- Email: [email protected]
Five cases of new onset refractory status epilepticus (NORSE) syndrome: Outcomes with early immunotherapy
Seizure 22 (2013) 217–220
Contents lists available at SciVerse ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Five cases of new onset refractory status epilepticus (NORSE) syndrome: Outcomes with early immunotherapy Claire R.E. Gall a, Odai Jumma b, Rajiv Mohanraj a,* a b
Greater Manchester Neurosciences Centre, Salford, UK Birmingham Heartlands Hospital, Birmingham, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 September 2012 Received in revised form 20 December 2012 Accepted 24 December 2012
Cryptogenic new onset refractory status epilepticus (NORSE) syndrome has been described in both adults and children, and is often associated with poor outcome. A variety of terms have been used in the literature to refer to this syndrome. The condition may be triggered by as yet unidentified infections or an immunological mechanism. We present a series of 5 patients with NORSE syndrome treated at 2 neuroscience centres in the North of England, in whom early use of immunotherapy appears to be associated with good neurological outcomes. Methods: Case note review of the index case and four other patients was undertaken to obtain details of clinical presentation, imaging and CSF findings, infectious/inflammatory tests, management of seizures, immunotherapy and outcome. Results: Case 1 was a 26 year old male with a prodrome of headache and vomiting. He developed refractory multifocal and generalised seizures, which required admission to intensive care unit and administration of general anaesthetic. Seizures recurred on withdrawal of barbiturate anaesthetic until day 29. MR imaging, CSF examination and serological tests for viral and autoimmune aetiologies were normal apart from positive anti-TPO antibodies: the patient had previously treated hyperthyroidism. He was initially treated with aciclovir and antibacterials. IV steroids were administered day 12 and IV immunoglobulin day 18. He made a good recovery being discharged home 2 months after admission. Seizures recurred on withdrawal of steroid therapy, and required longer term immunosuppressant treatment with azathioprine. Clinical features and investigations of the four other patients were similar. Two were given early immunotherapy with steroids and intravenous immunoglobulins and survived with few deficits. One patient who was not given immunotherapy died from complications associated with prolonged ICU stay. Outcome was not known for the fourth patient as she was repatriated to her home country in thiopentone coma. Conclusion: In our experience, early immunotherapy has been associated with good outcomes in NORSE. Multicentre collaboration is required to establish the diagnostic criteria and appropriate management of patients presenting with NORSE. ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: NORSE syndrome Super-refractory status epilepticus Immunotherapy Epilepsy
1. Introduction The term refractory status epilepticus is applied to SE refractory to two emergency antiepileptic drug (AED), typically benzodiazepines such as lorazepam, and a second line agent such as phenytoin or valproate.1 Induction of general anaesthesia is required in these patients. SE continuing for more than 24 h resistant to antiepileptic and anaesthetic drugs has been described as ‘super-refractory’ SE.2 It is estimated that approximately 15% of all cases of convulsive
* Corresponding author at: Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK. Tel.: +44 0 161 206 4626; fax: +44 0 161 206 2993. E-mail address: [email protected] (R. Mohanraj).
status epilepticus admitted to hospital will fall into this category.2 The term new onset refractory status epilepticus (SE) (NORSE) syndrome has been used to describe patients who develop refractory status epilepticus with no prior history of epilepsy, or identifiable causative factors.3 NORSE syndrome may be regarded as a form of super refractory SE where no aetiological factor is identified in a patient with no prior history of epilepsy. A variety of terms have been used in the literature to describe the phenomenon of new onset refractory status epilepticus, both in adults and children. These include De Novo Cryptogenic Refractory Multifocal Febrile Status Epilepticus,4 Idiopathic Catastrophic Epileptic Encephalopathy,5 Severe Refractory Status Epilepticus owing to Presumed Encephalitis,6 Devastating Epilepsy In SchoolAge Children (DESC)7 Acute Encephalitis with Refractory Repetitive Partial Seizures (AERRPS),8 and Fever-Induced Refractory
1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.12.016
218
C.R.E. Gall et al. / Seizure 22 (2013) 217–220
