TABLE 1.
Clinical features, diagnostic investigations, and treatment during NORSE and Epilepsy after NORSE
| PHASE 1: NORSE | Patient 1 | Patient 2 |
|---|---|---|
| Current Age/Age at onset (years) | 39/37 | 44/33 |
| Etiology | Unknown | Encephalitis anti‐NMDAR no tumor associated |
| NORSE duration | 37 days | 42 days |
| Serum and CSF studies | ||
| Infectious |
CSF(a): Encephalitis panel, bacterial and fungal culture: Negative Serum: Hepatitis, HIV, VDRL, CMV: Negative |
CSF (b): Encephalitis panel, bacterial and fungal culture, VDRL: Negative Serum: Hepatitis, HIV, VDRL, Lyme, CMV: Negative |
| Inflammatory/immune |
CSF: Autoimmune panel: negative Serum: Autoimmune panel, ANA, Anti dsDNA, anti‐nucleosomes, anti‐histones, anti DFS70, ANCA, anti‐tiroglobuline, Rheumatoid factor: Negative |
CSF: Autoimmune panel: anti‐NMDA positive Serum: ANA, anti dsDNA, anti‐ENA, ANCA, Rheumatoid factor: Negative |
| Paraneoplastic |
CSF (Neoplastic cytology): Negative CT (Thorax‐Abdomen‐Pelvis) and Ultrasound (abdomen, pelvis) were negative for tumor |
CSF (Neoplastic cytology): Negative CT (Thorax‐Abdomen‐Pelvis) and Ultrasound (scrotum, thyroid, abdomen) were negative for tumor |
| MRI findings |
At onset: Negative During NORSE: Hypersignal in FLAIR in the left mesial temporal lobe and left insular white matter 1.5 Years after, the abnormal signal disappeared |
At onset: Negative During NORSE: Hypersignal in FLAIR in bilateral mesial temporal lobe, left occipital and splenium At discharge from hospital: Subtle signal change in the left hippocampus and small residual signal in splenium |
| EEG findings | Continuous multifocal spikes and polyspikes (maximum right posterior temporal region) | Burst suppression pattern with multifocal spikes (left temporal, left frontal, right frontocentral and bifrontal) |
| Treatment | ||
| ASM | PHT, LEV, LCM, CLB, PB, VPA, PER, LZP | PHT, PB, LEV |
| Anesthetics | Midazolam, Ketamine, Propofol | Midazolam, Fentanyl, Ketamine, Propofol |
| Antimicrobials | Acyclovir, Ceftriaxone, Vancomycin, Piperacilin/tazobactam (partial treatment) | Acyclovir, Vancomycin, Piperacilin/tazobactam (Partial course) |
| Immunomodulatory agents | Methylprednisolone, IVIG, Rituximab (six doses‐weekly), azathioprine (maintenance therapy) | Methylprednisolone (followed by Prednisone), azathioprine (maintenance therapy) |
| VNS |
Cessation of NORSE was 7 days after VNS was implanted: Day 0: OC = 0.25 mA, F = 20 Hz, PW = 250 μs, ON = 30 s, OFF = 30 min Day 1: OC = 1.0 mA, F = 20 Hz, PW = 250 μs, ON = 30 s, OFF = 30 min Day 2: OC = 1.25 mA, F = 20 Hz, PW = 250 μs, ON = 30 s, OFF = 30 min Day 7: OC = 1.75 mA, F = 20 Hz, PW = 250 μs, ON = 30 s, OFF = 30 min |
Implanted after NORSE was controlled |
| PHASE II: Epilepsy after NORSE | Patient 1 | Patient 2 |
|---|---|---|
| Current Age/Age at onset (years) | 39/37 | 44/33 |
| Latent period after NORSE | No | 8 months |
| Seizure classification | Type 1: focal impair awareness nonmotor seizures to bilateral tonic clonic seizures: déjà vu/ hear voices and sounds ➔ behavioral arrest ➔ eyes deviation to the left ➔ left facial asymmetry ➔ left arm dystonia ➔ head and eyes deviation to the right ➔ sometimes bilateral clonic movements. Type 2: strange sensation ➔ touches her head ➔ smiling ➔ whistling ➔ speak some words with a bit delayed in reacting | Type 1: focal impair awareness nonmotor seizures: behavioral arrest ➔ staring ➔ loss of awareness ➔ right hand automatisms /dystonic posture of the left hand. (Type 1 sometime progress to bilateral tonic–clonic) |
