Mark J. Kupersmith

A Randomized, Controlled Trial of Corticosteroids in the Treatment of Acute Optic Neuritis

Background and Methods. The use of corticosteroids to treat optic neuritis is controversial. At 15 clinical centers, we randomly assigned 457 patients with acute optic neuritis to receive oral prednisone (1 mg per kilogram of body weight per day) for 14 days; intravenous methylprednisolone (1 g per day) for 3 days, followed by oral prednisone (1 mg per kilogram per day) for 11 days; or oral placebo for 14 days. Visual function was assessed over a six-month follow-up period. Results. Visual function recovered faster in the group receiving intravenous methylprednisolone than in the placebo group; this was particularly true for the reversal of visual-field defects (P = 0.0001). Although the differences between the groups decreased with time, at six months the group that received intravenous methylprednisolone still had slightly better visual fields (P = 0.054), contrast sensitivity (P = 0.026), and color vision (P = 0.033) but not better visual acuity (P = 0.66). The outcome in the oral-prednisone group did ...

The Effect of Corticosteroids for Acute Optic Neuritis on the Subsequent Development of Multiple Sclerosis

BACKGROUND Optic neuritis is often the first clinical manifestation of multiple sclerosis, but little is known about the effect of corticosteroid treatment for optic neuritis on the subsequent risk of multiple sclerosis. METHODS We conducted a multicenter study in which 389 patients with acute optic neuritis (and without known multiple sclerosis) were randomly assigned to receive intravenous methylprednisolone (250 mg every six hours) for 3 days followed by oral prednisone (1 mg per kilogram of body weight) for 11 days, oral prednisone (1 mg per kilogram) alone for 14 days, or placebo for 14 days. Neurologic status was assessed over a period of two to four years. The patients in the first group were hospitalized for three days; the others were treated as outpatients. RESULTS Definite multiple sclerosis developed within the first two years in 7.5 percent of the intravenous-methyl-prednisolone group (134 patients), 14.7 percent of the oral-prednisone group (129 patients), and 16.7 percent of the placebo group (126 patients). The adjusted rate ratio for the development of definite multiple sclerosis within two years in the intravenous-methylprednisolone group was 0.34 (95 percent confidence interval, 0.16 to 0.74) as compared with the placebo group and 0.38 (95 percent confidence interval, 0.17 to 0.83) as compared with the oral-prednisone group. The beneficial effect of the intravenous-steroid regimen appeared to lessen after the first two years of follow-up. Signal abnormalities on magnetic resonance imaging (MRI) of the brain were a strong indication of risk for the development of definite multiple sclerosis (adjusted rate ratio in patients with three or more lesions, 5.53; 95 percent confidence interval, 2.41 to 12.66). The beneficial effect of treatment was most apparent in patients with abnormal MRI scans at entry. CONCLUSIONS In patients with acute optic neuritis, treatment with a three-day course of high-dose intravenous methylprednisolone (followed by a short course of prednisone) reduces the rate of development of multiple sclerosis over a two-year period.

Multiple sclerosis risk after optic neuritis: Final optic neuritis treatment trial follow-up

OBJECTIVE To assess the risk of developing multiple sclerosis (MS) after optic neuritis and the factors predictive of high and low risk. DESIGN Subjects in the Optic Neuritis Treatment Trial, who were enrolled between July 1, 1988, and June 30, 1991, were followed up prospectively for 15 years, with the final examination in 2006. SETTING Neurologic and ophthalmologic examinations at 13 clinical sites. PARTICIPANTS Three hundred eighty-nine subjects with acute optic neuritis. MAIN OUTCOME MEASURES Development of MS and neurologic disability assessment. RESULTS The cumulative probability of developing MS by 15 years after onset of optic neuritis was 50% (95% confidence interval, 44%-56%) and strongly related to presence of lesions on a baseline non-contrast-enhanced magnetic resonance imaging (MRI) of the brain. Twenty-five percent of patients with no lesions on baseline brain MRI developed MS during follow-up compared with 72% of patients with 1 or more lesions. After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. Among patients without lesions on MRI, baseline factors associated with a substantially lower risk for MS included male sex, optic disc swelling, and certain atypical features of optic neuritis. CONCLUSIONS The presence of brain MRI abnormalities at the time of an optic neuritis attack is a strong predictor of the 15-year risk of MS. In the absence of MRI-detected lesions, male sex, optic disc swelling, and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS. This natural history information is important when considering prophylactic treatment for MS at the time of a first acute onset of optic neuritis.