Epileptic Encephalopathy (FIRES).9,10 In spite of the differences in terminology, it is possible that all of these reports describe the same entity.11 The common clinical features include superrefractory SE following a mild febrile illness and possible initial cerebrospinal fluid (CSF) pleocytosis in some cases, although no infective aetiological agent has been identified. The outcome is frequently fatal or survival with severe neurological sequelae.3–5 A few cases with favourable outcome have been reported.9,12 The optimal management for this devastating condition remains unclear. Standard treatment algorithms for status epilepticus are often unsuccessful, and a variety of additional treatment strategies have been reported in the literature, including immunotherapy, hypothermia, brain stimulation and surgery.2 These are uncontrolled observations in small numbers of patients. However, such observations can serve to direct the search for effective treatments to be explored in controlled studies. We describe super refractory SE occurring in 5 adults with no prior history of epilepsy and in whom after extensive investigation no cause was found. Of the five patients, 3 had good outcomes, all of whom received early immunotherapy. 2. Index case The patient was a 26 year old man with a past medical history of hyperthyroidism, but no risk factors for the development of epilepsy. He developed occipital headache and neck pain over a
period of five days with associated vomiting. Three days later, he was admitted to hospital with a series of generalised tonic clonic seizures, interspersed with complex partial seizures. He was treated with intravenous lorazepam and phenytoin, which appeared to control seizures for the first 72 h. CT scan of the brain was normal. On day 3, he developed status epilepticus requiring induction of general anaesthesia with propofol, and transferred to the intensive care unit at the neurosciences centre. He received further AED treatment with intravenous phenytoin, valproate and levetiracetam was added. Seizure control was monitored clinically as well as using the cerebral function monitor (CFAM) and intermittent electroencephalogram (EEG) recording. Because of ongoing electrographic seizure activity, thiopentone was initiated on day 5. MRI scan of the brain on day 6 showed no significant abnormalities. Seizures recurred on withdrawal of thiopentone on day 12. Additional AED treatment in the form of Phenobarbitone and Clobazam was instituted. Further recurrences of multifocal seizure activity continued up to day 29 (Fig. 1). CSF analysis on admission showed mild lymphocytosis but was normal on day 8 (see Table 1). Full blood count initially showed a mild neutropenia (0.6) and monocytosis (1.38) that resolved to normal within days. Magnetic resonance (MRI) brain scan on days 11 and day 42 with gadolinium contrast was also normal. Infective serology (including HIV serology and monospot) and PCR for viral nucleic acids on throat swabs and CSF were negative. Antinuclear antibody (ANA) was positive (1/100 titre speckled) as was anti-TPO
Fig. 1. EEG in patient 1, on day 10, showing seizures of right hemispheric origin.
C.R.E. Gall et al. / Seizure 22 (2013) 217–220
219
Table 1 Clinical characteristics of 5 patients with NORSE syndrome. Case
Age and gender
Prodrome
CSF Day
WCC
Protein (g/L)
Glucose
0.26
3.6 (plasma 5.7)
1
26 M
3 days of headache, vomiting
Day 1
2
34 M
5 days of fever and myalgia, GTCS
Day 3 Day 12
14 (90% L) <1
0.4 0.22
3.8 3.2 (plasma 7.5)
3
30 M
Day 3 Day6
10 9 (100% L)
0.5 0.8
4.6 3.6
4
23 F
Day 1
<1
1.22
4.3 (plasma 10.3)
5
22 F
3 days of headache, acute confusion 4 weeks of headache, pyrexia, vomiting Pyrexia for 1 week then acute confusion
Day 5
1
0.39
4.1 (plasma 6.5) 3.9 (plasma 5.6)
Day 10
1
11 (95% L)
0.28
antibodies (440, normal range < 50,). Thyroid function tests were normal. Serum assays for antibodies to voltage-gated potassium channel (VGKC), glutamate decarboxylase (GAD), NMDA glutamate receptors and paraneoplastic neuronal antigens were negative. The patient was initially treated with 14 days of aciclovir, ceftriaxone and amoxicillin. Once infective causes had been ruled out, because of the possibility that an autoimmune processes was responsible for sustaining the epileptic condition, intravenous steroids were administered on day 12 (3 days of 1 g IV methylprednisolone daily followed by oral prednisolone 60 mg/ day). Intravenous immunoglobulin (150 g over 5 days) was administered on day 18. Thiopentone was discontinued on day 30 without recurrence of seizures. Intensive care related complications included ventilator acquired pneumonia and a transient deterioration in renal function that resolved after discontinuation of aciclovir. The patient subsequently made a good recovery. Neuropsychological assessments at two months found moderate memory deficits and executive cognitive problems. Seizures recurred on withdrawal of steroids but responded to reintroduction of steroids. Following discharge, he has been able to return to his previous occupation in a full time capacity. Two years after discharge, he continues to take combination treatment with AED and mycophenolate mofetil. Anti-TPO antibodies are present in the serum. He continues to experience occasional focal seizures. Demographic and clinical details of the other 4 patients is summarised in Table 1. Patients were all previously healthy young adults, who presented with a febrile illness followed by several days of refractory seizure activity. The index case and 2 other cases given immunotherapy survived with relatively little neurological sequelae, while outcome was not known for the 5th patient. 3. Discussion Super refractory SE occurring in patients with no prior history of epilepsy and with no identifiable aetiology appears to be a distinct entity. There is some debate over whether a syndromic label such as ‘NORSE syndrome’ for such cases is appropriate, as the potential aetiologies could be diverse.2 However, many cases of cryptogenic de novo super refractory status described under various labels share clinical features, such as a younger age of patients, a febrile prodrome and initial CSF pleocytosis. Thus, it would appear that
