect the difference in the patients population included in these series. Our cohort included mainly patients with E200K fCJD, whereas the previous series studied patients with sCJD only. Interestingly, a subanalysis of our cohort revealed a higher incidence of seizures (43%) in patients with sporadic CJD versus a significantly lower incidence of 12% in patients with E200K familial CJD (P = 0.04 chi-square test). This finding is consistent with our previous reports of unique clinical, electrophysiological, and imaging characteristics of E200K familial CJD, including pruritus and early sleep disturbances (11, 12). A possible explanation is that as suggested in that study, sCJD tends to involve the hemispheral cortex per MRI and to produce the classical EEG finding of PSWC, whereas fCJD more often involves the less epileptogenic regions of deep gray matter with non-specific EEG slowing. (11) As implied by many case reports of status epilepticus (SE) in patients with CJD, our study found a high incidence of SE with 2 cases out of 64 patients (3%). SE is thought to occur due to failure to terminate an isolated seizure. Endocytosis of GABA-A receptors as SE evolves contributes to the progressive pharmacoresistance to benzodiazepines (13), and NMDA receptors translocation to the synaptic membrane increases the excitability (14) and leads to neuronal apoptosis. Recently, a few studies showed abnormal expression of GABA receptors and NMDA receptors in various regions in the cortex of patients with CJD (15). This may contribute to the hyperexcitability and the failure to inhibit seizures in CJD which may result in the tendency toward status epilepticus as shown in this study. In summary, seizures in E200K fCJD are less frequent compared to sCJD, most likely due to involvement of deep and less epileptogenic brain structures in E200K fCJD. Acknowledgements
The study was partially supported by NIH grant# NS043488. Conflict of interests
The authors declare no financial or other conflict of interests. References 1. MACDONALD ST, SUTHERLAND K, IRONSIDE JW. Prion protein genotype and pathological phenotype studies in
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2. 3.
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sporadic Creutzfeldt-Jakob disease. Neuropathol Appl Neurobiol 1996;22:285–92. KNIGHT RS, WILL RG. Prion diseases. J Neurol Neurosurg Psychiatry 2004;75:36–42. GOLDFARB LG, KORCZYN AD, BROWN P, CHAPMAN J, GAJDUSEK DC. Mutation in codon 200 of scrapie amyloid precursor gene linked to Creutzfeldt-Jakob disease in Sephardic Jews of Libyan and non-Libyan origin. Lancet 1990;336:637–8. LOWDEN MR, SCOTT K, KOTHARI MJ. Familial Creutzfeldt-Jakob disease presenting as epilepsia partialis continua. Epileptic Disord 2008;10:271–5. ESPINOSA PS, BENSALEM-OWEN MK, FEE DB. Sporadic Creutzfeldt-Jakob disease presenting as nonconvulsive status epilepticus, case report and review of the literature. Clin Neurol Neurosurg 2010;112:537–40. COKGOR I, ROZEAR M, MORGENLANDER JC. Seizures and Creutzfeldt-Jakob disease. A case report and series review. N C Med J 1999;60:108–9. IMFELD P, BODMER M, SCHUERCH M, JICK SS, MEIER CR. Seizures in patients with Alzheimer’s disease or vascular dementia: a population-based nested case-control analysis. Epilepsia 2013;54:700–7. MISRA UK, TAN CT, KALITA J. Viral encephalitis and epilepsy. Epilepsia 2008;49:13–8.