Idiopathic hypertrophic pachymeningitis

Background: Hypertrophic pachymeningitis is an uncommon disorder that causes a localized or diffuse thickening of the dura mater and has been associated with rheumatoid arthritis, syphilis, Wegener’s granulomatosis, tuberculosis, and cancer. Few series of the idiopathic variety have been described, particularly with respect to MRI correlation to clinical outcome and treatment. Objective: To investigate the clinical and laboratory evaluation, course, and treatment of patients with idiopathic hypertrophic pachymeningitis (IHP), to correlate the MRI findings with the clinical course, and to review the literature on IHP. Methods: Retrospective case series of 12 patients (9 men, 3 women), with a mean age of 55 years (range 39 to 88 years), who had IHP by imaging studies, meningeal or orbital biopsy, or both. The clinical features, laboratory evaluation, contrast-enhanced MRI, treatment, and clinical outcome were documented for each case. The mean duration of follow-up was 3.5 years (range 3 months to 16 years). Results: The main clinical features at presentation were headache (11 cases), loss of vision (7 cases), diplopia (4 cases), papilledema (2 cases), other cranial nerve involvement (3 cases), ataxia (2 cases), and seizures (1 case). On the initial MRI, the location of abnormal enhancement of the dura mater correlated with the clinical findings and the sphenoid wing area was affected in all patients. The sedimentation rate was elevated in five cases. The CSF had increased protein in six cases and lymphocytosis in four cases. Biopsy of the dura mater in five cases and the orbital soft tissue in one case showed infiltrates of small mature lymphocytes, plasma cells, and epithelioid histiocytes, but no neoplasia, vasculitis, or infectious agents. Cultures of the CSF and biopsy material remained sterile. Corticosteroid therapy improved the vision in 7 of 8 cases and controlled headache in 10 of 11 cases. Five cases had partial improvement of other neurologic symptoms and signs. Recurrence developed with steroid tapering in six cases. One case had progressive deterioration and died. In four cases methotrexate or azathioprine was added with reduction of the steroid dose. Follow-up MRI performed in 11 patients correlated 80% with the clinical state (p = 0.01). Conclusion: IHP can be suspected on MRI and defined pathologically on biopsy. Untreated, the clinical course is usually marked by severe headache and progressive neurologic deterioration and vision loss. Although initially steroid-responsive, clinical manifestations frequently recur with corticosteroid taper, requiring the addition of immunosuppressive agents in some cases.

Transvascular treatment of giant aneurysms of the cavernous carotid and vertebral arteries: Functional investigation and embolization

Functional angiographic investigation and percutaneous embolization using detachable balloons in nine carotid cavernous aneurysms, three petrous aneurysms, one vertebral artery aneurysm, and one posterior inferior cerebellar aneurysm are reported. A double-lumen balloon catheter is used to evaluate acute tolerance to occlusion of the carotid or vertebral arteries. Occlusion is tested under systemic heparinization. Local perfusion of heparinized saline, proximal as well as distal, to the balloon occlusion is used. The procedure was successful in all but one cavernous aneurysm. The arterial lumen was sacrificed in all cases. Clinical improvement occurred in all successful cases. Retro-orbital pain was relieved in all. Ocular cranial nerve palsies improved or resolved in most. One delayed ophthalmic episode that improved represents the only complication. No such embolic problems occurred in any case in which the cavernous carotid artery was occluded by balloon trapping. The delayed embolic complications after carotid artery occlusion are related to the collateral vessels to the C-4 and C-5 segments of the artery. Balloon trapping decreases the length of the thrombosed segment and prevents retrograde filing of the aneurysm.