CSF viral PCR
Immunotherapy
Outcome
Negative for HSV, CMV, VZV, Entero, Parecho, HBV, EBV, HHV, Parvovirus Negative for HSV 1 & 2, CMV, VZV, EBV, HHV6, HHV7, and adenovirus Negative for HSV 1&2, CMV, VZV, Entero, EBV and ECHO Negative for HSV 1&2, EBV, CMV and enterovirus Negative for HSV 1&2, VZV, EBV
High dose steroids, IVIg
No deficits. Seizures controlled on azathioprine and AEDs No deficits. Seizures controlled on AEDs
High dose steroids, IVIg
High dose steroids
None
None
Mild cognitive deficit, ongoing seizures partially controlled on AEDs Died on day 21
Unknown. Repatriated to home country in thiopentone coma on day 16
this entity has been labelled differently by different authors, which adds to the difficulty in interpreting the literature. We believe separating cryptogenic new onset super refractory SE from other causes of super refractory SE, and standardising terminology can aid the better understanding and advancement in management of this condition. The investigations required to exclude known causes of super-refractory SE, enabling the diagnosis of NORSE syndrome to be made have been described previously.1 We report 5 cases of NORSE syndrome treated with anaesthetic agents and AEDs in intensive care units. Our patients were previously healthy young adults, who had a non-specific prodrome lasting for 2–7 days before onset of seizures. There were mild and transient CSF abnormalities, unremarkable imaging, and no confirmatory evidence of CNS infection. One patient had antiTPO antibody. Duration of refractory status epilepticus requiring general anaesthesia was between 7 and 30 days. Immunotherapy was given in the 3 of the 5 cases, all of whom recovered without significant neuropsychological deficits, returning to full time employment in 2 cases. One patient who did not receive immunotherapy died of ICU related complications after 3 weeks, and outcome was not known for the other patient. Several short series in the literature describe purely cryptogenic refractory SE, which we believe fit our proposed definition of NORSE syndrome (see Table 2). A number of cases series in children have also reported a similar clinical presentation.5,7,13 There is some heterogeneity in the reported cases, with regards to the prodomal illness, and CSF abnormalities. It would appear that CSF analysis early in the course of illness is more likely to show pleocytosis, resolving in later analysis, which may indicate an initial infective or autoimmune precipitating factor. However, more cases will need to be studied to ascertain the true case definition of NORSE. It has been pointed out that the paediatric syndrome of FIRES is a different entity from NORSE, with no evidence of autoantibody production, and no apparent improvement with immunotherapy.14,15 Other series of super refractory status epilepticus of diverse aetiologies probably include some similar cases to ours. The California encephalitis project (CEP) for example included 43 patients presenting with status epilepticus following a febrile prodromal illness, the majority (72%) of whom did not have an identifiable viral pathogen.1,16,17 The mortality in this cohort was 28%, and the majority of survivors are described as suffering severe neurological impairment. According to definitions
C.R.E. Gall et al. / Seizure 22 (2013) 217–220
220
Table 2 Previously published case series that probably represent NORSE syndrome. Journal/authors
No of cases/ demographics
Prodrome
Immunotherapy
Outcomes
Comments
Costello et al. J Neurol Sci 2009
n=6 Aged 24–36 4 female
4 fever myalgia
1 PEx and IVIg (anti-TPO antibodies) Steroids-None > 3/7
1 died on ITU (propofol syndrome), 1 good outcome, 1 epilepsy surgery-survival with dependency
Wilder-Smith et al. Ann Acad Med Singapore 2005 Glaser et al. (California Encephalitis Project) Clin Infec Dis 2006 Van Lierde et al. Acta Neurol Belg 2003
n=7 All female
5 of 7
5 died on ITU, 2 vegetative
n = 57 Ages 0–74
Not stated
3/7 given IVIg (less than our standard dose) Not stated
One patient had anti-TPO antibodies (treated with PEx and IVIg) None given immunotherapy within first 5 days More pleocytic CSF than our patients, abnormal MRs
20% died in hospital, most of survivors required extensive rehab
Predominantly children (69%)
n=6 Ages 18–30 4 female n = 14
All patients had prodromal illness
PEx and high dose steroids in 2 patients, timing not stated Steroids in 6 patients
2 poor functional neurological recovery and refractory seizures 4 died Survival with major cognitive sequale and intractable seizures
No cortical dysplasia on autopsy
n=6
4 of 6 patients had fever
All given high dose steroids 2 given IVIg
3 died, 3 severe impairment and intractable seizures
Mikaeloff et al. Epilepsy Res2006
Baxter et al. Seizure 2003
