Donnell J. Creel

Children and adolescents with neurofibromatosis 1 : A behavioral phenotype

Twenty 6− to 17-year-old children with neurofibromatosis 1 (NF1) were compared to 20 age-and sex-matched siblings on a wide range of neuropsychological and behavioral dimensions. In familial cases, diagnostic status was confirmed by gene linkage with greater than 98% accuracy. Visual examinations that included assessments of visual evoked responses (VER) were performed on subjects with NF1. Forty-two percent of NF1 subjects had abnormal VER and underwent magnetic resonance imagery or computed tomography scans of the brain. On a variety of skills, subjects with NF1 performed more poorly than unaffected siblings. Children with NF1 were found to be less competent on measures of cognitive, language, and motor development, visual-spatial judgment, visual-motor integration, and academic achievement. Learning disabilities were common in children with NF1. Parents and teachers reported that NF1 subjects had internalizing problems and difficulty interacting with peers. A behavioral phenotype for NF1 and recommendations for preventative interventions are proposed.

Pattern reversal evoked potentials: gender differences and age-related changes in amplitude and latency.

This report is intended to complement the current body of literature by describing pattern reversal evoked potential (PREP) component amplitudes and latencies in a larger sample than has been previously studied and providing comparisons of males and females across the lifespan. Binocular PREPs were measured from 406 normal subjects, 6-80 years of age. In general, latencies were found to decrease during maturation, stabilize across early adulthood, then begin to increase sometime after the late 20s. There were minimal gender differences in latencies during development but males tended to have longer latencies than females during adulthood. Across the lifespan, amplitudes were larger for females. Results of regression analyses using the entire data set were compared to results of separate regression analyses for developmental years (6-20) and adulthood (21-80). Separate analyses appear to provide more useful descriptions of PREP latency and amplitude changes across the lifespan. It is clear that predicted normal values can vary depending on age range and relative proportion of males and females comprising a reference sample. Appropriate clinical values should be based on age- and sex-matched normal subjects and should be specific with regard to technical and methodological variables.

Auditory brainstem anomalies in albino cats. I. Evoked potential studies

The amount of melanin pigmentation in the inner ear is positively correlated with the general pigmentation of the body and specifically with the amount of pigment in the eye. The misrouting of retinofugal projections which accompanies ocular and oculocutaneous albinism has been thought to be a defect in decussation unique to the visual system. Evidence suggests that functional abnormalities may also exist in the auditory systems of albino humans and animals. To evaluate this possibility, evoked potential techniques were used to examine the functional anatomy of decussating brainstem auditory pathways in albino and pigmented cats. Auditory brainstem responses (ABRs) were recorded from albino, pigmented, and Siamese cats using monaural stimulation. ABRs were recorded ipsilateral and contralateral to the stimulated ear. The albinos were complete tyrosinase-negative (cc), not the dominant white (W) variety associated with deafness. In pigmented cats, the amplitudes of ABRs recorded with the reference electrode ipsilateral to the stimulated ear and the ABRs recorded using the reference contralateral to the stimulated ear did not differ by more than 40% for individual components appearing between 2 and 4 ms after stimulus onset. In albino cats the components at these latencies were obliterated or greatly attenuated in the ABR recorded using the reference contralateral to the stimulated ear. These data indicate that anomalies may exist in the brainstem at the level of the acoustic striae, superior olivary nuclei and/or trapezoid body in tyrosinase-negative albino cats.

Retinal Toxicity Associated With Occupational Exposure to the Fish Anesthetic MS-222

PURPOSE To report a case of retinopathy associated with chronic occupational exposure to ethyl-m-aminobenzoic acid methanesulfonate (MS-222), a retinotoxic fish anesthetic. METHOD Case report with electroretinograms to document changes in visual electrophysiology. RESULTS An ichthyologist with a long history of skin exposure to MS-222 was initially examined for decreased vision, photophobia, and photopsia. His electroretinogram abnormalities were similar to those seen in animal models of acute MS-222 toxicity. After terminating MS-222 contact for 7 months, his vision returned to normal, and his electroretinogram improved. CONCLUSION Individuals with occupational exposure to MS-222 should exercise caution to avoid systemic absorption of this retinotoxic compound.

Persistent severe visual and electroretinographic abnormalities after intravenous Cisplatin therapy.

A 55-year-old man inadvertently received four times the intended dose of intravenous cisplatin as part of a chemotherapeutic salvage regimen for non-Hodgkin lymphoma. Immediately after treatment, he developed bilateral irreversible visual loss. Visual acuity was 20/300 in OU and visual fields showed central scotomas bilaterally. Although the fundus examination findings were normal, an electroretinogram showed markedly reduced a-wave amplitudes and absent b-waves. At autopsy 8 months later, photoreceptors appeared normal. Splitting of the outer plexiform layer was present, consistent with loss of the ERG b-wave. This is the first reported case of persistent visual loss from intravenous cisplatin toxicity and the first case to describe ocular histopathologic findings.

