Walter K. Nahm

Venous malformations in blue rubber bleb nevus syndrome: variable onset of presentation ☆

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by discrete venous malformations of varying size and appearance that are present on the skin and within the gastrointestinal tract. The characteristic cutaneous lesions consist of deep-blue, soft, rubbery blebs, which are easily compressible. A serious complication is gastrointestinal bleeding. Because venous malformations were described historically as cavernous hemangiomas, the lesions of BRBNS were also inappropriately called hemangiomas in the literature. We describe 3 cases to delineate the venous malformations of BRBNS and to highlight their variable onset of presentation and progression. In one case, a venous malformation was noted during a prenatal ultrasound evaluation at 5 months gestation. The other 2 cases demonstrated a lack of the classic cutaneous lesions at birth. BRBNS consists of multiple venous malformations, rather than hemangiomas as described. Subcutaneous venous malformations may occasionally be the sole presenting finding in patients with this unusual syndrome, and may be evident even in the prenatal period.

Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice

Paradoxical seizure exacerbation by anti-epileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid) and MK-801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin-positive (PV +) fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV + cortical interneurons in stargazer show a near twofold decrease in the dendrite:soma GluA4 expression ratio compared to wild-type (WT) littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg 2 +-induced network discharges in WT but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor-dependent signaling defects in stargazer cortex and define an interneuron-dependent mechanism for paradoxical seizure exacerbation in absence epilepsy.

Molecular and Cellular Plasticity in Developing Epileptic Brain

Defined transgenic models of epilepsy in the mouse represent unique opportunities to examine interactions between synchronous synaptic activity and cellular programs of brain development. We are beginning to acquire a list of the kinds of genes favoring sudden, intermittent aberrant discharges in central neurons, and we have found that, rather than arising from a few gene superfamilies regulating membrane excitability, they are involved in many diverse functions of the cell. Whereas some primary gene defects impinge directly on membrane electrogenesis and neurotransmitter signaling at synapses, others are too far removed from these processes to clearly visualize the steps by which they promote epileptogenesis. We have tantalizing evidence that several, and probably all, epilepsy genes entrain some degree of secondary molecular and cellular plasticity, and we can guess that these downstream rearrangements may account for the delayed onset of epileptic phenotypes in some syndromes. It is too early to tell whether these, or other induced changes, provide the basis for the reversibility of some epilepsies. The diversity of epilepsy genes and their intervening cellular phenotypes promise to provide a rich source of novel molecular targets for therapeutic discovery and will have a lot to teach us in the future about the developmental potential of neural circuits in the mammalian brain.

Non‐obligatory role of prostaglandin D2 receptor subtype 1 in rosacea: Laropiprant in Comparison to a placebo did not alleviate the symptoms of erythematoelangiectaic rosacea

Erythematotelangiectatic rosacea shares facial flushing features with those seen after niacin. This study was performed to test the hypothesis whether prostaglandin D2 (PGD2) receptor subtype 1 antagonist (laropiprant) will improve the symptoms of rosacea. The purpose of this study was to evaluate the effect of laropiprant 100 mg administered once daily for 4 weeks on the signs and symptoms of erythematotelangiectatic rosacea. Subjects received laropiprant 100 mg once‐daily (n = 30) or placebo (n = 30) for 4 weeks. The primary pharmacodynamics endpoint was change in Clinicians Erythema Assessment (CEA) score from baseline to week 4. The patient self‐assessment (PSA) was a secondary endpoint. Laropiprant was generally well tolerated in this study for the primary endpoint of change in CEA score from Baseline to Week 4, the least‐squares mean of change from baseline to visit 4/week 4 was −3.7 and −3.4 for placebo and laropiprant (100 mg), respectively. The least‐squares mean difference (placebo minus laropiprant) with 90% confidence interval of change in CEA score from baseline to visit 4/week 4 was estimated as −0.3 (−1.6, 1.0). For the secondary endpoint, the least‐squares mean difference (placebo minus laropiprant) with 90% confidence interval of change from baseline to visit 4/week 4 was estimated as −0.7 (−7.7, 6.4) for PSA total score, −4.5 (−14.2, 5.3) for PSA emotion score, −1.3 (−7.8, 5.3) for PSA symptoms score, and 3.6 (−4.3, 11.4) for PSA functioning score. Laropiprant administered once daily for 4 weeks was generally well tolerated in this population of subjects with rosacea. However, there were no clinically meaningful changes in the primary endpoint of CEA given that the response to laropiprant could not be differentiated from that to placebo. There was also no clinically meaningful change in the secondary endpoint, PSA. A DP1 antagonist is not likely to be effective in rosacea.