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NORSE is associated with prodromal febrile illness and inflammatory CSF profile.
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Regional hypermetabolism is a common finding on FDG-PET in NORSE.
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The majority of patients had no clear etiology identified after extensive evaluation.
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Immunotherapy and the ketogenic diet are feasible treatments for NORSE.
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NORSE is associated with high mortality and drug-resistant epilepsy.
Abstract
Purpose
To describe the clinical, laboratory, neuroimaging, electroencephalographic features, etiology, treatment, as well as short-term and long-term outcomes of adults with new-onset refractory status epilepticus (NORSE).
Method
A retrospective, single institution cohort study (2010–2018) of consecutive adult patients with NORSE.
Results
Among 20 patients with NORSE, nine (45 %) had prodromal febrile illness, 12 (60 %) had evidence of inflammation on CSF profile. Six patients (30 %) met criteria for definite autoimmune encephalitis (AE) while 8 patients (40 %) had probable AE. Eleven out of 13 (85 %) patients had an abnormal FDG-PET scan with the most common finding being regional hypermetabolism. Fourteen patients (70 %) received immunotherapy and ten (50 %) received the ketogenic diet (KD). Fifteen patients (75 %) progressed to super-refractory status epilepticus (SRSE) and seven patients (35 %) died in the hospital or within six months of discharge. Among the surviving patients, eight (40 %) had a good outcome (i.e., modified Rankin Scale score 0–2); 12 (80 %) received a diagnosis of epilepsy of which nine (75 %) developed drug-resistant epilepsy.
Conclusions
New-onset refractory status epilepticus is a syndrome associated with multiple complications, high mortality, and subsequent intractable epilepsy. There are multiple causes, some of which are autoimmune encephalitides; however, in this series the majority of patients had no clear etiology identified after extensive evaluation. Prospective studies are needed to determine optimal evaluation and treatment.
Status epilepticus (SE) is a neurological emergency with more than 180 described causes; common causes include medication change or noncompliance in patients with known epilepsy, toxic-metabolic disturbances, sedative/hypnotic withdrawal, acute/remote stroke, and brain tumor [
]. The term new-onset refractory SE (NORSE) is applied to a patient without a prior diagnosis of epilepsy or other preexisting relevant neurological disorder, with new onset of refractory SE (RSE) that does not respond to first- and second-line antiseizure drugs and no clear acute or active structural, toxic, or metabolic cause. Recently proposed clinical consensus criteria emphasize that NORSE is a clinical presentation, not a specific diagnosis [
Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions.
]. In a series of 130 patients, autoimmune (19 %) and paraneoplastic (18 %) encephalitides were the most common identified etiologies so most centers focus diagnostic work-up around these entities. Unfortunately, most cases (52 %) remained cryptogenic after extensive evaluation [
]. There are no clear guidelines for the evaluation and management of NORSE.
This study aimed to describe a retrospective, single institution cohort of consecutive adult patients with NORSE with focus on clinical, laboratory, neuroimaging, electroencephalographic features, etiology, treatment, as well as short-term and long-term outcomes.
2. Methods
2.1 Standard protocol approvals, registrations, and patient consents
The Johns Hopkins University Institutional Review Board approved this study.
2.2 Study design
We conducted a retrospective review of all patients with NORSE presenting to The Johns Hopkins Hospital (JHH) in Baltimore, MD, between January 2010 and December 2018. We identified individuals with RSE by review of a continuous video EEG (cEEG) database which included all patients in whom a cEEG of any duration was obtained. Etiology of RSE was determined by neurologists’ review of patient charts including clinical notes, laboratory results, neuroimaging studies, and other supporting data.
2.3 Definitions
Status epilepticus was defined according to the Salzburg Consensus Criteria [
]. Electrographic seizures met criteria for SE if they were greater than 5 min or the ictal pattern was present in greater than 50 % of a one-hour epoch. The operational definition of SE was not used since all patients were on sedating medications at the time of diagnosis. Duration of SE was defined as the time between onset of electrographic SE and the time at which EEG suppression was no longer present. The raw cEEG was reviewed independently by two investigators (J.G and K.H). A third reviewer (M.C.C) reviewed the cEEG when there was disagreement regarding the duration of SE. Refractory SE was defined as SE that persisted despite administration of at least two appropriately selected and dosed parenteral medications and SRSE as SE that persisted at least 24 h after onset of anesthesia, recurring while on anesthesia, or after withdrawal from anesthesia [
Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions.
Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions.
] were defined according to consensus criteria. Epilepsy was defined as one or more unprovoked seizures occurring after discharge from the hospital. For patients receiving the ketogenic diet, ketosis was defined as first day of ketonuria (urine acetoacetate ≥ 40 mg/dL) or ketonemia (blood beta-hydroxybutyrate ≥ 2 mmol/L).
2.4 Inclusion/exclusion criteria
Patients were included in this study if they met the definition of NORSE and were 18 years of age or older. A subset of this group was previously described in a phase I/II study examining the use of a ketogenic diet in adults with super-refractory status epilepticus with regard to response to treatment and short-term outcomes [
Data collected included demographic information (age, sex, race), presence of comorbid conditions. Data regarding hospitalization included outside hospital length of stay, total length of stay, and ICU length of stay. Clinical information gathered on admission to JHH included the SE Severity Score (STESS), modified Rankin Scale (mRS) score, laboratory data including serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), and CSF profile (WBC count, red blood cell count, glucose, protein, culture/PCR data). Order, dose and duration of administration of antiseizure drugs (ASDs), IV anesthetic agents, other treatments for SE, and immunotherapies were recorded. Data on hospital course collected included number of medical complications, days of mechanical ventilation, and days on vasopressors. Radiographic data based on brain MRI and 18-fluorodexoy-glucose positron emission tomography (FDG-PET) were assessed.
2.6 Clinical outcome
On the day of discharge, all patients underwent a neurologic examination performed by a neurologist, and the outcome was graded according to the modified Rankin Scale (mRS). In those who survived, good outcome was defined as an mRS score 0–2 and poor outcome as mRS score 3–5.
2.7 Statistical analysis
Median and interquartile range (IQR) were calculated for all continuous variables. The Mann-Whitney U test was used to identify differences between groups for continuous variables. Fisher’s exact test was used to compare categorical variables. All statistical tests were 2-tailed and p-values < 0.05 were considered statistically significant. All statistical analyses were performed using STATA version 15.1 software (StataCorp, College Station, TX).
3. Results
Twenty patients met the inclusion criteria, 15 (75 %) of whom progressed to SRSE. The median duration of SE was 10 (7–25) days with a median SE Severity Score (STESS) of 2 (2–3). The median length of stay was 47.5 (25–69) days with a median ICU stay of 29.5 (16.5–43.5) days.
3.1 Demographics and baseline characteristics
The median age was 50.5 years (IQR 29–69.5 years); 10 patients (50 %) were male (Table 1). Four patients had a history of cancer and the remaining 16 had no significant past medical history.
Table 1Clinicoradiographic characteristics.
Demographics
n=20
Age, median (IQR)
50.5 (29–69.5)
Female, n (%)
10 (50%)
Remote history or recurrence of cancer, n (%)
4 (20%)
Prodromal symptoms
Fever or infectious symptoms, n (%)
9 (45%)
Headache, n (%)
5 (25%)
Encephalopathy, n (%)
12 (60%)
No. days of prodromal symptoms, median (IQR)
12 (3.5–30)
CSF characteristics
Pleocytosis (WBC > 5 mm3; n=20), n (%)
10 (50%)
WBC count in those with pleocytosis (n=10), median (IQR)
15, 10–19
Oligoclonal bands or elevated IgG index present (n=15), n (%)
Prodromal infectious symptoms and/or febrile illness occurred in nine patients (45 %). Serum inflammatory markers were measured in 13 patients at a median of 1 day after identification of SE; median ESR and CRP were 50 mm/hr and 11.6 mg/dL, respectively (reference range: ESR 1−15 mm/h; CRP < 0.5 mg/dL). After excluding 6 patients with a known infectious etiology or venous thromboembolism, inflammatory markers were elevated in five patients (71 %) with median ESR and CRP of 30 and 9.3, respectively. Twelve (60 %) had evidence of inflammation on CSF profile (i.e., pleocytosis, oligoclonal bands, or elevated IgG index). Serum or CSF neuronal antibodies were identified in three (17 %): one with high titer CSF anti-PCA-2, one with serum anti-CASPR-2, and another with low titer antibodies to voltage-gated potassium channel antibodies, nicotinic and muscarinic acetylcholine receptor, and striated muscle.