9. http://www.cdc.gov/ncidod/dvrd/cjd/diagnostic_criteria.htm 10. MEINER Z, KAHANA E, BAITCHER F, KORCZYN AD, CHAPMAN J, COHEN OS. Tau and 14-3-3 of genetic and sporadic Creutzfeldt-Jakob disease patients in Israel. J Neurol 2011;258:255–62. 11. APPEL SA, CHAPMAN J, PROHOVNIK I, HOFFMAN C, COHEN OS, BLATT I. The EEG in E200K familial CJD: relation to MRI patterns. J Neurol 2012;259:491–6. 12. COHEN OS, CHAPMAN J, LEE H et al. Pruritus in familial Creutzfeldt-Jakob disease: a common symptom associated with central nervous system pathology. J Neurol 2011;258:89–95. 13. MAZARATI AM, BALDWIN RA, SANKAR R, WASTERLAIN CG. Time dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res 1998;814:179–85. 14. WASTERLAIN CG, LIU H, MAZARATI A, BALWIN RA. NMDA receptor trafficking during the transition from single seizures to status epilepticus. Ann Neurol 2002;52:16. 15. FERRER I, PUIG B. GluR2/3, NMDAepsilon1 and GABAA receptors in Creutzfeldt-Jakob disease. Acta Neuropathol 2003;106:311–8.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Seizures in E200K familial and sporadic Creutzfeldt-Jakob disease Appel S, Chapman J, Cohen OS, Rosenmann H, Nitsan Z, Blatt I. Seizures in E200K familial and sporadic Creutzfeldt-Jakob Disease. Acta Neurol Scand: DOI: 10.1111/ane.12304. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Although seizures (other than myoclonus) are frequently reported in Creutzfeldt-Jakob disease (CJD), their frequency, clinical manifestations, and effect on the disease course is unknown. Objectives – To characterize the frequency of seizures in E200K familial and sporadic CJD, to describe its semiology, EEG and MRI findings. Methods – In this retrospective study, we reviewed all patients with CJD who were seen in the Sheba Medical Center between the years 2003–2012 and underwent clinical evaluation, genetic testing, EEG and MRI studies. The diagnosis of seizures was carried out based on documentation of episodes consistent with seizures or episode of unresponsiveness correlated with ictal activity in EEG. Results – Sixty-four probable patients with CJD were included in the study, 57 (89%) with E200K familial (fCJD) and 7 (11%) with sporadic (sCJD). Seizures occurred in 8 patients: 3 of 7 (43%) in patients with sCJD compared to 5/57 (9%) in patients with E200K fCJD (P = 0.04, chi-square test). Two of E200K fCJD patients with seizures had other non-prion etiologies for seizures (brain metastasis, known history of temporal lobe epilepsy which started 44 years before the diagnosis of CJD). Seizures occurred late in the course of the disease with an average of 12 days between the onset of seizures and death. Conclusion – Seizures in E200K fCJD were infrequent and occurred late in the disease course. This difference suggests that E200K fCJD represents a separate subtype of the disease with distinct clinical characteristics.
Introduction
Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease caused by formation and deposition of the abnormal prion protein (PrPSc) in the central nervous system (1). Several clinical subtypes of the disease have been characterized including sporadic (sCJD), acquired, and familial (fCJD) forms (2). The largest cluster of fCJD exists in the North African Jewish community of Libyan and Tunisian ancestry linked to the E200K mutation in the prion protein gene (PRNP) (3). Seizures (other than myoclonus) have been described in patients with CJD including cases of status epilepticus (4). Few
S. Appel1, J. Chapman2,3, O. S. Cohen2,3, H. Rosenmann4, Z. Nitsan1, I. Blatt2,3 1 Department of Neurology, Barzilai Medical Center, affiliated to Ben Gurion University, Ashkelon, Israel; 2 Department of Neurology, Sheba Medical Center, Ramat-Gan, Israel; 3Sackler Faculty of medicine, TelAviv University, Tel Aviv, Israel; 4Department of Neurology, Hadassah University Hospital, Jerusalem, Israel
Key words: E200K familial Creutzfeldt-Jakob disease; sporadic Creutzfeldt-Jakob disease epilepsy; prion disease; seizures S. Appel, Barzilai Medical Center, Hahistadrut 2, Askelon, 78278, Israel Tel.: +972-53-8272784 Fax: +972-8-6745463 e-mail: [email protected] Accepted for publication August 4, 2014
published series of patients with sCJD specifically reported seizures with an incidence of around 20% (5, 6). This incidence is higher than the incidence reported in other neurodegenerative disorders like Alzheimer disease (7) but lower than the incidence of seizures in fulminant diseases such as Herpes encephalitis, where seizure incidence in the acute phase is higher and varies between 40 and 60% (8). EEG examinations of patients with CJD often reveal generalized periodic epileptiform discharges, periodic lateralized epileptiform discharges (PLEDs), and interictal spikes. (IIS) One of the main symptoms of the disease is myoclonus, implying that epileptic activity frequently occurs in CJD. The goal of this study 1
Appel et al. was to characterize the frequency of seizures in patients with E200K and sporadic CJD and to describe its semiology, EEG and MRI findings.