Febrile event in all patients (URTI with or without rash)
used in the CEP study, our patients would have been classed as suffering from encephalitis. The apparent good response to immunotherapy hints at an autoimmune process involved in the pathogenesis of at least some cases of NORSE syndrome in adults. An immunological basis for NORSE syndrome has been suggested by other authors. In our series as well as the CEP series, one patient each had anti-thyroid peroxidise antibodies. Single case reports have also described occurrence of antibodies to Glure2 and neuropil, with good outcome from immunotherapy.18,19 A number of case reports have described antibodies to NMDA glutamate receptors and voltage gated potassium channel antibodies in patients with refractory status epilepticus.20–23 Immunotherapy including steroids and intravenous immunoglobulin has been used in super-refractory SE for a number of years.2 In addition to their immunological effects, steroids also have potentially beneficial effects on breakdown of blood brain barrier, GABA receptor activity and intracranial pressure. In the management scheme proposed by Shorvon and Ferlisi, it has been suggested that early immunotherapy should be instituted in cases of super refractory SE where no cause has been identified.2 Our cases give further support to the notion that early immunotherapy should be considered in patients classed as suffering NORSE syndrome. References 1. Costello DJ, Kilbride RD, Cole AJ. Cryptogenic new onset refractory status epilepticus in adults-infectious or not? Journal of the Neurological Sciences 2009;277:26–31. 2. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802–18. 3. Wilder-Smith EPV, Lim ECH, Teoh HL, Sharma VK, Tan JJH, Chan BPL, et al. The NORSE syndrome: defining a disease entity. Annals of the Academy of Medicine (Singapore) 2005;34:417–20. 4. Van Lierde I, Van Paesschen W, Dupont P, Maes A, Sciot R. De novo cryptogenic refractory multifocal febrile status epilepticus in the young adult: a review of six cases. Acta Neurologica Belgica 2003;103:88–94. 5. Baxter P, Clarke A, Cross H, Harding B, Hicks E, Livingston J, et al. Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status. Seizure 2003;12:379–87. 6. Kramer U, Shorer Z, Ben-Zeev B, Lerman-Sagie T, Goldberg-Sten H, Lahat E. Severe refractory status owing to presumed encephalitis. Journal of Child Neurology 2005;20:184–7.
Bilateral hippocampal high signal in 10 patients Neuropsychology – fronto temporal impairment Other childhood disorders not fully excluded as prior developmental delay in 2
7. Mikaeloff Y, Jambaque I, Hertz-Pannier L, Zamfirescu A, Adamsbaum C, Plouin P, et al. Devastating epileptic encephalopathy in school aged children: a pseudoencephalitis. Epilepsy Research 2006;69:67–79. 8. Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurologica Scandinavica 2010;21:251–6. 9. van Balen A, Hausler M, Boor R, Rohr A, Sperner J, Kurlemann G, et al. Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood. Epilepsia 2010;51:1323–8. 10. Nabbout R, Hubert P, Peudenniers S, Allaire C, Flurin V, Aberastury M, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51:2033–7. 11. Ismail FY, Kossoff EH. AERRPS, DESC, NORSE, FIRES: multilabeling or distinct epileptic entities? Epilepsia 2011;52:e185–9. 12. Standley K, Abdulmassih R, Benbadis S. Good outcome is possible after months of refractory status epilepticus: lessons learned. Epilepsia 2012;53:e17–20. 13. Fong JS, Hantus S, Erbayat Altay E, Tuxhorn I. De novo refractory status epiepticus and encephalopathy: a retrospective case series. Journal of Child Neurology 2010;25:1535–8. 14. Ko¨rtvelyessy P, Lerche H, Weber Y. FIRES and NORSE are distinct entities. Epilepsia 2012;53:1276. 15. van Baalen A, Ha¨usler M, Plecko-Startinig B, et al. Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012;43:209–16. 16. Glaser CA, Honarmand S, Anderson LJ, Schnurr DP, Forghani B, Cossen CK, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clinical Infectious Diseases 2006;43:1565–77. 17. Glaser CA, Gilliam S, Honarmand S, et al. Refractory status epilepticus in suspect encephalitis. Neurocritical Care 2008;9:74–82. 18. Okanishi T, Mori Y, Kibe T, Takahashi Y, Saito Y, Maegaki Y, et al. Refractory epilepsy accompanying acute encephalitis with multifocal cortical lesions: possible autoimmune etiology. Brain and Development 2007;29:590–4. 19. Milh M, Villeneuve N, Chapon F, Gavaret M, Girard N, Mancini J, et al. New onset refractory convulsive status epilepticus associated with serum neuropil auto-antibodies in a school aged child. Brain and Development 2011;33:687–91. 20. Bayreuther C, Bourg V, Dellamonica J, Borg M, Bernardin G, Thomas P. Complex partial status epilepticus revealing anti-NMDA receptor encephalitis. Epileptic Disorders 2009;11:261–5. 21. Mittal M, Hammond N, Lynch GS. Immunotherapy responsive autoimmune subacute encephalitis: a report of two cases. Case Reports in Medicine 2010;2010:837371. 22. Nath U, Warren NM, Ali H. NMDA receptor encephalitis—expanding the clinical spectrum. BMJ Case Report 2011. http://dx.doi.org/10.1136/bcr.12.2010.3579. 23. Suleiman J, Brenner T, Gill D, Brilot F, Antony J, Vincent A, et al. VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology 2011;76:1252–5.
