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Show Literature Commentary Koshy JC, Sharabi SE, Feldman EM, Hollier LH Jr, Patrinely JR, Soparkar CN. Effect of dietary zinc and phytase supplementation on botulinum toxin treatments. J Drugs Dermatol. 2012;11:507-512. Purpose: To determine whether oral zinc supplementation might affect the efficacy and duration of botulinum toxin treatments. Methods: In a double-blind, placebo-controlled, crossover pilot study, we examined the efficacy of 3 botulinum toxin preparations (onabotulinumtoxinA, abobotulinumtoxinA, and rimabotulinumtoxinB) following oral supplementation with zinc citrate 50 mg and phytase 3,000 PU, zinc gluconate 10 mg, or lactulose placebo in individuals treated for cosmetic facial rhytids, benign essential blepharospasm, and hemi-facial spasm. Results: In 77 patients, 92% of subjects supplemented with zinc 50 mg and phytase experienced an average increase in toxin effect duration of nearly 30%, and 84% of participants reported a subjective increase in toxin effect, whereas no significant increase in duration or effect was reported by patients following supplementation with lactulose placebo or 10 mg of zinc gluconate. The dramatic impact of the zinc/ phytase supplementation on some patients' lives clinically unmasked the study and prompted an early termination. Conclusions: This study suggests a potentially meaningful role for zinc and/or phytase supplementation in increasing the degree and duration of botulinum toxin effect in the treatment of cosmetic facial rhytids, benign essential blepharospasm, and hemifacial spasm. Botulinum toxin requires the presence of zinc to block neuromuscular function. Phytates are dietary compounds that block zinc absorption in the gut. Phytases are enzymes that degrade phytates and improve zinc absorption. Patients were randomized to 1 of 3 arms to be taken for 4 days prior to botulinum toxin injection: 1. oral zinc citrate 50 mg/phytase 3,000 PU 2. oral zinc gluconate 10 mg 3. oral placebo. After the first injection, the patient then returned for a second injection prn without any premedication (washout). For the third injection, the patient was randomly assigned to another arm followed by a washout injection and then finally participated in the final arm of the study. The patients kept journals documenting efficacy and duration of effect. The dramatic effect of the zinc/phytase arm over the other 2 groups resulted in early termination of the study. The senior author of this article notes that he has a patent pending for a zinc/phytase combination, which could result in some bias. The zinc/phytase combination pill comes in a pack of 10 with the trade name of Zytaze (Ocusoft, Inc, Richmond, TX) and requires a prescription. It is quite a bit more expensive than taking zinc alone. -Michael S. Lee, MD It would really be nice if a simple dietary supplement could increase the effect and duration of action of botulinum toxin. Although this study would suggest this is the case, the problems you have identified, the early termination because of apparent benefit and the conflict of interest of the senior author, limit the credibility of the report. I wonder whether the benefit of the combined zinc and phytase treatment was more related to a higher zinc dose (50 mg vs 10 mg) than the effect of the phytase. The improvement could have been based on the difference in zinc dose rather than the phytase. -Mark L. Moster, MD Sühs KW, Hein K, Sättler MB, Görlitz A, Ciupka C, Scholz K, Käsmann-Kellner B, Papanagiotou P, Schäffler N, Restemeyer C, Bittersohl D, Hassenstein A, Seitz B, Reith W, Fassbender K, Hilgers R, Heesen C, Bähr M, Diem R. A randomized, double-blind, phase II study on erythropoietin in optic neuritis. Ann Neurol. Epublished online ahead of print February 28, 2012. doi: 10.1002/ana.23573. Objectives: Based on findings in animal models of autoim-mune optic nerve inflammation, we have assessed the safety and efficacy of erythropoietin in patients presenting with a first episode of optic neuritis. Methods: Patients with optic neuritis who attended the University Hospitals of Homburg/Saar, Göttingen, or Hamburg (Germany) were included in this double-blind, placebo-controlled, phase II study (ClinicalTrials.gov, NCT00355095). They were randomly assigned to groups receiving either 33,000 IU recombinant human erythropoie-tin i.v. daily for 3 days, or placebo, as an add-on therapy to methylprednisolone. The primary outcome parameter was change in retinal nerve fibre layer (RNFL) thickness after 16 weeks. Secondary outcome parameters included optic nerve atrophy as assessed by magnetic resonance imaging, changes in visual acuity, visual field, and visual evoked potentials (VEPs). 