3.3 Radiological data
Brain MRI (see Fig. 1 for representative cases) was abnormal in 16 of 20 patients (80 %) with the most common finding being T2 hyperintensities in the medial temporal lobe in 12 (60 %). Brain FDG-PET was obtained in 13 patients, 11 (85 %) were abnormal (see Table 2 and Fig. 2). The most common finding was regional hypermetabolism which was present in six patients (46 %). FDG-PET/CT showed regional hypermetabolism in the right medial temporal lobe in one patient with non-concordant T2 hyperintensity in the left medial temporal lobe on MRI done several days earlier (Patient 1 in Table 2 and Fig. 2A.). FDG-PET showed regional hypometabolism in another patient (Patient 4 in Table 2 and Fig. 2C.) with a normal brain MRI.
Fig. 1Representative brain MRIs of patients with NORSE; all images are FLAIR. A., patient with genetic epilepsy and normal brain MRI; B., Unilateral medial temporal lobe hyperintensities in a patient with probable AE; C., bilateral medial temporal lobe hyperintensities in a patient with seronegative definite limbic encephalitis; D., multifocal neocortical and subcortical hyperintensities in a patient with bland CSF and diagnosis of possible AE; E., basal ganglia hyperintensities, involving the claustrum bilaterally in a patient with probable AE; F., insular and anterior cingulate cortex involvement in a patient with probable AE.
Table 2Brain FDG-PET findings relative to RSE and EEG findings.
Patient
Brain FDG-PET finding
Timing of FDG-PET relative to RSE (days)
Closest EEG relative PET (days)
EEG finding
Diagnosis
Hyper/Hypo- Metabolism
Location
1
Hyper
Hypermetabolism in the right medial temporal lobe and medial anterior right occipital lobe Additional global hypometabolism
During RSE
Same day
Right hemispheric LPDs 0.5–1 Hz
Probable AE
2
Hyper
Hypermetabolism in multifocal areas (left inferior and anterior frontal lobe, right parieto-occipital cortex, right superior frontal subcortex and paramedian left posterior occipital lobe
Before RSE
1 day after
Left hemispheric seizure, left frontotemporal LPD 1-2 Hz
Probable AE
3
Hyper and Hypo
Hypermetabolism in the inferior right frontal lobe and the left frontoparietal region Hypometabolism in the occipital lobe that extends into the parietal lobe,
During RSE
Same day
Left > right BIPDS, 1−2 Hz, with BIRDs
Possible AE
4
Hypo
Hypometabolism globally most prominent in the posterior temporoparietal occipital regions (worse on the left)
After RSE
Same day
Right focal slowing, right > left sharp waves, diffuse slowing. right hemispheric seizure one day before
Definite AE (seronegative)
5
Hypo
Multifocal asymmetric hypometabolism (bilateral inferior frontal and anterior temporal lobes)
After RSE
2 days before
diffuse alpha, minimal reactivity
Possible AE
6
Normal
Normal
After RSE
2 days before and 2 days after
mild bilateral theta slowing
Probable AE
7
Hypo
Global symmetric hypometabolism, sparing basal ganglia.
