An Unusual Cause of Status Epilepticus in a 2-Year-Old Boy

A 2-year-old boy presents to the emergency department in status epilepticus with acute respiratory failure. He has no past medical history aside from language delay. He has received all recommended routine pediatric immunizations and screening laboratory tests results, including normal hemoglobin and normal lead screening 1 year prior to admission. The day prior to admission, he was in his usual state of health without any recent history of fever, trauma, or travel. On the day of admission, he was irritable on waking, and shortly thereafter had a generalized tonic clonic seizure. The seizure stopped 10 minutes later when emergency medical services gave intranasal midazolam, but seizures recurred en route to the hospital for an estimated total duration of greater than 30 minutes, accompanied by respiratory failure. On arrival, Glasgow Coma Scale score is 6. He is intubated after several attempts and has severe bradycardia requiring cardiopulmonary resuscitation with chest compressions and several rounds of atropine, epinephrine, and sodium bicarbonate infusion, with return of spontaneous circulation after 30 minutes. Initial laboratory evaluation reveals a leukocytosis of 21.9 103/μL, microcytic anemia, and elevated lactate of 3.0 mmol/L; complete blood count (CBC), complete metabolic panel, and urinalysis are otherwise normal. He is treated with a dose of levetiracetam and transported to a tertiary care center, where electroencephalogram initially shows burst suppression with evolution into frequent brief generalized tonic clonic seizures that resolve with repeated doses of levetiracetam 50 mg/kg and phenobarbital 20 mg/kg. Magnetic resonance imaging (MRI) shows restricted diffusion in the posterior right cerebral hemisphere with T2/FLAIR hyperintensity (Figure 1a).Urine drug screen results and blood cultures are normal. Lumbar puncture is technically challenging; an opening pressure cannot be obtained, and a small amount of cerebrospinal fluid shows one nucleated cell. Viral and bacterial polymerase chain reaction study results are negative, and a culture shows no growth. Ophthalmologic examination is unremarkable. A skeletal survey shows no fractures but notes increased opacification of the metaphases of the femur and humerus bilaterally and abdominal intraluminal radiopaque material (Figure 1b). The patient’s family reports that they are renting an old house with chipping paint. Additional review of the CBC reveals basophilic stippling (Figure 2), and a zinc protoporphyrin-to-heme ratio is 426 (normal <70).It is important to consider a broad differential diagnosis for patients presenting with new onset status epilepticus, including central nervous system infection, metabolic disturbances, stroke, mass lesion, traumatic brain injury, drug or toxin ingestion, drug withdrawal, and hypoxic injury.1 Patient history, physical examination, social history, and nonneurologic ancillary studies, such as abdominal radiograph and skeletal survey, can prove essential clues for making a correct diagnosis. Identifying an underlying etiology of status epilepticus allows the clinician to provide better prognostic information, informs selection of antiseizure medications, and has the potential to identify life-saving treatments that improve long-term outcomes.2Although hypoxic ischemic encephalopathy initially appeared to be the cause for ongoing seizures and encephalopathy, additional history and testing suggested lead toxicity as a potential etiology for the patient’s seizures and encephalopathy. A venous lead level was sent; results were delayed for 5 days because of laboratory processing with a remarkably high level of 263 μL/dL (reference <1), confirming a diagnosis of lead toxicity as the mostly likely cause of encephalopathy and seizures.Lead encephalopathy is a life-threatening condition characterized by altered mental status, vomiting, ataxia, seizures, and coma, which may be associated with increased intracranial pressure.3 Cerebral imaging findings for patients with lead encephalopathy are varied and nonspecific. Chronic cases of lead toxicity in adults have reported varied T2 hyperintensities, as well as decreased white matter volume and cortical volume.4–7 In acute lead encephalopathy, endothelial cell dysfunction may compromise the blood brain barrier and result in vasogenic edema, and mitochondrial dysfunction may lead to energy failure and diffusion restriction, as are seen in this case (Figure 1c). With increased intracranial pressure, ventriculomegaly or effacement of cisterns and herniation may be seen.8 Diffusion restriction on this patient’s MRI suggests lead toxicity, although similar findings may also be seen due to hypoxic ischemic injury.Lead is one of the earliest recognized human toxins. Its oxidation state of 2+ allows it to masquerade as calcium in the body, explaining many of the mechanisms by which