Treatment of severe acute necrotizing encephalopathy of childhood with interleukin-6 receptor blockade in the first 24 h as add-on immunotherapy shows favorable long-term outcome at 2 years.

BACKGROUND: Acute necrotizing encephalopathy (ANE) of childhood is a rare and devastating infection-associated acute encephalopathy. While there are no consensus treatments for ANE, recent case reports suggest a beneficial role for the use of tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 (IL-6) receptor. The correlation of the timing of add-on tocilizumab in relation to long-term outcome has not been reported. METHODS: We report on the timing of administration of tocilizumab in two patients classified as high-risk using the ANE severity score (ANE-SS) with respect to the long-term outcome at 2 years. RESULTS: Case 1 was a 19-month-old previously well boy who presented to a tertiary children's hospital with seizures, evolving status dystonicus and shock. Case 2 was a three-year-old boy who presented to a peripheral hospital with fever, sepsis and encephalopathy. The patients were transferred to the tertiary intensive care unit and MRI confirmed ANE with extensive brainstem involvement. Case 1 received intravenous immunoglobulin (IVIg), methylprednisolone and tocilizumab at 21, 39 and 53 h respectively. His modified Rankin scale (mRS) at discharge and two years was unchanged at 5. The functional independence measure - for children (WeeFIM) at two years was very low (19/126). Case 2 received dexamethasone at 1 h, methylprednisolone at 21 h and IVIg and tocilizumab at 22 h. The mRS at discharge and two years was 4 and 3 respectively. The WeeFIM score at two years showed substantial improvement (96/126). CONCLUSION: The very early use of interleukin-6 blockade as 'add-on' immunotherapy in the first 24 h demonstrates potential for improving the long-term outcome in patients classified as high-risk using the ANE-SS.

Burning pain: axonal dysfunction in erythromelalgia.

Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus-response curve, strength-duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A-) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current-voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na/K pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology.