Nicholas J. Volpe

Safety and Efficacy of Gene Transfer for Leber’s Congenital Amaurosis

Lebers congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial

BACKGROUND Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Lebers congenital amaurosis. METHODS We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Lebers congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years. FINDINGS AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. INTERPRETATION The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. FUNDING Center for Cellular and Molecular Therapeutics at the Childrens Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging.

PURPOSE To examine the potential for visual acuity loss, and its relation to extent and location of optic pathway gliomas in a cohort of children with neurofibromatosis type 1 studied with magnetic resonance imaging. METHODS We reviewed the neuro-ophthalmologic records and brain/orbital magnetic resonance imaging scans for 43 consecutive pediatric patients with neurofibromatosis type 1 and optic pathway gliomas who were followed at the Childrens Hospital of Philadelphia. The presence of visual loss, defined as abnormal visual acuity for age in one or both eyes, was determined. Optic pathway gliomas were classified by tumor extent and location according to involvement of the optic nerves, chiasm, and postchiasmal structures by magnetic resonance imaging. RESULTS Involvement of the optic tracts and other postchiasmal structures at tumor diagnosis was associated with a significantly higher probability of visual acuity loss (P =.048, chi-square test). Visual loss was noted in 20 of 43 patients (47%) at a median age of 4 years; however, three patients developed visual acuity loss for the first time during adolescence. CONCLUSIONS In pediatric patients with neurofibromatosis type 1 and optic pathway gliomas, the likelihood of visual loss is dependent on the extent and location of the tumor by magnetic resonance imaging and is particularly associated with involvement of postchiasmal structures. Furthermore, older age during childhood (adolescence) does not preclude the occurrence of visual loss. Close follow-up beyond the early childhood years, particularly for those with postchiasmal tumor, is recommended.

Idiopathic intracranial hypertension: Relation of age and obesity in children

Article abstract The relation between obesity and age in children with idiopathic intracranial hypertension (pseudotumor cerebri) has remained uncertain. The authors reviewed the records of 45 consecutive children with newly diagnosed idiopathic intracranial hypertension seen at two medical centers. Forty-three percent of patients aged 3 to 11 years were obese, whereas 81% of those in the 12- to 14-year age group and 91% of those in the 15- to 17-year age group met criteria for obesity (p = 0.01). Younger children with idiopathic intracranial hypertension are less likely to be obese than are older children or adults.

Neuro-ophthalmologic Findings in Chordoma and Chondrosarcoma of the Skull Base

Review of the clinical features of 48 patients with chordoma and 49 patients with low-grade chondrosarcoma of the skull base disclosed overlapping clinical profiles but distinctive features. Both tumors occurred at all ages but chondrosarcoma tended to occur in the third and fourth decades. Twenty-five (52%) of the patients with chordoma and 24 (49%) of the patients with chondrosarcoma had ocular symptoms (diplopia or visual impairment) as the initial manifestation of the disease. Of the 59 patients (both groups) with diplopia, the diplopia was initially intermittent in 25 (42%). Headache and diplopia from an insidious abducens nerve palsy was most common in both groups. Abducens nerve palsy occurred in 22 (46%) of the patients with chordoma and 23 (47%) of the patients with chondrosarcoma. Normal examination results were more common in patients with chordoma, whereas visual loss, facial numbness, and multiple cranial neuropathies were more common in patients with chondrosarcoma. The similarities in the clinical features of these tumors reflect their common origin at the central skull base and the vulnerability of the abducens nerves at that site. The differences reflect the tendency of chordomas to originate from the clivus and chondrosarcomas to originate from the temporal bone.

Persistent positive visual phenomena in migraine

Article abstract-Ten patients with migraine developed persistent positive visual phenomena lasting months to years. The complaints were similar in their simplicity and involvement of the entire visual field and usually consisted of diffuse small particles such as TV static, snow, lines of ants, dots, and rain. Neurologic and ophthalmologic examinations were normal, and EEGs were normal in eight of eight patients tested. MRI was normal in all patients except one who had nonspecific biparietal white matter lesions and another with a small venous angioma. Treatment of this unusual complication of migraine was unsuccessful. NEUROLOGY 1995;45: 664-668

Sixth nerve palsies in children

The causes of sixth nerve palsies in 75 children, all of whom had undergone modern neuroimaging, were reviewed. Neoplasms or their neurosurgical removal was the most common cause (n = 34 [45%]); elevated intracranial pressure (nontumor) (15%), traumatic (12%), congenital (11%), inflammatory (7%), miscellaneous (5%), and idiopathic (5%) causes represented other categories but were less commonly present. Isolated sixth nerve palsies were relatively uncommon (9%). On the basis of the relatively high risk of neoplasm, the authors suggest neuroimaging early in the clinical course of children with sixth nerve palsies, even if the palsy is isolated.