A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapya

PURPOSE Comparison of treatment outcome in patients with primary optic nerve sheath meningioma (ONSM). DESIGN Retrospective, nonrandomized, comparative interventional case series. PARTICIPANTS Sixty-four patients with at least 50 months of well-documented follow-up. INTERVENTION Observation, surgery only, radiotherapy only, or surgery and radiotherapy. MAIN OUTCOME MEASURES Visual acuity expressed as ratio, radiographic progression, and treatment complications. RESULTS Sixty-four patients (55 women [85.9%] and nine men [14.1%]) were followed for a mean of 150.2 months (range, 51-516 months; standard deviation [SD], 74.7). The mean age at diagnosis was 47.1 years (range, 17-81 years; SD, 15.4). Fifty-eight patients had unilateral disease and six patients had bilateral disease. Of 59 patients with vision greater than no light perception at diagnosis, 13 patients were observed only, 12 had surgery only (four biopsies or partial resections, eight total resections), 18 received radiation alone, and 16 had surgery and radiation (14 biopsies or partial resections and radiation, two total resections and radiation). Irradiated patients received 4000 to 5500 cGy of conventional multiport or conformal external beam therapy, typically fractionated over 6 weeks. Visual acuity measurements at diagnosis among the four groups were not different (ratio, P = 0.186). Visual acuity at diagnosis was > or =0.5 in 56.3%, 0.4 to 0.050 in 12.5%, and <0.050 in 31.3%. Visual acuity measures at last follow-up were different among the four groups (ratio, P = 0.004). At last follow-up the acuity was > or =0.5 in 28.1%, 0.4 to 0.050 in 15.6%, and <0.050 in 56.3%. Visual acuity fell significantly for the observed only (ratio, P = 0.002), surgery only (ratio, P = 0.019), and surgery with radiation groups (ratio, P = 0.030). The radiation only group showed a decrease in visual acuity that was not significant (ratio, P = 0.301). Complication rate was 33.3% in radiation only cases, 66.7% in surgery only cases, and 62.5% in surgery with radiation cases. Twenty-one patients (32.8%) showed radiographic progression. Four patients who were observed, seven patients who had surgery alone, and eight patients who had surgery and radiation developed radiographic progression. Two patients who had radiation alone had radiographic progression before treatment. Only two patients treated with radiation only showed radiographic progression after radiotherapy, and both had at least one surgical procedure before the radiotherapy. CONCLUSIONS Patients with ONSM receiving radiation alone demonstrated the best visual outcome during the follow-up period. We recommend that fractionated external beam radiation (5000-5500 cGy) be considered as initial treatment in adults in selected cases of ONSM when preservation of visual function is a reasonable therapeutic goal.

Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial.

IMPORTANCE Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use. OBJECTIVE To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between -2 dB and -7 dB. The mean age was 29 years and all but 4 participants were women. INTERVENTIONS Low-sodium weight-reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6. RESULTS The mean improvement in PMD was greater with acetazolamide (1.43 dB, from -3.53 dB at baseline to -2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from -3.53 dB to -2.82 dB; n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: -1.31, from 2.76 to 1.45; placebo: -0.61, from 2.76 to 2.15; treatment effect, -0.70; 95% CI, -0.99 to -0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: -7.50 kg, from 107.72 kg to 100.22 kg; placebo: -3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, -4.05 kg, 95% CI, -6.27 to -1.83 kg; P < .001). CONCLUSIONS AND RELEVANCE In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be determined. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01003639.

Effects of weight loss on the course of idiopathic intracranial hypertension in women

Objective: To determine the role of weight loss in the treatment of idiopathic intracranial hypertension (IIH) in obese women. Methods: Chart review of 250 patients with suspected IIH revealed 58 women who met our criteria, did not undergo early surgical intervention, and had adequate documentation of visual status, papilledema, and weight at the baseline evaluation and at 6 months or longer. Patients were divided into two groups based on whether weight loss ≥2.5 kg occurred during any 3-month interval. Papilledema grade, visual acuity, and visual field grade at 6 months or longer and the time to improve each were recorded. Results: Mean time in months to improve one grade for papilledema and visual field in one eye was 4.0 versus 6.7 (p = 0.013) and 4.6 versus 12.2(p = 0.032), respectively, for the 38 patients with weight loss compared with the 20 patients with no weight loss. Papilledema resolved in 28/38 with weight loss (mean, 7.6 months) and 8/20 without weight loss (mean, 10.2 months; p = 0.352). There were no differences in final visual acuity or visual field between the two groups, but the papilledema grade was slightly better in the worst eye in each patient at baseline in the weight loss group (p = 0.03). Conclusions: Weight reduction is associated with more rapid recovery of both papilledema and visual field dysfunction in patients with IIH compared with those who do not lose weight.

Treatment of parkinson's disease with bromocriptine.

Bromocriptine in high doses (up to 100 mg per day) was administered to 14 patients with advanced Parkinsons disease whose disorder was progressing despite optimum treatment with levodopa combined with a peripheral dopa decarboxylase inhibitor (carbidopa). In 10, bromocriptine (mean dose, 57 mg) induced a statistically significant (P less than 0.01) improvement in rigidity, tremor, bradykinesia, gait disturbance and total score. In seven patients levodopa with carbidopa was completely replaced by bromocriptine (mean dose, 70 mg), with improvement in four. Adverse effects were similar to those observed with levodopa and carbidopa, except that in individual patients abnormal involuntary movements and diurnal oscillations in performance (on-off effect) were decreased whereas orthostatic hypotension and mental changes were increased. Bromocriptine appears to be a major new agent in Parkinsons disease that is especially promising in patients no longer responding to levodopa.

