Faculty Bibliography

BACKGROUND:Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. METHODS:15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. FINDINGS/RESULTS:All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001). INTERPRETATION/CONCLUSIONS:GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. FUNDING/BACKGROUND:National Institutes of Health.

Purpose: Despite weekly monitoring of fetuses exposed to maternal anti-SSA/Ro antibodies, immediate treatment has never permanently reversed complete heart block. This irreversibility strongly supports an emphasis on preventative strategies. A recent case-control study revealed that fetal exposure to Hydroxychloroquine (HCQ), which prevents endosomal acidification and Toll-Like Receptor ligation (proposed pathway involved in cardiac inflammation and scarring), decreases the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in Systemic Lupus Erythematosus (SLE) mothers with anti-SSA/Ro antibodies. That study did not address the effect of HCQ on the recurrence rate in subsequent pregnancies which is nearly 10 fold the frequency in anti-SSA/Ro positive women who have not had an affected child. Accordingly, this study explores whether HCQ prevents the development of cardiac-NL in these highest risk pregnancies. Methods: Twenty-four pregnancies of 22 mothers satisfied the inclusion criterion: exposure to HCQ in a pregnancy of a mother whose previous child had either cardiac or cutaneous-NL. Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation prior to 6 weeks gestation. In 19 of these 22 families the previous child had cardiac-NL (1-isolated cardiomyopathy and 18-advanced congenital heart block (CHB) 8 of whom died from complications of the disease) and in 3 families the prior child had cutaneous-NL. Of these 22 previous NL pregnancies, 15 were unexposed to HCQ (13 CHB, 1 cardiomyopathy and 1 rash), 6 were exposed to HCQ (4 CHB and 2 rash) and in 1 CHB child, exposure to HCQ was unknown. Results: Sixty-eight percent of the mothers were Caucasian. The maternal health status was SLE in 41%, Sjogren's Syndrome (SS) in 32%, SLE with secondary SS in 18%, and Undifferentiated Autoimmune Syndrome in 9%. Sixty-four percent (14/22) of the mothers were positive for both anti-SSA/Ro and anti-SSB/La antibodies. The mean daily dose of HCQ was 352.6 mg. Using prospective data from the Research Registry for Neonatal Lupus, the recurrence rate of cardiac-NL following a child with cardiac-NL is 18% (based on 161 pregnancies following a previous child with CHB) and the occurrence rate of cardiac-NL following a child with cutaneous-NL is 13% (based on 39 pregnancies following a previous child with cutaneous-NL). These data suggest that the expected rate of cardiac-NL in this cohort should be approximately 17.2%. Of the 24 subsequent pregnancies exposed to HCQ in this study only one fetus developed cardiac-NL (3^rd degree) and this mother's previous child had cutaneous-NL. Thus, the recurrence/occurrence rate was 4.2% (95% CI:(0.11% - 21.1%), a reduction of 75.7%. In addition to HCQ, 25% (6/24) of the mothers received intermittent low dose IVIG, 75% (18/24) non-fluorinated steroids, 17 of whom were on <= 10 mg of Prednisone, and 8.3% (2/24) fluorinated steroids, one after the diagnosis of CHB. Conclusion: This case series suggests that in mothers with anti-SSA/Ro antibodies and a previous child with NL, exposure to HCQ during a subsequent pregnancy may decrease the risk for fetal development of cardiac-NL

Epilepsy in women is influenced by endocrine status and antiepileptic drugs (AEDs), but without an animal model, the effects of endocrine variables and AEDs cannot be easily dissociated from the influence of epilepsy itself. Animal models have had limited utility because experimentally-induced seizures typically result in reproductive failure. This study was conducted to develop an improved animal model. The muscarinic convulsant pilocarpine was used to elicit status epilepticus (SE) in adult female Sprague-Dawley rats. The selective estrogen receptor modulator raloxifene was administered 30 min before pilocarpine. An anticonvulsant barbiturate, pentobarbital, was injected 5-10 min after the onset of SE, and at least once thereafter to minimize acute convulsions. Mortality, morbidity, estrous cyclicity, and the ultimate success of the procedure (i.e. induction of recurrent, spontaneous seizures) were monitored. The combination of raloxifene and pentobarbital led to significantly improved estrous cyclicity compared to previous methods. Animals treated with raloxifene and pentobarbital became epileptic, as defined by the recurrence of spontaneous convulsions in the weeks after SE. The results of this study provide an improved animal model to examine the interactions between seizures and ovarian hormone secretion. The results also suggest that treatment of SE with raloxifene may benefit women with SE

Some epilepsy patients quickly develop resistance to antiepileptic drugs (AEDs). We report a case of a patient with refractory epilepsy with daily seizures who initially responded to levetiracetam daily therapy, but then returned to baseline seizure frequency. However, when levetiracetam was given once weekly, the patient had significantly fewer seizures on the day of and after administration. These results suggest a useful treatment strategy for patients with refractory epilepsy who have developed resistance to AEDs

OBJECTIVES: The Tei Index (TI) is a useful, non-invasive, Doppler-derived myocardial performance tool which can be used to assess aspects of systolic and diastolic function. The aim of this study was to determine normal values of fetal left ventricular (LV) TI in second- and third- trimester fetuses and to compare these to other values reported in the literature. METHODS: Doppler waveforms of the LV outflow tracts were obtained in 74 second- and early third-trimester fetuses. The LV isovolumic contraction time (ICT), isovolumic relaxation time (IRT) and ejection time (ET) were measured and the TI calculated using the formula (ICT + IRT)/ET. The literature on LV myocardial function in the fetus was also reviewed. RESULTS: The normal TI in second- and early third-trimester fetuses (18-31 weeks' gestation) was 0.53 +/- 0.13. The ICT was 43 +/- 14 ms, the ET was 173 +/- 16 ms and the IRT was 48 +/- 13 ms. CONCLUSION: The TI can be easily obtained in the fetus without the need for precise anatomic imaging. The TI may be a useful tool to explore fetal myocardial function in different clinical situations