Febrile Seizures in Previously Controlled Status Epilepticus

What is a Febrile Seizure?

• Simple: generalized, <15 minutes, single episode within 24 hours
• Complex: focal features, duration >15 minutes, or >1 seizure per febrile illness

Why Does Fever Precipitate Seizures in Previously Controlled Epilepsy?

1. Fever directly lowers the seizure threshold — elevated body temperature increases neuronal excitability by altering ion channel kinetics (particularly sodium channels), making previously suppressed epileptic circuits more susceptible to discharge.
2. Genetic predisposition plays a major role. Some patients carry mutations (e.g., SCN1A sodium channel mutations as in Dravet syndrome) where fever is a consistent, potent trigger. These mutations impair GABAergic interneuron function, and heat selectively worsens this deficit. — Bradley and Daroff's Neurology in Clinical Practice
3. Dravet syndrome (severe myoclonic epilepsy of infancy) is a classic example: febrile seizures in this condition tend to be prolonged and often asymmetrical. Fever acts as a trigger even when baseline seizures are otherwise "controlled," and the subsequent course becomes progressive. — Bradley and Daroff's Neurology in Clinical Practice
4. Anti-seizure medication (ASM) levels may fall during febrile illness due to altered pharmacokinetics (increased metabolism, decreased absorption, vomiting), effectively dropping drug levels below the therapeutic threshold — a common cause of breakthrough seizures. — Bradley and Daroff's Neurology in Clinical Practice
5. Febrile status epilepticus carries additional risk: it can injure the hippocampus, with ~11.5% of affected children showing unilateral increased hippocampal T2 signal on MRI, which may later progress to hippocampal sclerosis — potentially worsening the underlying epilepsy over time. — Bradley and Daroff's Neurology in Clinical Practice

Can Methylprednisolone (MPS) Be Added?

• FIRES (Febrile Infection-Related Epilepsy Syndrome) — a subcategory of New-Onset Refractory Status Epilepticus (NORSE) preceded by a febrile illness 24 hours to 2 weeks prior. Immunotherapy including high-dose corticosteroids (methylprednisolone) is used in refractory cases. — Rosen's Emergency Medicine
• Autoimmune/inflammatory encephalitis presenting as febrile status epilepticus — MPS is a first-line immunotherapy.
• Dravet syndrome or refractory status with suspected neuroinflammatory component.

• Corticosteroids can themselves lower the seizure threshold and have been reported to provoke seizures in susceptible individuals.
• Fever management is central to treatment, and steroids can mask fever (masking the underlying infectious cause), complicate diagnosis (e.g., meningitis), and cause immunosuppression.
• Steroids are not part of standard febrile seizure management — the mainstay remains benzodiazepines (lorazepam 1–2 mg IV, or diazepam 5–10 mg IV), followed by antiepileptic escalation per status epilepticus protocol if seizure continues. — Rosen's Emergency Medicine

NORSE and FIRES

Note: The correct acronym is NORSE (not "NORES") — New-Onset Refractory Status Epilepticus.

NORSE — New-Onset Refractory Status Epilepticus

• Toxic exposure
• Metabolic derangements
• Structural brain injury

• Most common in adults (though can occur at any age)
• No prior epilepsy history
• Extensive workup often required; majority of cases remain cryptogenic even after investigation
• Autoimmune encephalitis (including paraneoplastic) is the most commonly identified cause, but over half of cases have no identifiable etiology — Adams and Victor's Principles of Neurology
• May have transient abnormal MRI signal in the claustrum
• Antibody testing is frequently negative, but an unidentified autoimmune mechanism is suspected — Localization in Clinical Neurology

FIRES — Febrile Infection-Related Epilepsy Syndrome

• Most common in children, but not exclusive to the pediatric population
• A febrile illness precedes the onset — this is the defining distinction from NORSE
• The status epilepticus that follows is refractory and severe
• Antibody testing has largely been negative to date, though an undiscovered autoimmune mechanism is suspected — Localization in Clinical Neurology
• May also show claustrum signal abnormality on MRI

Relationship Between NORSE and FIRES

NORSE (broad umbrella)
  └── FIRES (subset: febrile prodrome 24 hrs–2 weeks before SE onset)

Management Considerations

1. Aggressive seizure control — benzodiazepines → antiseizure medications → anesthetic coma (therapeutic coma with propofol/midazolam for super-refractory SE)
2. Immunotherapy — high-dose IV methylprednisolone, IVIG, plasmapheresis (used empirically when autoimmune cause is suspected)
3. Ketogenic diet — has shown benefit in refractory FIRES/NORSE cases
4. Anakinra (IL-1 receptor antagonist) — increasingly used in FIRES given evidence of neuroinflammation

Causes of Hypotension in Tuberculous Meningitis (TBM)

1. SIADH → Hyponatremia → Reduced Plasma Osmolality

• Inflammation at the base of the brain stimulates inappropriate ADH release from the hypothalamus/posterior pituitary
• This causes water retention and dilutional hyponatremia
• Severe hyponatremia leads to reduced plasma osmolality, cellular edema, and circulatory compromise contributing to hypotension

Differentiate from Cerebral Salt Wasting (CSW), which also causes hyponatremia but through renal sodium loss with hypovolemia — CSW directly causes hypotension by depleting intravascular volume. In SIADH, the patient is euvolemic or mildly hypervolemic; in CSW, they are hypovolemic. — Bradley and Daroff's Neurology in Clinical Practice

2. Sepsis / Systemic Inflammatory Response

• TBM is a serious CNS infection that can trigger a systemic inflammatory response
• Pro-inflammatory cytokines (TNF-α, IL-1, IL-6) cause peripheral vasodilation and capillary leak
• This results in distributive/septic shock-pattern hypotension
• Hypotension combined with peripheral circulatory failure is noted as a feature of advanced TBM — Adams and Victor's Principles of Neurology

3. Adrenal Insufficiency (Addison-type)

• Tuberculosis is the most common infectious cause of adrenal insufficiency worldwide
• Adrenal glands are frequently seeded during miliary or disseminated TB
• Destruction of adrenal cortex → cortisol and aldosterone deficiency
• Aldosterone deficiency → renal sodium wasting → hypovolemia and hypotension
• Cortisol deficiency → loss of vascular tone and catecholamine sensitivity
• This is a critical and reversible cause to exclude — patients will not respond to fluids/vasopressors without steroid replacement

4. Hypothalamic / Autonomic Dysfunction

• The base of the brain — the site most affected by TBM's basilar exudate — is where the hypothalamus and autonomic regulatory centres reside
• Direct inflammatory involvement disrupts central autonomic control of blood pressure (vasomotor centre)
• Autonomic instability (fluctuating pupil size, blood pressure lability) is documented in TBM — Plum and Posner's Diagnosis and Treatment of Stupor and Coma

5. Anti-TB Drug Side Effects

• Rifampicin: hepatotoxicity can reduce albumin synthesis → reduced oncotic pressure
• Isoniazid: autonomic neuropathy (pyridoxine-sensitive)
• In severe cases, adrenal crisis may be precipitated by rifampicin's induction of CYP450 enzymes, which accelerates cortisol metabolism — unmasking subclinical adrenal insufficiency

6. Reduced Oral Intake / Vomiting

• TBM patients are often obtunded, vomiting, or unable to take fluids orally
• This results in hypovolemic hypotension from dehydration

Summary Table