Contents lists available at SciVerse ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Five cases of new onset refractory status epilepticus (NORSE) syndrome: Outcomes with early immunotherapy Claire R.E. Gall a, Odai Jumma b, Rajiv Mohanraj a,* a b
Greater Manchester Neurosciences Centre, Salford, UK Birmingham Heartlands Hospital, Birmingham, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 September 2012 Received in revised form 20 December 2012 Accepted 24 December 2012
Cryptogenic new onset refractory status epilepticus (NORSE) syndrome has been described in both adults and children, and is often associated with poor outcome. A variety of terms have been used in the literature to refer to this syndrome. The condition may be triggered by as yet unidentified infections or an immunological mechanism. We present a series of 5 patients with NORSE syndrome treated at 2 neuroscience centres in the North of England, in whom early use of immunotherapy appears to be associated with good neurological outcomes. Methods: Case note review of the index case and four other patients was undertaken to obtain details of clinical presentation, imaging and CSF findings, infectious/inflammatory tests, management of seizures, immunotherapy and outcome. Results: Case 1 was a 26 year old male with a prodrome of headache and vomiting. He developed refractory multifocal and generalised seizures, which required admission to intensive care unit and administration of general anaesthetic. Seizures recurred on withdrawal of barbiturate anaesthetic until day 29. MR imaging, CSF examination and serological tests for viral and autoimmune aetiologies were normal apart from positive anti-TPO antibodies: the patient had previously treated hyperthyroidism. He was initially treated with aciclovir and antibacterials. IV steroids were administered day 12 and IV immunoglobulin day 18. He made a good recovery being discharged home 2 months after admission. Seizures recurred on withdrawal of steroid therapy, and required longer term immunosuppressant treatment with azathioprine. Clinical features and investigations of the four other patients were similar. Two were given early immunotherapy with steroids and intravenous immunoglobulins and survived with few deficits. One patient who was not given immunotherapy died from complications associated with prolonged ICU stay. Outcome was not known for the fourth patient as she was repatriated to her home country in thiopentone coma. Conclusion: In our experience, early immunotherapy has been associated with good outcomes in NORSE. Multicentre collaboration is required to establish the diagnostic criteria and appropriate management of patients presenting with NORSE. ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: NORSE syndrome Super-refractory status epilepticus Immunotherapy Epilepsy
1. Introduction The term refractory status epilepticus is applied to SE refractory to two emergency antiepileptic drug (AED), typically benzodiazepines such as lorazepam, and a second line agent such as phenytoin or valproate.1 Induction of general anaesthesia is required in these patients. SE continuing for more than 24 h resistant to antiepileptic and anaesthetic drugs has been described as ‘super-refractory’ SE.2 It is estimated that approximately 15% of all cases of convulsive
* Corresponding author at: Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK. Tel.: +44 0 161 206 4626; fax: +44 0 161 206 2993. E-mail address: [email protected] (R. Mohanraj).
status epilepticus admitted to hospital will fall into this category.2 The term new onset refractory status epilepticus (SE) (NORSE) syndrome has been used to describe patients who develop refractory status epilepticus with no prior history of epilepsy, or identifiable causative factors.3 NORSE syndrome may be regarded as a form of super refractory SE where no aetiological factor is identified in a patient with no prior history of epilepsy. A variety of terms have been used in the literature to describe the phenomenon of new onset refractory status epilepticus, both in adults and children. These include De Novo Cryptogenic Refractory Multifocal Febrile Status Epilepticus,4 Idiopathic Catastrophic Epileptic Encephalopathy,5 Severe Refractory Status Epilepticus owing to Presumed Encephalitis,6 Devastating Epilepsy In SchoolAge Children (DESC)7 Acute Encephalitis with Refractory Repetitive Partial Seizures (AERRPS),8 and Fever-Induced Refractory
1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.12.016
218
C.R.E. Gall et al. / Seizure 22 (2013) 217–220