288 Moster and Lee: J Neuro-Ophthalmol 2012; 32: 288-291 Literature Commentary Section Editors: Mark L. Moster, MD Michael S. Lee, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Results: Forty patients were assigned into either treatment group (21/19 erythropoietin/placebo). Safety monitoring revealed no relevant issues. Thirty-seven patients (20/17 erythropoietin/placebo) were analysed for the primary end-point according to the intention-to-treat protocol. RNFL thinning was less apparent after erythropoietin treatment: Thickness of the RNFL decreased by a median of 7.5 mm by week 16 (mean ± STD: 10.55 ± 17.54 mm) compared to a median of 16.0 mm (22.65 ± 29.18 mm) in the placebo group (P = 0.0357). Decrease in retrobulbar diameter of the optic nerve was smaller in the erythropoietin group (P = 0.0112). VEP latencies at week 16 were shorter in erythropoi-etin- treated patients than in the placebo group (P = 0.0011). Testing of visual functions revealed trends towards an improved outcome after erythropoietin treatment. Interpretation: These results give the first indications that erythropoietin might be neuroprotective in optic neuritis. This is an exciting Phase II trial of erythropoietin as neuroprotective agent in acute optic neuritis. When eryth-ropoietin was added to pulsed methylprednisolone and compared with placebo, there was less retinal nerve fiber layer (RNFL) thinning on Stratus optical coherence tomog-raphy (OCT), less delay in visual evoked potentials peak latency, and less atrophy of optic nerve on magnetic resonance image at 16 weeks. No serious adverse events were noted. Not surprisingly, visual function was not significantly different between placebo and erythropoietin groups, likely because patients had good visual recovery. However, low-contrast visual acuity was not tested and would have more chance at demonstrating a difference. Even if visual function was not affected in this study of acute optic neuritis, preservation of RNFL and therefore future "reserve" in the optic nerve is worthwhile and promising. -Mark L. Moster, MD Optic neuritis is a difficult disorder to study because of the natural history of near normalization of acuity and field. I agree, however, that the structural benefit on OCT is promising. I certainly like the idea of trying erythropoietin for optic neuropathies for the following reasons: 1. It is recognized as neuroprotective in multiple animal studies. 2. It is FDA approved for use in humans. 3. It is relatively safe. I look forward to future studies involving erythropoietin for optic neuropathies. -Michael S. Lee, MD Ragauskas A, Matijosaitis V, Zakelis R, Petrikonis K, Rastenyte D, Piper I, Daubaris G. Clinical assessment of noninvasive intracranial pressure absolute value measurement method. Neurology. 2012;78:1684-1691. Objective: To assess prospectively the accuracy and pre-cision of a method for noninvasive intracranial pressure (ICP) measurement compared with invasive gold standard CSF pressure measurement. Methods: Included were 62 neurologic patients (37 idio-pathic intracranial hypertension, 20 multiple sclerosis, 1 Guillain-Barré syndrome, 1 polyneuropathy, and 3 hydroceph-alus). The average age was 40 +/2 12 years. All patients had lumbar puncture indicated as a diagnostic procedure. ICP was measured using a noninvasive ICP measurement method, which is based on a two-depth high-resolution trans-cranial Doppler insonation of the ophthalmic artery (OA). The OA is being used as a natural pair of scales, in which the intracranial segment of the OA is compressed by ICP and the extracranial segment of the OA is compressed by extra-cranial pressure (Pe) applied to the orbit. The blood flow parameters in both OA segments are approximately the same in the scales balance case when Pe = ICP. All patients had simultaneous recording of noninvasive ICP values and inva-sive gold standard CSF pressure values. Results: Analysis of the 72 simultaneous paired recordings of noninvasive ICP and the gold standard CSF pressure showed good accuracy for the noninvasive method as indicated by the low mean systematic error (0.12 mm Hg; confidence level [CL] 0.98). The method also showed high precision as indicated by the low SD of the paired record-ings (2.19 mm Hg; CL 0.98). The method does not need calibration. Conclusion: The proposed noninvasive ICP measurement method is precise and accurate compared with gold standard CSF pressure measured via lumbar puncture. Here is the logic used in this study. The blood flow velocity of the intracranial segment of the ophthalmic artery is modulated by the intracranial pressure (ICP). A controlled pressure to the closed eyelid alters the blood flow velocity of the extracranial segment of the ophthalmic artery. When the blood flow parameters in both segments of the ophthalmic artery become equal, the external pressure should theoret-ically equal the ICP. Using a custom-made device, the authors used a transcranial Doppler to measure the blood flow in each segment. The external pressure device delivered the controlled pressure in steps of 4 mm Hg or 5.4 cm H2O (for reference, 1 mm Hg equals 1.36 cm H2O). The authors measured the opening pressure by lumbar puncture in the lateral decubitus position at the same time as the noninva-sive method and compared the results. This is an interesting concept, which could be of great value, because it is noninvasive and takes less than 10 minutes to perform. It could certainly represent a screening test for possible papilledema, and if the noninvasive pressures were borderline, then one could proceed with lumbar puncture. However, there are some issues here. Both measurements in this study occurred simultaneously, which opens the risk of unmasking. The number of patients tested is small, and it is unclear if the results could be affected by any local or systemic disorders such as hypertension, glaucoma, ophthal-mic artery stenosis, or occlusion and orbital disease. -Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2012; 32: 288-291 289 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. I agree with all of your concerns, Michael. The authors plan future studies conducted in the intensive care unit dealing with traumatic brain injury patients who have intraventricular ICP monitoring devices. This will provide data about whether the fluctuations in ICP can be picked up with this noninvasive technique and will study patients with markedly elevated ICP. Other factors that might affect the measurements, such as elevated intraocular pressure (IOP), also will have to be addressed in future studies. For instance, will this be valid with an IOP of 35 mm Hg? Nonetheless, this is an innovative study of what might become a valid noninvasive alternative for measuring ICP. -Mark L. Moster, MD Helenius J, Arsava EM, Goldstein JN, Cestari DM, Buonanno FS, Rosen BR, Ay H. Concurrent acute brain infarcts in patients with monocular visual loss. Ann Neurol. Epublished online ahead of print March 29, 2012. doi: 10.1002/ana.23597. Objective: Embolism from a proximal source to the retinal circulation could be a sign of embolism from the same source to the hemispheric circulation. We sought to de-termine the frequency of acute brain infarcts on diffusion-weighted imaging (DWI) in patients with monocular visual loss of presumed ischemic origin (MVL). Methods: We retrospectively studied 129 consecutive patients with MVL secondary to retinal ischemia. All patients underwent DWI, comprehensive ophthalmologic and neurologic examination, and diagnostic evaluations for the underlying etiology. Statistical analyses explored univariable and multivariable predictors of DWI evidence of acute brain infarcts. Results: DWI revealed concurrent acute brain infarct(s) in 31 of the 129 patients (24%). The probability of positive DWI was higher in embolic versus non-embolic MVL (28% vs. 8%, P = 0.04), in MVL characterized by permanent visual loss versus transient symptoms (33% vs. 18%, P = 0.04), and in MVL associated with concurrent hemispheric symp-toms versus isolated MVL (53% vs. 20%, P , 0.01). Patients with positive DWI were more likely to harbor a major underlying etiology as compared to those with normal DWI (OR 3.7, 95% CI 1.5-9.4). Interpretation: This study demonstrates that MVL does not always represent an isolated disease of the retina; approximately one out of every 4 patients with MVL demonstrates acute brain infarcts on DWI. Since patients with concurrent brain infarcts are more likely to exhibit a cardiac or vascular source of embolism, imaging evidence of brain injury in patients with MVL may be a useful marker to guide the timing and extent of the diagnostic examinations. It is not surprising that patients with monocular visual loss can have simultaneous ipsilateral brain ischemia, as found 24% of the time. It is also