Faculty Bibliography

BACKGROUND: Visual dysfunction is one of the most common causes of disability in multiple sclerosis (MS). The Multiple Sclerosis Functional Composite (MSFC), a new clinical trial outcome measure, does not currently include a test of visual function. OBJECTIVE: To examine contrast letter acuity as a candidate visual function test for the MSFC. METHODS: Binocular contrast letter acuity testing (Sloan charts) was performed in a subgroup of participants from the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial (IMPACT Substudy) and in MS patients and disease-free control subjects from a cross-sectional study of visual outcome measures (Multiple Sclerosis Vision Prospective cohort [MVP cohort]). High-contrast visual acuity was measured in both studies; MVP cohort participants underwent additional binocular testing for contrast sensitivity (Pelli-Robson chart), color vision (D-15 desaturated test), and visual field (Esterman test, Humphrey Field Analyzer II). RESULTS: Contrast letter acuity (Sloan charts, p < 0.0001, receiver operating characteristic curve analysis) and contrast sensitivity (Pelli-Robson chart, p = 0.003) best distinguished MS patients from disease-free control subjects in the MVP cohort. Correlations of Sloan chart scores with MSFC and Expanded Disability Statue Scale (EDSS) scores in both studies were significant and moderate in magnitude, demonstrating that Sloan chart scores reflect visual and neurologic dysfunction not entirely captured by the EDSS or MSFC. CONCLUSIONS: Among clinical measures, contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli-Robson chart) demonstrate the greatest capacity to identify binocular visual dysfunction in MS. Sloan chart testing also captures unique aspects of neurologic dysfunction not captured by current EDSS or MSFC components, making it a strong candidate visual function test for the MSFC.

A 47-year-old woman presented with headache, acute monocular vision loss, and ipsilateral Horner syndrome. Apart from the optic neuropathy, all cranial nerve function was intact. Magnetic resonance imaging revealed an enlarged pituitary gland with compression of the orbital apex. The surgical specimen was consistent with pituitary apoplexy. The combination of headache, acute visual loss, and ipsilateral Horner syndrome without ophthalmoplegia, which may suggest carotid artery dissection, is evidently an unusual manifestation of pituitary apoplexy.

SPECT scanning using (99)Tc-TRODAT-1, a ligand that binds to dopamine transporters, may be useful for detection of early Parkinson's disease (PD), diagnosis of presymptomatic individuals, and monitoring disease progression. Understanding whether genetic factors contribute to inter-individual variability is crucial for interpreting imaging results in the context of disease pathophysiology. We tested whether polymorphisms in the genes for catechol-O-methyltransferase (COMT), monoamine-oxidase B (MAO-B), and the dopamine transporter (DAT) influence dopamine uptake parameters in the striatum in vivo in asymptomatic volunteers and patients with PD as measured with (99)Tc-TRODAT-1. (99)Tc-TRODAT-1 binding declined with age in both asymptomatic volunteers and PD patients, and depended on disease duration in PD patients. We found no significant association between COMT, MAO-B, and DAT polymorphisms and results of (99)Tc-TRODAT-1 testing in asymptomatic volunteers or patients with PD. In PD patients, the age of disease onset and speed of progression did not differ based on these polymorphisms. These results demonstrate that these specific genetic variations do not alter the fidelity of (99)Tc-TRODAT-1 as a measure of dopaminergic function in asymptomatic volunteer individuals or patients with PD.

A 52 year old man developed a supranuclear gaze palsy and opsoclonus after Diazinon poisoning. The diagnosis was confirmed by low plasma and red blood cell cholinesterase activity and urine mass spectroscopy. Saccadic control may be mediated in part by acetylcholine. Opsoclonus in the setting of organophosphate intoxication may occur as a result of cholinergic excess which overactivates the fastigial nuclei.

PURPOSE: To examine the role of unilateral temporal artery biopsy (TAB) in suspected giant cell arteritis (GCA). DESIGN: Retrospective interventional case series. PARTICIPANTS: We identified 181 subjects from pathology and diagnostic code databases at the University of Pennsylvania Medical Center who underwent TAB between January 1990 and January 2001. METHODS: The medical records for all subjects who underwent TAB were reviewed. Follow-up information was obtained by telephone or record review for those patients who had negative unilateral TAB. MAIN OUTCOME MEASURES: Follow-up information for patients with unilateral negative TAB was reviewed for potential adverse outcomes caused by missed or delayed diagnoses of GCA. Presenting signs and symptoms and laboratory values were recorded for all subjects. Comparisons of clinical profiles between subsets of subjects were performed using Fisher's exact test, significance level alpha = 0.01. RESULTS: Follow-up information was available for 88 (86%) of 102 subjects who had unilateral negative biopsy samples. One (1%) subjects of 88 had a subsequent positive contralateral TAB; no adverse outcomes occurred for this subject or for any other subjects with unilateral negative TAB. Compared with subjects who had unilateral positive or who underwent bilateral TAB (n = 74), those who had unilateral negative TAB (n = 88) had a significantly lower prevalence of jaw claudication (P = 0.007). Compared with subjects diagnosed with GCA (n = 39), those with unilateral negative TAB (n = 88) had significantly lower frequencies of jaw claudication (P = 0.001), "chalky white" optic disc edema (P = 0.002), and fever (P < 0.0001). Compared with subjects with positive TAB (n = 33), subjects with negative TAB (n = 148) had significantly lower prevalence of jaw claudication (P < 0.0001), "chalky white" disc edema (P = 0.0002), pale disc edema (P = 0.006), or any systemic symptom other than headache (P = 0.0002). ("Chalky white" denotes notably extreme disc pallor). The most common indications for biopsy in subjects with unilateral negative TAB were elevated erythrocyte sedimentation rate (ESR) (74%), headache (69%), visual complaints (58%), and ophthalmic signs (52%). Although ESR was a significant predictor of positive TAB overall (unilateral and bilateral TAB) in logistic regression models accounting simultaneously for subject age (P = 0.04), ESR did not significantly predict unilateral negative status in our patients (P = 0.13). CONCLUSIONS: In this cohort of patients, unilateral TAB was associated with an extremely low frequency (1%) of subsequent positive contralateral TAB and was not associated with adverse visual or neurologic outcomes for any subject. We conclude that in the hands of experienced physicians, a unilateral TAB is sufficient to exclude a diagnosis of GCA in populations for which clinical suspicion is low. Jaw claudication, pale optic disc edema, particularly "chalky white" disc edema, fever, or any systemic symptom other than headache should raise suspicion for a diagnosis of GCA.