Hypermetabolism in the right sylvian fissure, right medial temporal lobes/hippocampi, and right posterior frontal lobe. Additional global hypometabolism
During RSE
Same day
NCSE arising from right hemisphere
Probable AE
9
Hypo
Global symmetric hypo-metabolism
Before RSE
3 days before
diffuse slow delta activity
Probable AE
10
Hyper
Multifocal Hypermetabolism (most prominent at the right insular cortex, right anterior temporal lobe & left middle temporal gyrus)
Before RSE
1 day after
recurrent right hemispheric seizures, LRDA, LRDA + S with spatiotemporal evolution
Probable AE
11
Hyper
Hypermetabolism in right frontal and bilateral mesial temporal lobes
Before RSE
2 days before
Diffuse delta slowing
Definite AE (limbic encephalitis with low titer antibodies to voltage-gated potassium channel, nicotinic and muscarinic acetylcholine receptor, and striated muscle)
12
Hypo
Right hemispheric hypometabolism
After RSE
4 days before
Focal right delta slowing, intermittent diffuse slowing
Fig. 2Representative brain FDG-PET/CT of patients from Table 2. A., Patient 1 with probable AE, demonstrating hypermetabolism in the right mesial temporal lobe; B., Patient 2 with probable AE, demonstrating multifocal hypermetabolism in the right hemisphere; C., Patient 4 with possible AE, demonstrating bilateral posterior hypometabolism (left greater than right); D., Patient 11 with definite limbic encephalitis with multiple low titer antibodies, demonstrating hypermetabolism in the right frontal and bilateral (left greater than right) mesial temporal lobes; E. and F., Patient 10 with probable AE, demonstrating multifocal hypermetabolism in the left inferior frontal, left temporal (E.), right perisylvian regions (F.).
In terms of timing of FDG-PET in relationship to SE, 3 were obtained while the patient was in RSE, 4 before the identification of RSE, and 6 after identification of RSE (Table 2). Regional hypermetabolism was seen in patients where the FDG-PET was obtained during or before the identification of RSE, whereas the predominant findings in studies obtained after resolution of SE was hypometabolism.
3.4 Etiology
Six patients (30 %) met criteria for definite autoimmune encephalitis (AE). Of these patients, five (25 %) had definite limbic encephalitis; one of whom had small cell lung cancer and was seropositive for PCA-2 and another had low serum titers to multiple antibodies including voltage-gated potassium channel. One patient with definite AE had antibodies to CASPR-2. Eight patients (40 %) had probable AE; four (20 %) had possible AE, of which one patient had relapsed B-cell lymphoma diagnosed prior to onset of SRSE. In the remaining patients, no occult malignancy or recurrence of malignancy was detected. One patient (5 %) had genetic epilepsy (CACNA1A mutation) and one patient was cryptogenic despite extensive evaluation. Pathologic specimens were available in five patients (25 %), brain biopsy in two and post-mortem examination in three; all were non-diagnostic. Next-generation sequencing applied to a brain biopsy specimen in one patient did not reveal any pathogenic microbes, as described in a previous report [
Treatment strategies, including therapies for seizures and immune modulating medications varied (Table 3). Fourteen patients (70 %) received immunotherapy, of which all received methylprednisolone 1000 mg IV for 5 days. Immunotherapy was initiated at a median of 4 days (IQR 3–14 days) after the onset of SE. Median time from initiation of immunotherapy to resolution of SE was 12 days (IQR 4–32 days). Out of the 14 patients, two patients (14 %) died in SRSE after initiation of immunotherapy.
Table 3Treatments.
Intravenous anesthetics, n (%) Days on IV anesthetic agent, median (IQR) Number of anesthetic agents, median (IQR)
Ten (50 %) patients received an enteral formula ketogenic diet (KD) to treat RSE, SRSE, or drug-resistant seizures (4:1 ratio of fat to carbohydrate and protein combined in grams). Median time from identification of SE to initiation of KD was 12.5 days (IQR 5–33 days). All achieved ketonuria (≥ 40 mg/dl urine acetoacetate); median time to ketonuria was 3.5 days (IQR 1–8 days). Status epilepticus resolved in one patient prior to initiation of KD. Status epilepticus resolved in 7 patients (70 %) after initiation of KD; median time from initiation of KD to resolution of SE was 14 days (IQR 4–25 days). Status epilepticus resolved in 6 patients after the onset of ketonuria and in one patient prior to onset of ketonuria. The median time from onset of ketonuria to resolution of SE was 13.5 days (IQR 2–16 days). Out of the 10 patients, 2 patients (20 %) died in SRSE after initiation of KD.