Epileptic Encephalopathy (FIRES).9,10 In spite of the differences in terminology, it is possible that all of these reports describe the same entity.11 The common clinical features include superrefractory SE following a mild febrile illness and possible initial cerebrospinal fluid (CSF) pleocytosis in some cases, although no infective aetiological agent has been identified. The outcome is frequently fatal or survival with severe neurological sequelae.3–5 A few cases with favourable outcome have been reported.9,12 The optimal management for this devastating condition remains unclear. Standard treatment algorithms for status epilepticus are often unsuccessful, and a variety of additional treatment strategies have been reported in the literature, including immunotherapy, hypothermia, brain stimulation and surgery.2 These are uncontrolled observations in small numbers of patients. However, such observations can serve to direct the search for effective treatments to be explored in controlled studies. We describe super refractory SE occurring in 5 adults with no prior history of epilepsy and in whom after extensive investigation no cause was found. Of the five patients, 3 had good outcomes, all of whom received early immunotherapy. 2. Index case The patient was a 26 year old man with a past medical history of hyperthyroidism, but no risk factors for the development of epilepsy. He developed occipital headache and neck pain over a
period of five days with associated vomiting. Three days later, he was admitted to hospital with a series of generalised tonic clonic seizures, interspersed with complex partial seizures. He was treated with intravenous lorazepam and phenytoin, which appeared to control seizures for the first 72 h. CT scan of the brain was normal. On day 3, he developed status epilepticus requiring induction of general anaesthesia with propofol, and transferred to the intensive care unit at the neurosciences centre. He received further AED treatment with intravenous phenytoin, valproate and levetiracetam was added. Seizure control was monitored clinically as well as using the cerebral function monitor (CFAM) and intermittent electroencephalogram (EEG) recording. Because of ongoing electrographic seizure activity, thiopentone was initiated on day 5. MRI scan of the brain on day 6 showed no significant abnormalities. Seizures recurred on withdrawal of thiopentone on day 12. Additional AED treatment in the form of Phenobarbitone and Clobazam was instituted. Further recurrences of multifocal seizure activity continued up to day 29 (Fig. 1). CSF analysis on admission showed mild lymphocytosis but was normal on day 8 (see Table 1). Full blood count initially showed a mild neutropenia (0.6) and monocytosis (1.38) that resolved to normal within days. Magnetic resonance (MRI) brain scan on days 11 and day 42 with gadolinium contrast was also normal. Infective serology (including HIV serology and monospot) and PCR for viral nucleic acids on throat swabs and CSF were negative. Antinuclear antibody (ANA) was positive (1/100 titre speckled) as was anti-TPO
Fig. 1. EEG in patient 1, on day 10, showing seizures of right hemispheric origin.
C.R.E. Gall et al. / Seizure 22 (2013) 217–220
219
Table 1 Clinical characteristics of 5 patients with NORSE syndrome. Case
Age and gender
Prodrome
CSF Day
WCC
Protein (g/L)
Glucose
0.26
3.6 (plasma 5.7)
1
26 M
3 days of headache, vomiting
Day 1
2
34 M
5 days of fever and myalgia, GTCS
Day 3 Day 12
14 (90% L) <1
0.4 0.22
3.8 3.2 (plasma 7.5)
3
30 M
Day 3 Day6
10 9 (100% L)
0.5 0.8
4.6 3.6
4
23 F
Day 1
<1
1.22
4.3 (plasma 10.3)
5
22 F
3 days of headache, acute confusion 4 weeks of headache, pyrexia, vomiting Pyrexia for 1 week then acute confusion
Day 5
1
0.39
4.1 (plasma 6.5) 3.9 (plasma 5.6)
Day 10
1
11 (95% L)
0.28
antibodies (440, normal range < 50,). Thyroid function tests were normal. Serum assays for antibodies to voltage-gated potassium channel (VGKC), glutamate decarboxylase (GAD), NMDA glutamate receptors and paraneoplastic neuronal antigens were negative. The patient was initially treated with 14 days of aciclovir, ceftriaxone and amoxicillin. Once infective causes had been ruled out, because of the possibility that an autoimmune processes was responsible for sustaining the epileptic condition, intravenous steroids were administered on day 12 (3 days of 1 g IV methylprednisolone daily followed by oral prednisolone 60 mg/ day). Intravenous immunoglobulin (150 g over 5 days) was administered on day 18. Thiopentone was discontinued on day 30 without recurrence of seizures. Intensive care related complications included ventilator acquired pneumonia and a transient deterioration in renal function that resolved after discontinuation of aciclovir. The patient subsequently made a good recovery. Neuropsychological assessments at two months found moderate memory deficits and executive cognitive problems. Seizures recurred on withdrawal of steroids but responded to reintroduction of steroids. Following discharge, he has been able to return to his previous occupation in a full time capacity. Two years after discharge, he continues to take combination treatment with AED and mycophenolate mofetil. Anti-TPO antibodies are present in the serum. He continues to experience occasional focal seizures. Demographic and clinical details of the other 4 patients is summarised in Table 1. Patients were all previously healthy young adults, who presented with a febrile illness followed by several days of refractory seizure activity. The index case and 2 other cases given immunotherapy survived with relatively little neurological sequelae, while outcome was not known for the 5th patient. 3. Discussion Super refractory SE occurring in patients with no prior history of epilepsy and with no identifiable aetiology appears to be a distinct entity. There is some debate over whether a syndromic label such as ‘NORSE syndrome’ for such cases is appropriate, as the potential aetiologies could be diverse.2 However, many cases of cryptogenic de novo super refractory status described under various labels share clinical features, such as a younger age of patients, a febrile prodrome and initial CSF pleocytosis. Thus, it would appear that