it causes pathology. It affects nearly every organ system, including the central and peripheral nervous system. It crosses the blood brain barrier, in which it causes neuronal apoptosis, excitotoxicity, mitochondrial dysfunction, disruption of second messenger signaling cascades, endothelial cell dysfunction, and demyelination. It can be sequestered for decades in glial cells and bone, compounding its long-term toxicity.9 Lead affects both children and adults, although the developing brain is more susceptible to its effects.Individuals with a serum lead level less than 50 μg/dL are often asymptomatic. However, there is no safe serum lead level; even levels as low as 2–5 μg/dL are associated with neurocognitive deficits and increased mortality.10,11 Patients with a serum lead level less than 50 μg/dL may present with chronic intermittent stomach pain, anorexia, anemia, and developmental delay or neurocognitive decline. Long-term exposure is associated with psychiatric disorders, permanent neurocognitive deficits, distal motor greater than sensory neuropathy, tremor, and hearing loss. Patients with a lead level greater than 70 μg/dL are more likely to present with subacute onset of irritability, somnolence, abdominal pain and anorexia; over days to weeks, these symptoms may progress to lead encephalopathy.Lead encephalopathy is treated with chelation. Use of calcium disodium ethylenediamine tetraacetate (CaEDTA) reduces mortality to 25%,12 and dual chelation therapy with CaEDTA and dimercaprol or succimer further reduces mortality.13 Hospitalization for treatment with dual chelation therapy is recommended for patients who are encephalopathic or have a lead level greater than 70 μg/dL.14 In a study from Nigeria, treatment with succimer alone during hospitalization was also effective, yielding a mortality rate of 2%.15 However, although chelation therapy is life-saving, it does not improve long-term neurodevelopmental outcomes.16 The only intervention that has been shown to improve the neurodevelopmental outcomes for those with lead exposure is prevention of further lead exposure.14 This is achieved through education, removal of lead sources from the home, notification of public health officials, hospitalization for lead levels greater than 70 μg/dL, and in some cases emergent relocation of the patient and family. Patients with a lead level less than 70 μg/dL with no encephalopathy on examination can generally be managed safely at home.14Polyethylene glycol was given to expedite clearance of radiopaque material seen on abdominal imaging, and he passed paint chips in his stool. Poison Control recommended dual chelation therapy with CaEDTA and dimercaprol. The patient began empirical therapy with dimercaprol on hospital day 3 while the lead level was pending, but CaEDTA initially could not be obtained commercially or from other hospitals in the region. When the elevated lead level was confirmed, oral succimer and zinc supplementation were added to the chelation regimen. Dimercaprol was stopped on hospital day 10 with a repeat lead level of 69 μl/dL and then was restarted several days later because of an increase in blood lead level to 76 μl/dL. Although CaEDTA remained commercially unavailable, pharmacy was able to create a nonformulary alternative, and he completed a full 5-day course of CaEDTA (hospital days 28–32). The patient’s lead level at discharge was 47 μL/dL.On hospital day 5, the patient again had clinical seizures that were treated with lacosamide. Repeat brain MRI showed evolving injury in the bilateral occipital cortices, basal ganglia, and subcortical structures, with no evidence of increased intracranial pressure (Figure 1c). Throughout his 4-week hospitalization, the patient worked with physical, occupational, and speech therapy. He gradually became more alert, made some vocalizations, and began to raise his head. Phenobarbital and lacosamide were weaned and he was discharged on levetiracetam monotherapy. At the time of discharge, he was left with profound axial hypotonia, spastic quadriplegia with no purposeful movements, no visual tracking and paroxysmal sympathetic hyperactivity.The differential diagnosis for new-onset status epilepticus is broad. Completing a thorough workup, including a detailed medical and social history, can provide clues and assist with targeted treatment of the underlying cause.Thanks to heroic public health efforts, lead encephalopathy, once an all-too-common cause of neurologic devastation, has been all but forgotten in clinical practice. However, because lead is still present in the environment, it is important that pediatric providers remain vigilant and consider lead intoxication in children with unexplained altered mental status.The authors would like to thank Susan Rebsamen, MD, for her assistance with interpreting and choosing neuroimaging, and Fred Edelman, MD, for his clinical care of this patient and review of the article.