Visual Loss in Pregnant Women with Pituitary Adenomas

Pituitary adenomas in women of childbearing age present a potential contraindication to pregnancy because of the risk for developing visual loss during pregnancy as a result of tumor expansion. Earlier reports have not resolved whether patients with macroadenomas are at greater risk than those with microadenomas [1, 2]. Enlargement of an adenoma can be caused by tumor growth or an infarction or hemorrhage of the tumor. In addition, the 70% increase in the volume of the pituitary gland that normally occurs during pregnancy may contribute to the mass effect on the optic apparatus in the suprasellar region [3, 4]. Also, prolactinomas, previously reduced in size by treatment with bromocriptine (a dopamine agonist), may enlarge as soon as the drug is withdrawn, which is frequently done during pregnancy [5]. The advent of high-resolution computed tomography and magnetic resonance imaging made it possible to accurately assess tumor size and study its relation to visual loss during pregnancy [2, 6-11]. Only two previous studies [6, 7] have correlated visual performance with abnormal radiologic test results, using sellar radiograph or tomography findings. We tried to determine whether factors such as tumor size, secretory characteristics, or other clinical features could be used to predict those women with pituitary adenomas who were at risk for developing visual loss during pregnancy. Methods Patients We examined the records of all women with pituitary adenomas who had been evaluated by the New York University neuro-ophthalmology service between 1982 and 1992 and who became pregnant. Sixty-six patients became pregnant who had not had previous surgery or radiation therapy directed at the adenoma (mean age at pregnancy, 30.6 years; range, 21 to 38 years). Except for one patient (patient 3), a diagnosis of pituitary adenoma had been established before referral by endocrinologists or gynecologists for consultation and baseline visual function testing (see vision analysis) during the first trimester or before conception. During pregnancy, a neuro-ophthalmologist (MJK) prospectively repeated visual testing at least once, usually in the third trimester. Missing endocrine data and neuroimaging studies for review were sought by mail and telephone inquiries with the assistance and consent of the patients and referring physicians for all patients. Neuroimaging Analysis High-resolution computed tomography or magnetic resonance imaging (or both) were done in all but two patients before the first pregnancy. Coronal- and axial-oriented images (2.5- to 5.0-mm thick) for computed tomography studies and coronal-, axial-, and sagittal-oriented images (3-mm thick) for magnetic resonance imaging were all evaluated for the presence of an adenoma. On the coronal images, the maximum vertical height (the direction of growth toward the optic chiasm and typically the largest dimension) of the tumor mass was measured. Eight patients had adenomas that were smaller than 0.3 cm and difficult to distinguish from the surrounding pituitary gland. These patients were considered to have an adenoma because of abnormal tilting of the pituitary stalk, asymmetric fullness of a pituitary hemisphere, amenorrhea, infertility, and high levels of serum prolactin. The tumor height in these patients was considered to be zero for the purpose of data analysis. In general, patients with adenomas of 1.0 cm or larger and no visual loss were counseled to avoid pregnancy unless they had previous treatment to decrease the probability of optic structure compression. This may partially explain the small number (eight) of patients with adenomas larger than 1.1 cm in this series. Vision Analysis We prospectively collected data on the visual and ocular motor systems. Before pregnancy, 55 patients had a normal baseline neuro-ophthalmologic examination. Within 3 weeks of the calculated conception date, 10 additional patients were found to have normal vision. Only 1 patient was not examined until the end of the second trimester (patient 3). This patient was included because she had a normal ophthalmologic examination, done by the referring ophthalmologist, 1 year before her pregnancy. The evaluation included the best corrected visual acuity; color vision testing using pseudoisochromatic plates; the evaluation of lid, pupil, and ocular motility functions; and ophthalmoscopy. Visual field measurement was done with tangent or Goldmann perimetry in 52 patients and, in later years (after 1987), with computerized threshold perimetry in 14 patients. Table 1. Cases of Pituitary Adenoma That Were 1.2 cm or Larger Each patient was encouraged to return at yearly intervals if she was not pregnant and during the first trimester if she was pregnant. Patients were examined at least one other time, usually in the last trimester, or more often if a potential problem occurred (such as frequent headaches, visual loss, or concern by the patient or referring