| EEG findings | Interictal: Multifocal independent spikes augmented during sleep (almost 2 years after NORSE). Ictal: onset changes among seizures with the majority over right posterior temporal region and a few over left temporal region (almost 2 years after NORSE) | Inter Ictal: Independent bitemporal spikes, maximum right (8 years after NORSE) Ictal: Onset over left temporal region mostly and over right temporal region in a lesser degree (3 years after NORSE) |
| MRI findings | Slightly increased T2 signal is present in both hippocampi. The abnormal signal in left insular region disappeared (almost 2 years after NORSE) | Bilateral hippocampal atrophy and T2 hyperintense signal abnormality. Resolution of signal abnormality in splenium (9 years after NORSE) |
| Epilepsy classification | Multifocal Epilepsy | Independent Bi Temporal Epilepsy |
| Etiology | Unknown | Structural (Bilateral MTS)/“Autoimmune‐associated” |
| Past ASM | PHT, LEV, LCM, CLB, PB, VPA, PER, LZP | LCS, ESL, PER, PHT, BRV |
| Current ASM | LEV, LCM, PER, ESL | PB, VPA, TPM, LTG |
| Other treatment | Immunotherapy: Azathioprine 150 mg/d since NORSE | None |
| VNS | Implanted at 30 days after NORSE (cessation of SRSE occurred 7 days after VNS was implanted) | Implanted 9 years after NORSE |
| Frequency of seizures before VNS | N.A. | 12 per month |
| Frequency of seizures after VNS (Output current mA) |
1 month: Up to 5 (2.5) 3 months: 1‐2 per day (2) 6 months: 1‐2 per day (2) 12 months: 1‐3 per day (2) 18 months: 1‐3 per day (2.25) 22 months: 1‐3 per day (3) 24 months: 1‐3 per day (3) |
3 months: 15 per month (0.85) 6 months: 10 per month (1.75) 8 months: 2‐3 months (2) 12 months: 2 months (2) 18 months: 2‐3 month (2) 21 months: 12 per month (2.75) 24 months:8‐12 per month (3) |
| Cognitive outcome | Mild‐to‐severe generalized impairments across all cognitive domains (Neuropsychological evaluation) | Multifocal Cognitive Impairment. Probably nondominant (more likely right) mesial temporal impairment and frontal dysfunction (not clearly lateralized). Dominant temporal impairment (more likely left) not ruled out |
| Emotional outcome | Mild symptoms of depression and anxiety (She took antidepressants when symptoms were severe) | No evidence of depression or any other mood disturbance |
| Social outcome | She is unable to carry out all of her previous activities but is able to take care of her own affairs without help. She works from home as a writer of educational material | Not currently working as truck driver. He is on a disability support program |
Note: Cytochemical study in CSF showed mild pleocytosis: a:14 cel; b: 20 cel (lymphocyte predominance). Encephalitis panel: Herpes Simple Virus I‐II, varicella zoster, and enterovirus RNA. Autoimmune panel: Anti‐AMPA, anti‐CASPR, anti DPPX, anti‐GABA antibody, anti‐LGI1, anti‐NMDA, anti‐GAD65, anti IgLON5.
Abbreviations: ANA, Antinuclear antibodies; ANA, Nuclear Antigen Antibodies; ANCA, Antineutrophil cytoplasmic antibody; ASM, antiseizure medication; BRV, brivaracetam; CLB; clobazam; CMV, Cytomegalovirus; CSF, cerebrospinal fluid; CT, Computerized tomography; dsDNA, double stranded DNA; EEG, electroencephalogram; ESL, eslicarbazepine; HIV, human immunodeficiency virus; IVIG, Intravenous Immunoglobulin; LCM, lacosamide; LEV, Levetiracetam; LTG, lamotrigine; LZP, Lorazepam; MRI, magnetic resonance imaging; MTS, mesial temporal sclerosis; N.A, not applicable; NMDAR, N‐methyl‐D‐aspartate receptor; PB, phenobarbital; PER, perampanel; PHT, phenytoin; SRSE, super refractory status epilepticus; TPM, topiramate; VDRL, test for syphilis; VNS, Vagus nerve stimulator; VPA, valproic acid.