BACKGROUND: Friedreich ataxia is a progressive neurodegenerative disorder affecting afferent cerebellar pathways and other neuronal systems, including afferent visual pathways. A systematic clinical outcome measure for examination of visual dysfunction in Friedreich ataxia has not been identified. We sought to identify a simple, reliable method for assessing clinical and subclinical visual dysfunction in patients with Friedreich ataxia. METHODS: Contrast letter acuity was measured binocularly in Friedreich ataxia patients and age-matched visually asymptomatic volunteers (control group) using the Low-contrast Sloan Letter Charts at three different low-contrast levels (5.0%, 1.25%, and 0.6%). Binocular high-contrast visual acuity (100% level) was also determined for each participant. RESULTS: Despite equal median binocular high-contrast visual acuities between the two groups, patients with Friedreich ataxia had significantly lower (worse) Low-contrast Sloan Letter Chart scores compared with controls, particularly at the lowest contrast levels (1.25% and 0.6%). Ambulation status significantly predicted Low-contrast Sloan Letter Charts scores in linear regression models accounting for patient age, suggesting a potential complementary role for Low-contrast Sloan Letter Chart testing in the assessment of disease status as well as visual function in Friedreich ataxia. CONCLUSIONS: This study demonstrates that Low-contrast Sloan Letter Chart testing may provide a useful clinical outcome measure for Friedreich ataxia and other neuro-ophthalmologic disorders.

Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, can be a serious vision-threatening disease. Visual acuity, visual fields, and ocular fundus appearance should be followed closely in all patients with IIH. Obese patients with IIH should be encouraged to lose weight. Medications that might cause or exacerbate IIH should be identified and discontinued if possible. Mild headaches can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or migraine prophylactic agents. Some patients may not require additional treatment if they are otherwise asymptomatic and have no evidence of vision loss. Symptomatic patients (significant headache, visual complaints, tinnitus) or patients with visual field or acuity loss should be treated initially with acetazolamide. Furosemide may be a useful second-line agent. If vision loss is progressive despite maximal medical therapy or severe at the time of diagnosis, surgical intervention may be required. Optic nerve sheath fenestration is effective and safe, and may be repeated if initially unsuccessful. Lumboperitoneal shunting is also an option, especially if symptoms of headache are prominent and refractory to medical therapy, but it has significant complication and failure rates. Bariatric surgery can be an effective treatment for IIH in severely obese patients, but is not a useful acute intervention. Special issues must be considered when treating IIH in children or pregnant women.

The discovery of the genetic cause of Friedreich ataxia has significantly affected our understanding of the disorder at both the clinical and basic science levels. Friedreich ataxia results from a deficiency of functional frataxin, a protein that appears to be involved in mitochondrial iron homeostasis. This leads to iron accumulation and mitochondrial abnormalities with consequent oxidant damage. The clinical spectrum of Friedreich ataxia has also expanded with the recognition of broader phenotypic features, including the absence of classical Friedreich ataxia features, later age at onset, and spasticity instead of ataxia. Although no proven therapy is yet available, antioxidants are a potential method for therapeutic intervention.

Friedreich's ataxia is a progressive neurodegenerative disorder of the afferent cerebellar pathways associated with mitochondrial dysfunction at the cellular level. We have used noninvasive continuous near infrared muscle spectroscopy (NIRS) to investigate the delivery and utilization of oxygen in response to exercise in this disorder. Patients performed an incremental treadmill walking protocol in which levels of muscle deoxygenation or oxygenation were continuously measured in the medial calf muscle. The kinetics of recovery from exercise-induced deoxygenation, called the half-time of recovery (t(1/2)) were determined. The t(1/2) was prolonged in patients with Friedreich's ataxia compared with controls, and the degree of prolongation correlated with the length of the shorter GAA repeat, a genetic measure that correlates with the age of onset of disease. The t(1/2) also correlated inversely with patient age and with the maximum treadmill speed attained. Several patients also displayed features consistent with inadequate oxygen utilization by muscle. These results suggest that NIRS may be an effective tool for monitoring the biochemical and functional features of Friedreich's ataxia in parallel.