3.7 Outcomes
Hospital and long-term outcomes are detailed in Table 4.
Table 4Complications, hospital course, and long-term outcomes.
Complications and Hospital Course
n = 20
Number of medical complications, median (IQR)
3.5 (2.5–4)
Days on vasopressors, median (IQR)
5.5 (3.5–9.5)
Days of mechanical ventilation, median (IQR)
16 (12.5–28)
Ventilator-free days, median (IQR)
25 (13–44.5)
Length of stay, median (IQR)
47.5 (25–69)
ICU length of stay, median (IQR)
29.5 (16.5–43.5)
Death in the hospital, n (%)
5 (25 %)
mRS at discharge, median (IQR)
4 (3.5–5.5)
Long-term Outcomes
Follow up time in months, median (IQR)
14 (2–42)
mRS of surviving patients at last follow-up (n = 13), median (IQR)
2 (2–4)
mRS at last follow up (n = 15), median (IQR)
2 (2–4)
Good outcome (mRS 0–2; n = 20), n (%)
8 (40 %)
Diagnosis of epilepsy at last follow-up (n = 15), n (%)
12 (80 %)
Drug-resistant epilepsy at last follow-up (n = 12), n (%)
9 (75 %)
Number of AEDs at last follow-up (n = 15), median (IQR)
Fifteen patients (75 %) developed super-refractory SE. Three patients died in SRSE; median duration of SE for the remaining 17 patients was 10 days (IQR 7–25 days). Five patients died in the hospital and two died within six months of hospital discharge.
3.9 Long-term outcomes
The median follow-up time was 14 months (IQR 2–42). Among the surviving patients, eight (40 %) had a good outcome; 12 (80 %) received a diagnosis of epilepsy of which nine (75 %) had intractable epilepsy. Patients were treated with a median of 3 ASDs (IQR 2–4 ASDs); four (27 %) received some form of chronic immunotherapy and three (20 %) treated with the ketogenic diet for SRSE were maintained on the modified Atkins Diet. Besides age, there were no differences in the outcome and the development of epilepsy between several variables (as detailed in Table 5). Older age was associated with poor outcome (p < 0.05).
Table 5Association of demographics and clinical characteristics with outcome and diagnosis of epilepsy at follow-up.
Good outcome (n = 8)
Poor outcome (n = 12)
p-value
Epilepsy (n = 12)
No epilepsy (n = 3)
p-value
Age, median (IQR)
34.5 (24–43.5)
65 (50.5–73.5)
0.03*
44 (29–62.5)
67 (45–72)
0.25
Female, n (%)
3 (38 %)
7 (58 %)
0.36
5 (41.7 %)
2 (66.7 %)
0.45
Cancer history, n (%)
0 (0 %)
4 (33 %)
0.12
1 (8.3 %)
0 (0 %)
0.8
Prodromal fever, n (%)
6 (75 %)
3 (25 %)
0.07
5 (41.7 %)
1 (33.3 %)
0.66
Days of prodrome, median (IQR)
17.5 (8.5–30)
8.5 (1–25.5)
0.29
17.5 (3.5–30)
7 (1–45)
0.77
Pleocytosis, n (%)
4 (50 %)
6 (50 %)
1.0
5 (41.7 %)
2 (66.7 %)
0.45
WBC count in those with pleocytosis
11 (10–15)
19 (8–20)
0.44
13 (9.5–17)
16 (10–22)
0.64
Inflammatory CSF, n (%)
4 (50 %)
8 (67 %)
0.65
7 (58 %)
2 (67 %)
1.0
Abnormal MRI, n (%)
6 (75 %)
10 (83 %)
1.0
10 (83 %)
3 (100 %)
1.0
Abnormal PET, n = 13, n (%)
5 (83 %)
6 (86 %)
1.0
8 (80 %)
2 (100 %)
1.0
Definite or probable AE, n (%)
5 (63 %)
9 (75 %)
0.64
8 (67 %)
3 (100 %)
0.51
Days on IV anesthetic agent, median (IQR)
7 (3.5–15)
8 (3–12.5)
0.67
10 (3.5–15.5)
4 (3–5)
0.25
Number of anesthetic agents, median (IQR)
1.5 (1–3.5)
2 (1–2.5)
0.87
2 (1–3.5)
1 (1-1)
0.11
IT, n (%)
6 (75 %)
8 (67 %)
1.0
10 (83 %)
2 (67 %)
0.51
Time to IT (No. of days from onset of SE to IT), n = 13 median (IQR)
We report the results of a retrospective cohort study of 20 adult patients with NORSE. In our cohort, we found that (1) more than 2/3 of patients had a diagnosis of either probable or definite AE; (2) most patients had an abnormal brain FDG-PET scan; (3) all patients who received the ketogenic diet achieved ketosis and 20 % remained on a KD at hospital follow up; and (4) 40 % of survivors had a good functional outcome.