CSF viral PCR
Immunotherapy
Outcome
Negative for HSV, CMV, VZV, Entero, Parecho, HBV, EBV, HHV, Parvovirus Negative for HSV 1 & 2, CMV, VZV, EBV, HHV6, HHV7, and adenovirus Negative for HSV 1&2, CMV, VZV, Entero, EBV and ECHO Negative for HSV 1&2, EBV, CMV and enterovirus Negative for HSV 1&2, VZV, EBV
High dose steroids, IVIg
No deficits. Seizures controlled on azathioprine and AEDs No deficits. Seizures controlled on AEDs
High dose steroids, IVIg
High dose steroids
None
None
Mild cognitive deficit, ongoing seizures partially controlled on AEDs Died on day 21
Unknown. Repatriated to home country in thiopentone coma on day 16
this entity has been labelled differently by different authors, which adds to the difficulty in interpreting the literature. We believe separating cryptogenic new onset super refractory SE from other causes of super refractory SE, and standardising terminology can aid the better understanding and advancement in management of this condition. The investigations required to exclude known causes of super-refractory SE, enabling the diagnosis of NORSE syndrome to be made have been described previously.1 We report 5 cases of NORSE syndrome treated with anaesthetic agents and AEDs in intensive care units. Our patients were previously healthy young adults, who had a non-specific prodrome lasting for 2–7 days before onset of seizures. There were mild and transient CSF abnormalities, unremarkable imaging, and no confirmatory evidence of CNS infection. One patient had antiTPO antibody. Duration of refractory status epilepticus requiring general anaesthesia was between 7 and 30 days. Immunotherapy was given in the 3 of the 5 cases, all of whom recovered without significant neuropsychological deficits, returning to full time employment in 2 cases. One patient who did not receive immunotherapy died of ICU related complications after 3 weeks, and outcome was not known for the other patient. Several short series in the literature describe purely cryptogenic refractory SE, which we believe fit our proposed definition of NORSE syndrome (see Table 2). A number of cases series in children have also reported a similar clinical presentation.5,7,13 There is some heterogeneity in the reported cases, with regards to the prodomal illness, and CSF abnormalities. It would appear that CSF analysis early in the course of illness is more likely to show pleocytosis, resolving in later analysis, which may indicate an initial infective or autoimmune precipitating factor. However, more cases will need to be studied to ascertain the true case definition of NORSE. It has been pointed out that the paediatric syndrome of FIRES is a different entity from NORSE, with no evidence of autoantibody production, and no apparent improvement with immunotherapy.14,15 Other series of super refractory status epilepticus of diverse aetiologies probably include some similar cases to ours. The California encephalitis project (CEP) for example included 43 patients presenting with status epilepticus following a febrile prodromal illness, the majority (72%) of whom did not have an identifiable viral pathogen.1,16,17 The mortality in this cohort was 28%, and the majority of survivors are described as suffering severe neurological impairment. According to definitions
C.R.E. Gall et al. / Seizure 22 (2013) 217–220
220
Table 2 Previously published case series that probably represent NORSE syndrome. Journal/authors
No of cases/ demographics
Prodrome
Immunotherapy
Outcomes
Comments
Costello et al. J Neurol Sci 2009
n=6 Aged 24–36 4 female
4 fever myalgia
1 PEx and IVIg (anti-TPO antibodies) Steroids-None > 3/7
1 died on ITU (propofol syndrome), 1 good outcome, 1 epilepsy surgery-survival with dependency
Wilder-Smith et al. Ann Acad Med Singapore 2005 Glaser et al. (California Encephalitis Project) Clin Infec Dis 2006 Van Lierde et al. Acta Neurol Belg 2003
n=7 All female
5 of 7
5 died on ITU, 2 vegetative
n = 57 Ages 0–74
Not stated
3/7 given IVIg (less than our standard dose) Not stated
One patient had anti-TPO antibodies (treated with PEx and IVIg) None given immunotherapy within first 5 days More pleocytic CSF than our patients, abnormal MRs
20% died in hospital, most of survivors required extensive rehab
Predominantly children (69%)
n=6 Ages 18–30 4 female n = 14
All patients had prodromal illness
PEx and high dose steroids in 2 patients, timing not stated Steroids in 6 patients
2 poor functional neurological recovery and refractory seizures 4 died Survival with major cognitive sequale and intractable seizures
No cortical dysplasia on autopsy
n=6
4 of 6 patients had fever
All given high dose steroids 2 given IVIg
3 died, 3 severe impairment and intractable seizures
Mikaeloff et al. Epilepsy Res2006
Baxter et al. Seizure 2003
Febrile event in all patients (URTI with or without rash)
used in the CEP study, our patients would have been classed as suffering from encephalitis. The apparent good response to immunotherapy hints at an autoimmune process involved in the pathogenesis of at least some cases of NORSE syndrome in adults. An immunological basis for NORSE syndrome has been suggested by other authors. In our series as well as the CEP series, one patient each had anti-thyroid peroxidise antibodies. Single case reports have also described occurrence of antibodies to Glure2 and neuropil, with good outcome from immunotherapy.18,19 A number of case reports have described antibodies to NMDA glutamate receptors and voltage gated potassium channel antibodies in patients with refractory status epilepticus.20–23 Immunotherapy including steroids and intravenous immunoglobulin has been used in super-refractory SE for a number of years.2 In addition to their immunological effects, steroids also have potentially beneficial effects on breakdown of blood brain barrier, GABA receptor activity and intracranial pressure. In the management scheme proposed by Shorvon and Ferlisi, it has been suggested that early immunotherapy should be instituted in cases of super refractory SE where no cause has been identified.2 Our cases give further support to the notion that early immunotherapy should be considered in patients classed as suffering NORSE syndrome. References 1. Costello DJ, Kilbride RD, Cole AJ. Cryptogenic new onset refractory status epilepticus in adults-infectious or not? Journal of the Neurological Sciences 2009;277:26–31. 2. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802–18. 3. Wilder-Smith EPV, Lim ECH, Teoh HL, Sharma VK, Tan JJH, Chan BPL, et al. The NORSE syndrome: defining a disease entity. Annals of the Academy of Medicine (Singapore) 2005;34:417–20. 4. Van Lierde I, Van Paesschen W, Dupont P, Maes A, Sciot R. De novo cryptogenic refractory multifocal febrile status epilepticus in the young adult: a review of six cases. Acta Neurologica Belgica 2003;103:88–94. 5. Baxter P, Clarke A, Cross H, Harding B, Hicks E, Livingston J, et al. Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status. Seizure 2003;12:379–87. 6. Kramer U, Shorer Z, Ben-Zeev B, Lerman-Sagie T, Goldberg-Sten H, Lahat E. Severe refractory status owing to presumed encephalitis. Journal of Child Neurology 2005;20:184–7.
Bilateral hippocampal high signal in 10 patients Neuropsychology – fronto temporal impairment Other childhood disorders not fully excluded as prior developmental delay in 2
7. Mikaeloff Y, Jambaque I, Hertz-Pannier L, Zamfirescu A, Adamsbaum C, Plouin P, et al. Devastating epileptic encephalopathy in school aged children: a pseudoencephalitis. Epilepsy Research 2006;69:67–79. 8. Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurologica Scandinavica 2010;21:251–6. 9. van Balen A, Hausler M, Boor R, Rohr A, Sperner J, Kurlemann G, et al. Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood. Epilepsia 2010;51:1323–8. 10. Nabbout R, Hubert P, Peudenniers S, Allaire C, Flurin V, Aberastury M, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51:2033–7. 11. Ismail FY, Kossoff EH. AERRPS, DESC, NORSE, FIRES: multilabeling or distinct epileptic entities? Epilepsia 2011;52:e185–9. 12. Standley K, Abdulmassih R, Benbadis S. Good outcome is possible after months of refractory status epilepticus: lessons learned. Epilepsia 2012;53:e17–20. 13. Fong JS, Hantus S, Erbayat Altay E, Tuxhorn I. De novo refractory status epiepticus and encephalopathy: a retrospective case series. Journal of Child Neurology 2010;25:1535–8. 14. Ko¨rtvelyessy P, Lerche H, Weber Y. FIRES and NORSE are distinct entities. Epilepsia 2012;53:1276. 15. van Baalen A, Ha¨usler M, Plecko-Startinig B, et al. Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012;43:209–16. 16. Glaser CA, Honarmand S, Anderson LJ, Schnurr DP, Forghani B, Cossen CK, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clinical Infectious Diseases 2006;43:1565–77. 17. Glaser CA, Gilliam S, Honarmand S, et al. Refractory status epilepticus in suspect encephalitis. Neurocritical Care 2008;9:74–82. 18. Okanishi T, Mori Y, Kibe T, Takahashi Y, Saito Y, Maegaki Y, et al. Refractory epilepsy accompanying acute encephalitis with multifocal cortical lesions: possible autoimmune etiology. Brain and Development 2007;29:590–4. 19. Milh M, Villeneuve N, Chapon F, Gavaret M, Girard N, Mancini J, et al. New onset refractory convulsive status epilepticus associated with serum neuropil auto-antibodies in a school aged child. Brain and Development 2011;33:687–91. 20. Bayreuther C, Bourg V, Dellamonica J, Borg M, Bernardin G, Thomas P. Complex partial status epilepticus revealing anti-NMDA receptor encephalitis. Epileptic Disorders 2009;11:261–5. 21. Mittal M, Hammond N, Lynch GS. Immunotherapy responsive autoimmune subacute encephalitis: a report of two cases. Case Reports in Medicine 2010;2010:837371. 22. Nath U, Warren NM, Ali H. NMDA receptor encephalitis—expanding the clinical spectrum. BMJ Case Report 2011. http://dx.doi.org/10.1136/bcr.12.2010.3579. 23. Suleiman J, Brenner T, Gill D, Brilot F, Antony J, Vincent A, et al. VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology 2011;76:1252–5.