Neonatal lupus erythematosus (NLE) is an autoimmune disease caused by the transplacental passage of pathological autoantibodies from the mother to the fetus. These antibodies are the anti-Ro/SS-A and anti-La/SS-B and less commonly the anti-U1-ribonucleoprotein (U1RNP) (1). Congenital heart block (CHB) occurs in 2% of mothers with anti-Ro/SS-A and/or anti-La/SS-B. This number increases up to 20% with subsequent pregnancies. The diagnosis for NLE involves the presence of one of the above antibodies in addition to a system involvement. It may present with multi-system involvement, including the skin, cardiac, hematologic, neurologic, and/or hepatobiliary system, usually manifesting as cutaneous lesions, cytopenia, elevated aminotransferases, and rarely heart block (1). Cutaneous manifestations have been associated with positive anti-U1RNP (1). Skin, hepatobiliary, and hematologic symptoms usually resolve within 6 months with the washout of maternal antibodies. On the other hand, the development of complete CHB is irreversible (2), with a mortality rate of 4%–29% (2). The cardiac involvement is not only limited to CHB but can also include structural abnormalities. In addition to CHB, the structural heart abnormalities carry a higher rate of mortality. Thus, detection and early intervention are required to decrease this risk of mortality (2). Here, we detail a case of NLE presenting with seizure and incomplete heart block, with positive anti-U1RNP-70kD and negative anti-Ro/SS-A and anti-La/SS-B.

This 7-day-old male was born full term, by a normal vaginal delivery. The mother was gravida 2, para 2. She was found to have group B streptococcus (GBS) and appropriately received antibiotics. She was also known to have hypothyroidism and was on levothyroxine but with an otherwise unremarkable perinatal history. The infant was brought to the emergency department (ED) with a cough and an increased difficulty in breathing. He was found to have respiratory syncytial virus (RSV) and was discharged with supportive management. The next day, he presented again to the ED with decreased activity and decreased oral intake. The mother reported symptoms of choking, coughing up frothy secretions, and experiencing weak extremities for a period of 4–5 min. A physical examination showed a hypoactive infant with normal suckling and Moro reflexes, an open anterior fontanelle, and no skin lesions. He was hemodynamically stable with no fever, weighing 2.6 kg (in the second percentile), with a length of 45 cm (less than second percentile), and a head circumference of 33 cm (in the fourth percentile).

The infant was admitted to the ward for observation, further management, and investigation. Full septic workup was sent, except for the lumbar puncture, which was refused by the parents. An electrocardiogram (ECG) and an electroencephalogram (EEG) were ordered. During the EEG session, the neurology physician noted an irregular heart rhythm on the ECG monitor, which was an evidence of an incomplete heart block (Figure 1). The extended history taken revealed that the mother had systemic lupus erythematosus (SLE), which, despite her being aware of it, was not previously revealed. She did not disclose this earlier as she did not think that it was of relevance because she was in remission, stopped taking her medication, and had not been followed up with a rheumatologist for over 18 months. This history alerted the team to investigate the infant for NLE. The neonate was then put on a Holter monitor and was sent to the pediatric intensive care unit (PICU) for close monitoring.

The EEG reported an underlying regional disturbance and a low threshold for seizures (the background was continuous with mixed frequencies and short epochs of discontinuity, in addition to frequent bilateral temporal sharp wave activity with no clinical activity). Subsequently, the patient was loaded with an intravenous (IV) levetiracetam at a dose of 30 mg/kg, with a maintenance dose of 15 mg/kg every 12 h. He was also started on empiric antibiotics, cefotaxime, and ampicillin for possible meningitis.

The detailed laboratory studies for the patient are presented in Table 1. In summary, his complete blood count and renal and liver function tests were within a normal range. His ammonia and glucose levels were normal. The anti-nuclear antibody (ANA) by indirect immunofluorescence (IIF) was 1:320 (positive speckled), complement 3 (C3) was low, complement 4 (C4) was normal, the extractable nuclear antigen (ENA) antibody test was positive, anti-Sm/RNP was detected by solid-phase assay, and anti-Sm antibody, anti-Ro/SS-A, and anti-La/SS-B were negative. The other autoantibodies were negative. His cardiac N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and troponin T were high. His blood and urine cultures had no growth of any organism.

As for the imaging, the echocardiogram showed a structurally normal heart with no signs of pulmonary hypertension. The cranial ultrasound showed a slightly increased periventricular echogenicity bilaterally, probably due to mild leukomalacia. No hemorrhage or hydrocephalus was observed. A brain computerized tomography (CT) angiogram was performed to exclude any vascular phenomena as a possible etiology for the seizure in the context of NLE, and it was found to be normal. The Holter monitor showed episodes of sudden sinus slowing, followed with junctional escape beats and periods of marked sinus bradycardia. He remained stable under observation in the PICU without requiring a pacemaker or any additional interventions. He was then discharged and put on oral levetiracetam at a dose of 40 mg twice per day.

Two weeks later, a follow-up in the clinic revealed no recurrence of seizures or development of new symptoms. Repeated laboratory workup showed improved cardiac function tests, with a decrease in ENA, but levels had not yet normalized. The EEG, ECG, and echocardiogram were normal. A month after discharge, a repeat EEG showed a normal result; therefore the levetiracetam was discontinued. With a normal physical exam, a follow-up at 6 months of age revealed that he was appropriately meeting his developmental milestones and the parents refused to repeat the laboratory workup at this visit.