doctor). Patients were also instructed to be examined before having a subsequent pregnancy. Visual loss was diagnosed when visual field defects typical of optic nerve or chiasm compression occurred (Figure 1)not when minor degrees of nonspecific threshold elevation were presentwith or without a decrease in acuity or color vision. Figure 1. Visual fields measured by tangent perimetry of patients 1 to 6 are listed (top to bottom) at the time that visual loss occurred during pregnancy. R L Endocrine Studies The patients had no other disorders and were receiving no drugs known to influence prolactin levels at the time of diagnosis [12]. Serum prolactin levels were measured in all 65 patients in the analysis and were increased in 58 (range, 40 g/L to 2000 g/L; normal, 0 to 25 g/L). The prolactin level was greater than 100 g/L in 27 patients. Two patients had acromegaly with serum growth hormone levels of 55.2 g/L and 81.2 g/L (normal <8 g/L) and prolactin levels of 7.8 g/L and 69.8 g/L (patients 6 and 8, respectively). Five patients had data consistent with nonsecretory tumors. In patients diagnosed as having a prolactinoma, bromocriptine mesylate (Parlodel; Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey), 2.5 mg one to three times daily, was prescribed. Although some patients admitted to not taking the bromocriptine, an accurate rate of compliance was not determined. Bromocriptine was stopped at a mean of 4.45 weeks from the calculated date of conception in 56 pregnancies (range, 2 days to 23 weeks). Neither patient with acromegaly received medication before or during pregnancy. The presence of a clinical pregnancy reported by each patient was confirmed by a conventional laboratory pregnancy test [13]. Failure to sustain the pregnancy to term was considered a spontaneous abortion. Examination for fetal tissue was not uniformly done. Data Analysis One patient with a 2.0-cm tumor conceived three times and immediately had medical abortions each time because of her fear of visual loss. Because all her pregnancies were terminated, we omitted data from this patient, leaving 65 patients in the final data analysis. Data were analyzed using simple logistic regression analysis for yes-no outcomes and using simple regression analysis for continuous outcomes. The small sample size precluded the use of any multiple regression procedures. Linear regression [14] data were interpreted by the size and significance of their -coefficients, whereas the logistic regression data [15] were assessed by examination of odds ratios. The odds ratio in such patients was obtained using the -coefficients (an exponential calculation). Confidence intervals (95% CI) accompanied the odds ratio or -coefficient for each condition. A two-tailed Fisher exact test was used to calculate exact P values. All statistical calculations were done using SAS [16]. Results A total of 111 pregnancies was noted. The neuro-ophthalmologic examination showed visual field defects from tumor compression of the anterior visual pathway in six patients during pregnancy (Table 1); five of these patients were in their first pregnancy (patient 3 was first seen during the second trimester). The visual field defects occurred in one eye in one patient and in both eyes in five patients (Figure 1). An incomplete superior temporal quadrantanopia was found in eight eyes of six patients. A complete superior temporal quadrantanopia was found in two eyes of two patients. An incomplete temporal hemianopia (progressed from a partial quadrantanopia) was found in the one patient (patient 3) with decreased visual acuity in one eye. Concomitant with the field loss, the visual acuity was 20/30 or better in eyes from all patients except for one eye of one patient (patient 3), which was 20/80. When patient 3 was first examined by the neuro-ophthalmologist (MJK), the acuity of this eye was 20/30. The color vision was normal in all the eyes except in the 1 patient with decreased acuity in one eye. All of the patients having visual loss had adenomas of 1.2 cm or more. No women developed dysfunction of cranial nerves III, IV, V, or VI, clinical signs of an infarction, or hemorrhage in the pituitary gland or adenoma. No patients had any other signs of central nervous system dysfunction or increased intracranial pressure. Treatment was individualized for each patient with visual loss (Table 1). When treated postpartum with bromocriptine, two patients had normal visual examinations within 3 months. Bromocriptine administered during the last 5 months of pregnancy normalized the vision in one patient (within 3 months). Bromocriptine therapy combined with a therapeutic abortion in one patient led to a return of normal vision (within 1 month). Trans-sphenoidal adenomectomy, done in the third trimester in patient 3 and done postpartum in a second patient, resulted in normal visual function (visual acuity > 20/30, normal color vision, full visual fields) within 4 months. Eight patients had adenomas with a vertical height of 1.2