Effects of aging on normal hearing loss and noise-induced threshold shift in albino and pigmented guinea pigs

In a previous investigation into noise-induced hearing loss by comparing 2-month-old albino with pigmented guinea pigs, albinos displayed significantly greater shifts in cochlear microphonic (CM) threshold and less recovery than the pigmented animals 7 days after noise exposure. The present study compared the responses of 14-month-old albino and pigmented guinea pigs to the same noise parameters used previously. Thresholds for the first detectable elicitation of CM for three pure tones were recorded prior to, at 90 min and at 7 days after a 45-min exposure to 126 dB broadband noise. Before exposure to noise, thresholds for pigmented guinea pigs were 24 dB higher than those in the albinos. Following noise exposure, the pigmented animals showed less than half the amount of threshold shift displayed by the albinos. This change ws attributed to the higher pre-exposure thresholds in the pigmented guinea pigs. Converging lines of evidence suggest that cochlear pigmentation may have both protective and toxic influences on the inner ear.

A novel method for screening the multifocal electroretonogram in patients using hydroxychloroquine.

Purpose: To evaluate retinal function in patients on hydroxychloroquine using multifocal electroretinography. Methods: A retrospective chart review was performed for 23 patients (46 eyes) on hydroxychloroquine therapy and referred for multifocal electroretinogram (mfERG) testing. Duration of treatment, daily hydroxychloroquine dose, visual acuity, fundus examination, color vision testing, Amsler grid testing, visual field examination, and fluorescein angiography results were obtained when available. Multifocal electroretinogram response amplitudes were calculated for the central and paracentral regions and compared with previously published normal values. The central and paracentral regions of the mfERG color difference plot, which assigns colors to localized areas of the mfERG based on deviation from normal, were assessed using a novel Color Difference Plot Scoring System which relies on the color pattern observed within each region. Results: Ninety-two regions were assessed for response amplitudes, 31 of which showed a depressed response amplitude. Of the 17 eyes which had at least one region with a depressed response amplitude, clinical examination findings were relatively benign. Color difference plot scoring showed strong agreement with response amplitude, with a Color Difference Plot Scoring System score of 2 or 3 showing 93.55% sensitivity and 60% specificity for a depressed response amplitude. Interrater reliability of the scoring system as measured by Kendall’s W coefficient of concordance was 0.6484 (P < 0.00001). Conclusion: The mfERG appears to be able to detect decreased retinal function in hydroxychloroquine patients with normal clinical examinations, and may be useful in identifying patients that require close monitoring for the development of clinically relevant toxicity. The Color Difference Plot Scoring System may be used as a tool to aid in the interpretation of results of the mfERG in the clinic setting.

Clofazimine-induced bull's-eye retinopathy.

Bulls-eye retinopathy has multiple associations. We report a case of bulls-eye retinopathy presumed to be secondary to clofazimine (Lamprene®) treatment of a 30-year-old patient with acquired immunodeficiency syndrome (AIDS). Pretreatment baseline eye exam of this patient was normal except for bilateral cotton-wool spots. However, follow-up exam 5 months later revealed bilateral anterior pigmentary corneal deposits in a whorl pattern, a presumed infectious retinitis in the left eye, and bilateral annular macular pigmentary abnormalities. The patient was taken off clofazimine treatment, but died 1 month later. The authors suggest that patients being treated with clofazimine be examined for drug-related corneal and retinal lesions.

Differential Effects of Gentamicin on the Distribution of Cochlear Function in Albino and Pigmented Guinea Pigs

It has been suggested that the high affinity of melanin pigment for aminoglycoside antibiotics may cause these drugs to bind preferentially to the pigmented inner ear, producing greater ototoxicity than in the amelanotic albino cochlea. However, evidence of greater ototoxicity in albinos has led to the hypothesis that melanin inhibits the toxicity of these drugs in the pigmented inner ear. On the other hand, ototoxicity in the pigmented animals may simply be delayed relative to the albinos, only to become equal or even more severe with time. The present study was conducted to determine whether a relatively low dose of gentamicin (68.5 mg/kg) would produce differential ototoxicity between albino and pigmented guinea pigs which would persist long after drug exposure had stopped. Nine pigmented and eight albino guinea pigs were given gentamicin sulfate for 14 consecutive days, and were then allowed a two-month recovery period before cochlear analysis; 11 pairs of saline-injected or untreated albino and pigmented guinea pigs served as controls. The results showed that the gentamicin-treated albinos had significantly elevated thresholds for the compound action potential from the auditory nerve (CAP), and significantly lower endocochlear potentials (EP) and cochlear microphonic (CM) input-output voltage functions when compared to their respective controls, or to either group of pigmented guinea pigs. The CAP in drug-treated pigmented animals did not differ significantly from controls, and the differences in EP and CM were marginally significant. The results indicate that the pigmented cochlea is less susceptible to gentamicin than the albino cochlea, and support the hypothesis that melanin may inhibit aminoglycoside ototoxicity in the pigmented inner ear.

Dominant optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, and myopathy. A new syndrome.

Twenty-three members of a 96-member family exhibited an autosomal dominant disorder which has not previously been described. This disorder involves progressive optic atrophy, abnormal electroretinography without retinal pigment changes, and progressive sensorineural hearing loss usually evident in the first or second decade of life. In midlife, ptosis, ophthalmoplegia, dystaxia, and a nonspecific myopathy occur.