Retrospectively looking at this case, although the mother did not disclose her history of SLE to the pediatric team, she was followed up with an obstetrics medicine physician who was aware of her SLE and immunology status. Since the mother lacked the classical anti-Ro/SS-A and anti-La/SS-B, this did not prompt the obstetrician to do further surveillance or education regarding the possibility of NLE. Table 2 presents the mother's immunology in early pregnancy.

In this case, the interpretation of the immunology workup is important. Please note that this panel may appear differently in different labs. To summarize the immunology workup, ENA was high with negative anti-Ro/SS-A and anti-La/SS-B and positive Sm/RNP with negative anti-smith (anti-Sm) antibody. Sm/RNP is also known as U1-small nuclear RNP (U1-SnRNP) complex (Figure 2) (3). It is an ENA and is a complex protein consisting of both anti-Sm and anti-RNP. Both have their own subtypes. The protein subtypes of anti-RNP are 70kD, A, and C. U1RNP A and C are seen more in SLE patients, while U1RNP-70kD is specific for mixed connective tissue disease (MCTD) (4). In our lab, the anti-Sm is ordered as a separate entity, and it is negative. Hence, this concludes that the anti-RNP is positive. The U1RNP subtypes are not routinely tested as they pose no clinical significance or implication. We ordered it for our patients for future reference and for further studies. We have found that the U1RNP-70kD subtype is positive. No available data are reported on U1RNP subtypes in the literature in the context of NLE to compare this with.

Limited data on the clinical significance and pathogenicity of U1RNP subtypes in NLE were found; however some evidence from adult studies was outlined. Specifically looking at the central nervous system (CNS) involvement, the cerebrospinal fluid (CSF) of SLE and MCTD had been examined and found to have elevated indices of anti-U1RNP-70kD (5). Another study investigating the U1RNP in MCTD found that CNS involvement is higher in MCTD patients who have symptoms associated with SLE (6). The long-term follow-up of patients with MCTD found that 17% developed CNS involvement (7). Different subtypes of U1RNP may be associated with different clinical manifestations; therefore, we hypothesize that neonates of SLE mothers with U1RNP A/C present with cutaneous lesions, while neonates of SLE mothers with U1RNP-70Kd present with CHB and/or CNS involvement.

NLE rarely presents with neurologic manifestations. Few patients described in the literature that presented with neurologic symptoms, with the majority of cases finding CNS abnormalities in the imaging as a part of the NLE evaluation, were reported. Subependymal cysts, increased echogenicity, and hydrocephalus were the most widely seen radiologic changes. Table 3 summarizes the NLE patients in the literature with CNS manifestations (8–22). Psychiatric research and publications not in English are not included in this table. Development of seizure was reported in 10 patients (14, 16, 17, 19, 20, 22), eight of which had an underlying cerebral infarct or hemorrhage. The antibody profile is summarized in Table 3. One of the patients without a stroke is the most similar to our patient (14), but unfortunately, the U1RNP profile was not reported. The other symptomatic patients varied in presentation having myelopathy (8), spastic paraparesis (9), tetraplegia (15), facial nerve palsy with hemiparesis (18), phrenic nerve palsy (21), and hydrocephalus (10, 23). The majority of these neurologic symptoms resolved with no long-term sequelae.

CHB is mostly seen with anti-Ro/SS-A and/or anti-La/SS-B. Only recently, CHB is being reported with anti-U1RNP with negative anti-Ro/SS-A and anti-La/SS-B (24). Similar to our case, a total of three patients who reported of having CHB with positive U1RNP (protein subtype not mentioned) and negative anti-Ro/SS-A and anti-La/SS-B but without any neurologic symptoms (24–26) were reported.

The current NLE recommendations for mothers with rheumatic diseases are targeted only for those with anti-Ro/SS-A and/or anti-La/SS-B antibodies. One of the recommendations is to use hydroxychloroquine during pregnancy (27). The other recommendation is early detection of CHB in the most vulnerable period of gestation. This is performed by measuring the mechanical PR interval with a weekly or bi-weekly Doppler fetal echocardiogram during 16–28 weeks of gestation (28).

It is important to rule out other possible causes or insults to diagnose NLE. In our case, GBS meningitis cannot be fully ruled out in the presence of a positive GBS result in the mother. In this admission, the mother received one dose of IV antibiotics, and the baby received a course of antibiotics. Our limitation here was the missing lumbar puncture. On the other hand, GBS meningitis was unlikely as it cannot explain the presence of heart block, and the patient remained well, afebrile with negative blood and urine cultures.

In summary, our patient had negative anti-Ro/SS-A and anti-La/SS-B and positive anti-U1RNP-70kD, presented with a seizure episode, and was found to have an incomplete heart block. The mother with SLE did not receive surveillance during pregnancy as the current guidelines are tailored for mothers with anti-Ro/SS-A and anti-La/SS-B. It is important to consider testing for U1RNP-70kD in newborns presenting with seizure and maternal SLE. In our case, the 70kD subtype of U1RNP is positive which may have a role in this unusual presentation. Further research looking at U1RNP and its subtypes in the context of NLE is needed to improve the care of mothers and babies with this antibody.