Acute ocular motor mononeuropathies: prospective study of the roles of neuroimaging and clinical assessment

The role for immediate neuroimaging in patients 50 years of age or older with acute isolated third, fourth, and sixth nerve palsies is controversial. We prospectively evaluated 66 patients, aged 50 years and older (median 67 years, range 50-85), with acute isolated ocular motor mononeuropathies. Our purpose was to evaluate both the role of neuroimaging and the role of clinical assessment in determining etiology. We found that clinical features, including time to maximal diplopic symptoms, were not predictive of etiology (median 2 days to maximal diplopic symptoms for both peripheral microvascular and other etiologies). The presence of any common vascular risk factor, including diabetes mellitus, hypertension, hypercholesterolemia, or coronary artery disease, was significantly associated with peripheral microvascular etiology in this cohort (p=0.0004, Fishers exact test). Despite the high prevalence of peripheral microvascular ischemia as an etiology in this age group, other causes were identified by magnetic resonance imaging (MRI) or computed tomography (CT) scanning in 14% of patients. Diagnoses included brainstem and skull base neoplasms, brainstem infarcts, aneurysms, demyelinating disease, and pituitary apoplexy. Neuroimaging procedures may have a role in the initial evaluation of patients 50 years of age or older with acute ocular motor mononeuropathies.

Isolated Third, Fourth and Sixth Cranial Nerve Palsies From Presumed Microvascular Versus Other Causes: A Prospective Study

PURPOSE To estimate the proportion of patients presenting with isolated third, fourth, or sixth cranial nerve palsy of presumed microvascular origin versus other causes. DESIGN Prospective, multicenter, observational case series. PARTICIPANTS A total of 109 patients aged 50 years or older with acute isolated ocular motor nerve palsy. TESTING Magnetic resonance imaging (MRI) of the brain. MAIN OUTCOME MEASURES Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment. RESULTS Among 109 patients enrolled in the study, 22 had cranial nerve III palsy, 25 had cranial nerve IV palsy, and 62 had cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5%; 95% confidence interval, 10.7-24.6). The presence of 1 or more vasculopathic risk factors (diabetes, hypertension, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke, and smoking) was significantly associated with a presumed microvascular cause (P = 0.003, Fisher exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other significant medical condition, 10% of patients (8/80) were found to have other causes, including midbrain infarction, neoplasms, inflammation, pituitary apoplexy, and giant cell arteritis (GCA). By excluding patients with third cranial nerve palsies and those with GCA, the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64). CONCLUSIONS In our series of patients with acute isolated ocular motor nerve palsies, a substantial proportion of patients had other causes, including neoplasm, GCA, and brain stem infarction. Brain MRI and laboratory workup have a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present.

Weight gain and recurrence in idiopathic intracranial hypertension A case-control study

Objective: To determine whether weight gain is associated with recurrence in idiopathic intracranial hypertension (IIH). Methods: Medical records of adult patients with IIH seen between 1993 and 2009 at 2 university hospitals were reviewed to identify those with and without recurrence. Patients with documented height and weight at presentation and at subsequent visits were studied. The Wilcoxon rank sum test was used to compare mean body mass index (BMI) and percent weight change between the groups of patients with recurrence and without recurrence. The signed-rank test was used for comparing BMI within groups at the various time points. Results: Fifty women with IIH were included in the analyses: 26 had IIH recurrence and 24 did not. Patients with recurrence had greater BMI at the time of recurrence compared to BMI at diagnosis (p = 0.02, signed-rank test). They also demonstrated a greater degree of weight gain between initial resolution and recurrence (BMI change +2.0 kg/m2 [−1.5 to 10.8]) compared to patients without recurrence (−0.75 kg/m2 [−35 to 3.6], p = 0.0009, Wilcoxon rank sum test). Patients without recurrence demonstrated stable weights (0%[95% CI −9.6 to 10.1%]), while patients with recurrence demonstrated a 6% weight gain ([−3.5 to 40.2%], p = 0.005), with an average rate of BMI gain of 1.3 kg/m2/year vs −0.96 kg/m2/year in those without recurrence. Conclusion: Patients with IIH recurrence had significant increases in BMI compared to patients without recurrence in this cohort. Patients with resolved IIH should be advised that weight gain may be a risk factor for IIH recurrence.