If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
New-onset refractory status epilepticus (NORSE), is mostly attributed to autoimmune causes; however, infectious etiologies represent an important, albeit rare, cause of this devastating neurologic syndrome. We describe a patient with NORSE who failed to respond to multiple anticonvulsants, immunomodulatory therapy, and anaesthetic agents, used in ‘refractory’ status epilepticus. Our patient was ultimately diagnosed with Bartonella henselae infection, making this an atypical presentation of NORSE that failed to respond to conventional management until targeted antibiotics were initiated.
2. Case Presentation
A 5-year-old, previously healthy, boy was found unresponsive with generalized body jerking, eyelid twitching, and left gaze deviation. There were no febrile illnesses in the weeks leading up to his presentation. Seizures continued despite repeated doses of benzodiazepines and therapeutic doses of levetiracetam, valproic acid, and fosphenytoin. EEG showed continuous bilateral independent electrographic seizures consistent with electrographic status epilepticus (Fig. 1), necessitating midazolam infusion. Due to continued status, it was switched to continuous pentobarbital infusion for burst suppression.
An exhaustive toxic, metabolic, infectious, and autoimmune (serum and CSF encephalopathy panel, including antineuronal antibodies) workup was performed. CSF results (2 WBC, 0 RBC, protein 35, glucose 86; negative cultures, HSV, Enterovirus, and Arbovirus) necessitated discontinuation of empiric vancomycin, ceftriaxone, and acyclovir. CSF IL-1 (cell-based assay [
]) was 13.08+/-0.71 pg/ml. Head CT and MRI brain +/- contrast were normal.
Empiric high dose methylprednisolone was tried for possible autoimmune encephalitis. Attempts at discontinuing pentobarbital, led to recurrence of status epilepticus requiring the addition of lacosamide and phenobarbital. Plasma exchange (PLEX) was initiated on hospital day 7 (given four rounds), followed by one dose of rituximab. Pentobarbital was then discontinued and patient was instead maintained on continuous midazolam infusion along with previous anticonvulsants. EEG showed signs of diffuse cortical irritability.
Due to cat exposure, serum Bartonella titers were checked and revealed a recent infection (IgG >1:1024, IgM >1:20). No signs of neuroretinitis. On day 11, doxycycline and rifampin were initiated, with marked improvement in cortical irritability (Fig. 2). Bartonella PCR was negative in CSF. On day 12, Anakinra was started. He was successfully weaned off the midazolam infusion by day 14 without return of electrographic status epilepticus. Anakinra was stopped on day 24.
Repeat MRI brain 2 weeks after initial presentation showed slight, symmetric increase in hippocampal T2 signal intensity, without associated cerebral atrophy.
During inpatient rehabilitation, the patient rapidly regained his motor, language, and cognitive skills. He was gradually weaned off all anticonvulsants within three months, without seizure recurrence.
Status epilepticus in cat-scratch disease has been reported, as well as management with conventional antiepileptics in combination with immunomodulatory drugs and anesthetics. However, NORSE secondary to B. henselae infection is rare. Refractory status epilepticus (RSE) is status epilepticus non-responsive to two appropriately selected and dosed antiepileptic medications, including a benzodiazepine [
]. In NORSE, no structural, toxic, or metabolic cause can be identified. FIRES, or febrile infection related epilepsy syndrome, is considered a subcategory of NORSE in which there is a preceding febrile infection between 2 weeks and 24 hours before the onset of RSE. Most patients with NORSE and FIRES develop super refractory status epilepticus (SRSE), or status epilepticus that persists despite treatment with anesthetic agents for 24 hours or more (or status epilepticus that recurs after the withdrawal of anesthesia); this is invariably associated with high mortality and significant long-term neurologic sequelae. One commonly identified cause of NORSE is autoimmune encephalitis, accounting for up to 40% of cases [
] in one study but infectious etiologies have also been found.
B. henselae, causing cat-scratch disease, is endemic worldwide, with cats being their major reservoir. The organism is transmitted to humans by cat scratches or saliva, whereby it infects CD34+ hematopoietic progenitor cells in humans. Its clinical presentation is variable based on host immunity. Common symptoms are fever and regional lymphadenopathy.
Neurologic complications of B. henselae are rare and occur in only 2% of infected patients, but typically manifest with altered mental status and seizures. CSF usually demonstrates normal glucose, protein, and cell count. Only a small minority of patients (19% in one study) have abnormality on neuroimaging. In patients with encephalopathy, EEG typically shows generalized, nonspecific slowing.
Diagnosis of cat-scratch disease is clinical with supportive serologic data. In acute disease (within 3 months), IgM titers are brief, and IgG antibody titers > 1:256 strongly suggest active/recent infection. Our patient did not exhibit the classic symptoms before presenting with NORSE. However, this presentation has been reported in adults.
The pathophysiologic link between B. henselae and neurologic complications, such as NORSE and FIRES, is not well understood. Several hypotheses include direct bacterial invasion of brain tissue versus immune-mediated damage, perhaps through a vasculitic process. In NORSE and FIRES, an immune-mediated inflammatory process has suggested the production of intrathecal proinflammatory cytokines like IL-1. Anakinra, a recombinant human interleukin-1 receptor antagonist is used to block IL-1 pathways and mitigate seizures in cryptogenic cases. [
] Our patient showed marked improvement of cortical irritability before initiation of anakinra.
In conclusion, we aim to increase awareness of NORSE associated with B. henselae and its management. A two week course of doxycycline and rifampin is recommended, although their mechanism on NORSE disease course and outcome is unclear. Our patient’s severe clinical course mandated concurrent enactment of multiple anti-inflammatory and immunomodulating drugs without improvement. The initiation of targeted antibiotics was temporally associated with rapid improvement in the EEG and clinical status. The use (and efficacy) of anakinra supports a post-infectious immune mechanism in cases of NORSE, although the concomitant use of antibiotics should mitigate any conclusion.
We emphasize the possibility of this infection presenting as NORSE, rather than assuming an autoimmune etiology. This case stresses the importance of early identification of this infectious condition as a potential cause of NORSE in the pediatric population. This knowledge impacts treatment decisions, including the early initiation of appropriate antimicrobials, over embarking on immunomodulatory and anesthetic agents. This could lead to a quicker cessation of seizures with a favorable neurodevelopmental outcome in this potentially devastating neurological syndrome, when an infectious cause is present.
Declaration of Competing Interest
The authors report no declarations of interest.
IL-1β is an innate immune sensor of microbial proteolysis.