were compared to the CJD patients without seizures. Statistics
Methods
In this retrospective study, we reviewed the medical records of all patients with CJD who were evaluated in the CJD Clinic or hospitalized in the Department of Neurology of the Sheba Medical Center during the years 2003–2012. The diagnosis of probable CJD was established according to the 1998 WHO criteria (9) with the modification of using CSF Tau protein level instead of the 14-3-3 level. Tau concentrations were measured by an ELISA (Innotest hTau-Ag, Innogenetics, Ghent, Belgium). Using a cutoff value of 1000 pg/ml, our sensitivity was 72% for patients with fCJDE200K and 83.3% for patients with sCJD, with a specificity of 93.1%, as published by us previously (10). The study was approved by the Institutional review Board of the Sheba Medical Center, and all patients signed an informed consent prior to inclusion in this study. The evaluation included personal and family history review, physical examination, DNA testing for PRNP gene mutations, CSF analysis for Tau protein, EEG and MRI studies. The diagnosis of seizures was carried out based on documentation of episodes consistent with seizures or episode of unresponsiveness correlated with ictal activity in EEG. Patients were classified as ‘E200K familial CJD’ (fCJD) if they had a positive family history and/or were positive for E200K mutation in the PRNP gene. Cutoff level of Tau protein above 1000 was considered as consistent with the diagnosis of CJD. MRI was conducted using a 1.5 Tesla system and included T1, T2, DTI, and DWI sequences. Digital EEG was performed with an electrode array according to the international 10–20 method. The demographic data, genetic, EEG and MRI findings, and the clinical course
ANOVA or chi-square test was used to compare the groups. Significance was set at P < 0.05. Results
Sixty-four probable patients with CJD were included in the study (for demographic and clinical data see Table 1). Thirty-five (55%) were men, and the average age was 59.5 8.3 years. Fifty-seven patients (89%) who were of LibyanJewish ancestry and positive for the typical mutation of E200K in the PRNP gene were classified as E200K familial CJD (fCJD). Seven patients (11%) were negative for the E200K mutation, had no family history of CJD and were classified as sporadic CJD (sCJD). Eight patients (14%) had seizures. Six patients had generalized tonic–clonic seizures (most likely secondarily generalized) and 2 patients (one with E200K fCJD and one with sCJD) presented with acute alerted mental status and unresponsiveness correlated with ictal activity per EEG consistent with the diagnosis of non-convulsive status epilepticus. Seizures were more common in patients with sCJD (3/7 in patients with sCJD vs. 5/57 in patients with E200K fCJD (P = 0.04 chi-square test)). The seizures were related to the diagnosis of CJD in all patients with sCJD but in only 3 of the patients with E200K fCJD. One patient with E200K fCJD (case 38) had been diagnosed with epilepsy at the age of 12, 44 years before the diagnosis of CJD. Her seizures consisted of episodes of unresponsiveness and secondarily generalized tonic–clonic seizures. Another patient E200K fCJD (case 44) was diagnosed with brain metastasis from lung adenocarcinoma which presented with seizures 12 months before the presentation of CJD. The seizures related to CJD
Table 1 Demographic and clinical features CJD patients without history of seizures
Number Gender (male) Average age (years) Clinical presentation
2
CJD patients with history of seizures
sCJD
fCJD
sCJD
fCJD
4 2 61.25 9.09 Gait imbalance-2, cognitive decline-1, vertigo-1
