Joshua Joung1, John Sollee6, Kathryn Gallison1, Geraldine Liu1, Hannah Cooper1, Walter Faig5, Heather McClung2, Elizabeth Drum2, Sona Narula1, Grant Liu3, Robert Avery3, Arastoo Vossough4, Amy Waldman1
1Pediatrics (Division of Neurology), 2Anesthesiology and Critical Care Medicine, 3Pediatrics (Division of Ophthalmology), 4Radiology, Children's Hospital of Philadelphia, 5Children's Hospital of Philadelphia, 6Warren Alpert Medical School of Brown University
Objective:
To determine the prevalence of elevated intracranial pressure (ICP) in subjects with Alexander disease (AxD).
Background:
AxD is caused by a gain of function mutation in GFAP and formation of Rosenthal fibers. With a predilection for perivascular, subpial, and subependymal astrocytes, Rosenthal fibers are hypothesized to impair CSF circulation, resulting in increased ICP.
Design/Methods:
Subjects with AxD, confirmed by GFAP testing and enrolled in a natural history study, were included. Study procedures included neurologic exam, LP with opening pressure (OP), and brain MRI. OP was conservatively defined as elevated if >28 cm H2O. MRIs were reviewed by a neuroradiologist (masked to clinical data and OP) for imaging signs of elevated ICP (e.g., flattened sclerae, enlarged optic nerve sheaths, empty sella, and sinus venous stenoses). Linear mixed effects regression was used to explore OP as a function of age. Random forest analysis was used to predict OP from imaging variables.
Results:
Sixty-one LPs were performed in 40 subjects; 20 (50%) had elevated OP on at least one LP. Eighteen subjects had longitudinal LPs; 9 demonstrated an increase in OP compared to baseline, while the others were stable (N=2) or decreased (N=5, all asymptomatic and untreated). The remaining 2 subjects received acetazolamide for headache and vomiting with symptom benefit and reduced OP. There was no association between age and OP (p=0.19). Anesthesia (N=35) and procedures were well tolerated without complications.
Twenty-one subjects (totaling 28 LPs) had an undilated fundus exam ≤1 day prior to the LP; none had papilledema. MRI features of elevated ICP predicted high OP (R2=0.637). Conclusions:
Elevated OP and MRI features of elevated ICP occur frequently in AxD, even in the absence of clinical signs. The implications of elevated ICP on patients’ outcomes and whether elevated ICP requires treatment need to be determined in patients with AxD.