To our knowledge, this is the first consecutive cohort to report FDG-PET finding in patients with NORSE. Thirteen patients had FDG-PET scans of which eleven (85 %) were abnormal with the most common finding being regional hypermetabolism, which occurred in patients where the PET was obtained either during or before the identification of RSE. The implication is that if a patient presents with encephalitis and seizures, the finding of regional hypermetabolism on FDG-PET may be a heralding sign of impending NORSE. Simultaneous EEG during the FDG-PET as well as continuous video EEG monitoring may help identify these patients prior to onset of NORSE and prompt aggressive treatment. Among the five patients with global hypometabolism, four (80 %) were obtained in patients after the resolution of the RSE. The finding of hypometabolism may be the result of administration of multiple ASDs and, in some cases, IV anesthetic agents; however, hypometabolism is the most commonly reported finding by FDG-PET in autoimmune encephalitis independent of these medications [
] indicate that FDG/PET may be diagnostically useful in patients with NORSE. However, the regional metabolic changes associated with focal seizures and the post-ictal/inter-ictal state must also be taken into consideration in interpreting FDG-PET results.
] patients with NORSE often presented with a febrile prodrome, which in this study was not associated with a specific etiology or outcome. Moreover, these patients met criteria for febrile infection-related epilepsy syndrome (FIRES), which was initially used to describe children ages 3–15 years with this condition and has recently been expanded and recognized as a subcategory of NORSE, including individuals of all ages [
Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions.
]. Serum inflammatory markers were elevated even after excluding patients with a known infection or venous thromboembolism. This is in line with recent evidence showing elevated cytokines (particularly IL-1 and IL-6) in CSF and serum of NORSE patients [
]. These cytokines cause hepatic synthesis of acute phase reactants (e.g., CRP). Furthermore, there are several case reports of efficacious therapies targeting IL-1 (anakinra [
Markers of CSF neuroinflammation were present in 60 % of patients identified and medial temporal or neocortical T2 hyperintensities were present in 80 % of patients leading to a diagnosis of either probable or definite AE in 70 % of patients. However, antibody detection rate was relatively low though, which was likely due to a combination of factors: incorrect antibody panel selection, inconsistent use of antibody testing in the CSF, lack of commercially available antibody assay (e.g., for GABAA-receptor antibodies [
Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.
]), and as yet undefined antibodies. One patient in particular had an MRI that was compatible with anti-GABAA-receptor encephalitis (Fig. 1, panel D); however, her CSF antibody panel was negative and therefore the most appropriate diagnosis was probable AE. Three patients had claustrum hyperintensities, which have been described previously in NORSE. [
] It is unclear if this finding is a consequence of prolonged SE or a signature of an as yet undefined etiology of NORSE.
Patients were treated with IV anesthetic agents for a median of 8 days (IQR 3.5–13.5 days). Over half of patients received at least two forms of immunotherapy (most commonly pulse dose IV methylprednisolone and plasma exchange). Immunotherapy was instituted early, a median of 4 days after identification of SE. Despite early intervention, receiving any form of immunotherapy was not associated with outcome or diagnosis of epilepsy at follow-up. Of the ten patients who received the KD, all achieved ketosis providing further evidence that the KD is a feasible treatment option in patients with NORSE.
