A 3 year-old male child who presented with fever and cerebellar ataxia two weeks after varicella was subsequently diagnosed with hemophagocytic lymphohistiocytosis in a report from the Hospital de Cruces, Barakaldo, Bizkaia, Spain. CSF showed a slight increase in protein and pleocytosis of 36 cells/mL, 97% lymphocytes. CT scan of the brain was normal. Fever recurred 1 week later and was associated with hepatosplenomegaly and pancytopenia. At one month after varicella was diagnosed he became comatose and developed status epilepticus. An EEG was compatible with diffuse encephalopathy or encephalitis. Treatment with acyclovir was without benefit. MRI revealed cerebellitis with swelling and multiple enhancing lesions. Severe increased intracranial pressure with tonsillar herniation and hydrocephalus responded to dexamethasone. Hemophagocytic lymphohistiocytosis (HLH) was suspected, and treatment with dexamethasone, etoposide, and cyclosporin A (HLH-94 protocol) resulted in a dramatic clinical response, with normal CSF and EEG, and improvement in the MRI. Cord blood stem cell transplantation was performed 10 months later, with initial infectious complications and neurologic sequelae (seizures, behavior disorder, and visual field defects), but subsequent clinical improvement. Genetic studies with DNA sequencing showing a mutation in the perforin gene confirmed the diagnosis of familial HLH. [1]

COMMENT. Familial histophagocytic lymphohistiocytosis (HLH) is often triggered by infection, and varicella preceded the onset of neurologic symptoms in this case. The disease is characterized by activation of T cells and macrophages leading to an inadequate immune response. CNS involvement is common and symptoms include bulging fontanel, neck stiffness, seizures, ataxia, visual disturbance, hemiplegia, and coma with increased intracranial pressure. In the above report, cerebellar signs preceded the systemic presentation with hepatosplenomegaly and cytopenia. HLH should be suspected in children with progressive encephalopathy and pancytopenia of unknown cause, and therapy instituted early. Dexamethasone, etoposide, and cyclosporine followed by stem cell transplantation are effective, and result in a 3-year probability survival in 62% cases.

HLH or ’hemophagocytic syndrome’ with lamotrigine [2]. An 8 year-old male with porencephaly and epilepsy unresponsive to topiramate and valproate developed a skin rash 2 weeks after beginning antiepileptic treatment with lamotrigine. One month later, impaired liver function, pancytopenia and hemophagocytosis without evidence of infection led to a diagnosis of HLH. The blood count and liver function improved dramatically when AEDs were discontinued and IV immunoglobulin and steroid were administered. Pancytopenia during treatment with new AEDs such as lamotrigine should alert to a possible HLH. Phenytoin may also trigger HLH, and valproate, also suspect in this case, may elevate blood levels of lamotrigine.