52 28 59.3 8.3 Cognitive decline-14, gait imbalance-11, insomnia-8, hemiparesis-2 illusions-3, headache-3, neuropathy-3, behavioral change-1, weight loss-1, pruritus-1, tiredness-1, depression-1, low back pain-1, hearing loss-1, focal dystonia-1
3 2 44.65 4.6 Illusions-1, behavioral change-1, hemiparesis 1
5 3 61.8 9.9 Gait imbalance-2, illusions-1, cognitive-1, numbness-1
Seizures in CJD (excluding the 2 cases with other etiologies mentioned above) occurred late in the course of the disease with an average period of 12 days between the onset of the seizures and death. No correlation was found between the demographic characteristics (gender, age of onset, first clinical presentation) and the occurrence of seizures (data is not shown). In 4 other patients, anti-epileptic treatment was started without any history of established seizures. Two patients were started on treatment due to myoclonic jerks and 2 others patients due to PLEDs on their EEG. No clinical improvement was noticed in any of these patients with AED treatment. EEG findings
EEG records were available for 52 patients. (see Table 2) EEG was normal in 4 patients (8%). In
those patients with abnormal EEG, the most frequent findings were non-specific slowing (focal or diffuse), seen in 28 (54%) patients, and the typical finding of Periodic Sharp Wave Complexes (PSWCs) which was seen in 20 patients (38%) (See Figs 1 and 2). Epileptiform abnormalities were seen in 11 patients (21%): Three (4%) had isolated focal interictal spikes (IIS), 6 had PLEDs, 1 had BiPLEDs, and 1 had a pattern of Generalized Periodic Epileptiform Discharges (GPEDs). An EEG study of one of the patients who presented with altered mental status showed non-convulsive focal status epilepticus. Another patient presented to another hospital with decreased mental status and his EEG was consistent with non-convulsive focal status epilepticus. However, his EEG was not available to us. Seizures were not associated with epileptiform activity on interictal EEG (P = 0.6, chi-square), and
Table 2 EEG finding CJD patients with history of seizures
CJD patients without history of seizures fCJD** Number Background Slow activity: diffuse/focal Periodic Sharp Wave Complex: diffuse/focal Normal Epileptiform abnormalities Individual abnormalities
sCJD
fCJD*
sCJD
41
4
4
3
21/5 9/4 2
0 2/1 1
1/0 0/2 1
1/0 1/1 0
1 NCSE
1 PLED
5 PLEDs, 3 IIS, 1 BiPLEDs, 1GPED
0
*EEG of 1 patient was not available. **EEG of 13 patients was not available. PLEDs, periodic lateralized epileptiform discharges; NCSE, non-convulsive status epilepticus; IIS, interictal spike; BiPLEDs, bilateral periodic lateralized epileptiform discharges, GPEDs, generalized periodic epileptiform discharges.
Figure. 1. Diffuse Periodic Sharp Wave Complexes in EEG of patient with fCJD.
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Figure. 2. Focal Periodic Sharp Wave Complexes in EEG of patient with fCJD.
epileptiform activity did not predict clinical seizures (P = 0.5, chi-square). Epileptiform activity was not correlated with any of the demographic and clinical features as well (data not shown). The epileptiform activity was frequently associated with PSWC activity elsewhere in the same record (epileptiform abnormalities in 8/20 patients with PSWC vs. 3/32 patients with no PSWC, P < 0.01 chi-square). PSWC was more common in patients with sCJD. (5/7 vs. 14/45, P = 0.04 chi-square).
CJD. Fifty patients (86%) had basal ganglia MRI involvement, 14 patients (24%) had thalamic involvement, and 35 patients (60%) had cortical involvement. No association was found between cortical involvement and history of seizures (P = 0.19, chi-square) or epileptiform activity on the EEG (P = 0.5, chi-square). No significant difference was found between demographic characters, EEG and MRI findings of patients with E200KfCJD and with sCJD.
MRI findings
MRI records of 58 patients were available (for details see Table 3). In 51 patients (88%), MRI showed the typical hyperintense signals from the basal ganglia (See Fig. 3), thalamus and/or cortex (see Fig. 4). In 2 patients, MRI was normal and in 5 patients MRI showed non-specific ischemic/ hyperintense lesions, unrelated to the diagnosis of Table 3 MRI finding
Number Deep gray matter involvement Cortical involvement Cortical and deep matter involvement Non-specific finding** Normal
CJD patients without history of seizures
CJD patients with history of seizures
fCJD
sCJD
fCJD
sCJD
46* 15 1 24 4 2
4 1 0 3 0 0
5 0 0 4 1 0
3 0 0 3 0 0
*MRI of 6 patients were not found. **Non-specific/ischemic white matter changes.
4
Figure. 3. MRI images of patient with CJD (including FLAIR, DWI, and ADC squences) showing hyperintense signals from the basal ganglia.
Seizures in CJD
Figure. 4. MRI images of patient with CJD (including FLAIR, DWI, and ADC squences) showing hyperintense signals from the basal ganglia and right frontal cortex.
Discussion
The incidence of seizures in our cohort was 14%. This incidence is similar to the one reported in chronic dementia (7) and previous CJD series (5, 6) unlike the significantly higher incidence of seizures seen in fulminant diseases such as herpes encephalitis (8). The seizures in our patients tended to occur later in the disease course and might be related to critical conditions with unstable metabolic/electrolyte imbalance or sepsis, rather than epileptogenicity directly caused by CJD pathology. A possible explanation may be found in the histopathological characteristics of these entities. Herpes encephalitis is characterized by well-demarcated necrotizing lesions and hemorrhages with meningeal cell exudates and perivascular cuffing with neuronophagia, in contrast to spongiform changes, neuronal loss and reactive gliosis with no significant inflammatory infiltrate seen in CJD. The typical brain area involved may offer an alternative explanation. Herpes encephalitis typically involves highly epileptogenic regions of the temporal lobe and orbitofrontal gyrus versus frontal regions and deep gray matter as seen in patients with CJD. The incidence of seizures in our cohort is lower than the figures seen in previous series (5, 6) reporting on incidence of 20% of seizures in patients with CJD. Due to the limited numbers of patients included in the series, the difference is non-significant and may be incidental.
However, it may reflect the difference in the patients population included in these series. Our cohort included mainly patients with E200K fCJD, whereas the previous series studied patients with sCJD only. Interestingly, a subanalysis of our cohort revealed a higher incidence of seizures (43%) in patients with sporadic CJD versus a significantly lower incidence of 12% in patients with E200K familial CJD (P = 0.04 chi-square test). This finding is consistent with our previous reports of unique clinical, electrophysiological, and imaging characteristics of E200K familial CJD, including pruritus and early sleep disturbances (11, 12). A possible explanation is that as suggested in that study, sCJD tends to involve the hemispheral cortex per MRI and to produce the classical EEG finding of PSWC, whereas fCJD more often involves the less epileptogenic regions of deep gray matter with non-specific EEG slowing. (11) As implied by many case reports of status epilepticus (SE) in patients with CJD, our study found a high incidence of SE with 2 cases out of 64 patients (3%). SE is thought to occur due to failure to terminate an isolated seizure. Endocytosis of GABA-A receptors as SE evolves contributes to the progressive pharmacoresistance to benzodiazepines (13), and NMDA receptors translocation to the synaptic membrane increases the excitability (14) and leads to neuronal apoptosis. Recently, a few studies showed abnormal expression of GABA receptors and NMDA receptors in various regions in the cortex of patients with CJD (15). This may contribute to the hyperexcitability and the failure to inhibit seizures in CJD which may result in the tendency toward status epilepticus as shown in this study. In summary, seizures in E200K fCJD are less frequent compared to sCJD, most likely due to involvement of deep and less epileptogenic brain structures in E200K fCJD. Acknowledgements
The study was partially supported by NIH grant# NS043488. Conflict of interests
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