Patients had a complicated hospital course, with 15 (75 %) progressing to SRSE and suffering a median of 3.5 medical complications; five patients (25 %) died in the hospital and another two patients died shortly after hospitalization. This in line with previous reports [
] describing the high morbidity and mortality associated with NORSE. Fortunately, good outcome occurred in 40 % of patients after a median follow-up of 14 months, which is similar to prior reports [
]. Duration of prodromal symptoms and duration of SE were not associated with outcome. Similar to prior reports, twelve patients (80 %) received a diagnosis of epilepsy of which nine (75 %) had intractable epilepsy. Duration of prodrome, CSF or neuroimaging findings, and etiology were not associated with epilepsy diagnosis. More patients with NORSE who progressed to SRSE had a diagnosis of chronic epilepsy at follow-up than those who did not progress to SRSE, but this was not statistically significant. There was no association between definite or probable AE and diagnosis of epilepsy at follow-up.
Recent evidence shows that unprovoked seizures are relatively uncommon in patients with anti-NMDA receptor, anti-LGI1, or anti-GABAB receptor encephalitis in remission [
]. In contrast to the autoimmune encephalitides, intractable epilepsy is common in survivors of NORSE. This important distinction may have implications for the etiology of NORSE. Although some cases of NORSE are unequivocally associated with autoimmune or paraneoplastic encephalitis (as in the patient with definite LE and PCA-2 antibodies), others likely are not. Recent evidence shows that some patients with NORSE may have a disorder of innate immunity, rather than antibody-mediated encephalitis [
]. In such patients, an immunologic trigger such as a viral illness may cause elevation of serum inflammatory mediators and cytokines (i.e., IL-1, IL-6). These cytokines are elevated in both the serum and CSF of patients with NORSE and preliminary data indicate that modulators of these cytokines may be effective treatments for NORSE [
There is a critical need to understand the pathophysiology of NORSE given the important therapeutic implications. Currently, whether a specific type of immunotherapy is effective in some cases and not others, and whether patients would benefit from chronic immunotherapy remains unknown. Moreover, whether or not the consensus criteria for AE [
] apply to patients with NORSE is also unclear, as seizures and RSE per se can cause mild CSF abnormalities and T2 hyperintensities on brain MRI, which if present in a patient with NORSE, would meet the criteria for probable AE. A minority of cases of NORSE are due to a CNS infection that is often clinically unsuspected and the implementation of unbiased sequencing methods to diagnose infections of the brain such as next generation sequencing hold promise in improving the diagnostic evaluation of NORSE as well [
]. Finally, improved and more wide-spread use of neuronal antibody assays (including those for GABAA receptor antibodies) will improve the diagnostic evaluation.
This study has several important limitations including retrospective design and data collection via chart review. Although data was collected over several years, the sample size was likely too small to identify small differences. During the early years of the study, some patient had intermittent routine EEGs performed rather than continuous EEG. Follow-up data was frequently limited or unavailable. In terms of generalizability, the study was performed at a referral center where relatively more severe forms of NORSE may be overrepresented. Prospective studies are needed to avoid these pitfalls and to better determine optimal evaluation and treatment for patients with NORSE.
5. Conclusions
Three quarters of adults with new-onset RSE progressed to SRSE with multiple complications and relatively high mortality. There are multiple causes, some of which are autoimmune encephalitides; however, in this series the majority of patients had no clear etiology identified after extensive evaluation. Although patient have a protracted clinical course, 40 % of the survivors achieve a good functional outcome. Results of prospective studies are awaited to better determine optimal evaluation and treatment.
Declaration of Competing Interest
Dr. Cervenka receives grants from Nutricia, Vitaflo, BrightFocus Foundation, and Army Research Laboratory. Honoraria from American Epilepsy Society, The Neurology Center, Epigenix, LivaNova, and Nutricia. Royalties from Demos. Consulting for Nutricia, Sage Therapeutics.
References
Gofton T.
Gaspard N.
Hocker S.
Loddenkemper T.
Hirsch L.
New onset refractory status epilepticus research: what is on the horizon?.
Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions.
Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.
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