not surprising that those with hemispheric symptoms had a higher frequency of stroke on diffusion-weighted imaging (53%) than those with isolated monocular visual loss (MVL) (20%). Many neuro-ophthalmologists do not obtain a magnetic resonance image (MRI) of the brain in cases of transient MVL or even retinal artery occlusion. The results of this study suggest that it may be important to consider MRI of the brain in patients with isolated MVL. -Mark L. Moster, MD I clearly remember when I was an ophthalmology resident seeing patients with branch retinal artery occlusions who were not referred to a stroke neurologist or a neuro-ophthalmologist. They often were sent back to their primary care doctor. These patients often underwent an evaluation of their carotids and heart but did not undergo a systematic evaluation including neuroimaging. Many of our retinal colleagues should also read this article and consider a change to their practice. -Michael S. Lee, MD Kleiter I, Hellwig K, Berthele A, Kümpfel T, Linker RA, Hartung HP, Paul F, Aktas O. Neuromyelitis Optica Study Group. Failure of natalizumab to prevent relapses in neuromyelitis optica. Arch Neurol. 2012;69:239-245. Objective: To describe first experiences with the integrin inhibitor natalizumab, given to patients with suspected relapsing-remitting multiple sclerosis (MS) who were later diagnosed with aquaporin 4-positive neuromyelitis optica (NMO). Design: Retrospective case series. Setting: Neurology departments at tertiary referral centers in Germany. Patients: Patients with NMO who tested positive for anti-bodies to aquaporin 4. Intervention: Treatment with natalizumab. Main Outcome Measures: Relapses and accumulation of disability. Results: We identified 5 patients (4 female; median age, 45 years) who were initially diagnosed with MS and treated with natalizumab before diagnosis of NMO was established. Natalizumab was given as escalation therapy after failure of first- or second-line immunomodulatory therapies for MS. During natalizumab therapy (median duration, 8 infusions; range, 2-11 infusions), all 5 patients displayed persisting disease activity; a total of 9 relapses occurred (median duration to relapse, 120 days; range, 45-230 days) after the start of treatment. Four patients had an accumulation of disability and 1 patient died 2 months after cessation of natalizumab treatment. Conclusions: Our results suggest that natalizumab fails to control disease activity in patients with NMO. Neuromyelitis optica should be considered as a differential diagnosis in patients with suspected MS who are unresponsive to natalizumab therapy. These 5 patients were initially misdiagnosed with multiple sclerosis (MS) and treated with natalizumab before 290 Moster and Lee: J Neuro-Ophthalmol 2012; 32: 288-291 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. the correct diagnosis of neuromyelitis optica (NMO). Despite receiving a median of 8 natalizumab treatments, 2 patients experienced 1 relapse, 2 patients had 2 relapses, and 1 patient had 3 relapses. I would agree that anyone should rethink the diagnosis for any MS patient who fails natalizumab therapy. How-ever, this is such a small group of patients that one cannot conclude that natalizumab fails to control disease activity in patients with NMO. There may be many more NMO patients misdiagnosed with MS whose disease is well controlled on natalizumab therapy. We need better data! -Michael S. Lee, MD This anecdotal series does not provide scientific evidence but is enough to raise some clinical concerns. The diagnosis of NMO really did exist in 3 patients who had known longitudinally extensive spinal lesions before initiation of natalizumab; it just seems to have been overlooked. However, this report does add a few more cases to the literature demonstrating a poor therapeutic response and perhaps a worsening in NMO patients treated with conven-tional MS treatments. Because the outcomes in NMO patients without treatment are worse than with MS, I now send NMO antibody tests on all atypical, isolated optic neuritis patients. -Mark L. Moster, MD Platt D, Griggs RC. Use of acetazolamide in sulfonamide-allergic patients with neurologic channelopathies. Arch Neurol. 2012;69:527-529. Objective: To report the safe and successful use of the carbonic anhydrase inhibitor acetazolamide for treatment of patients with episodic ataxia and periodic paralysis who had been denied treatment because of a history of severe allergic reactions to antibiotic sulfonamides. Design: Case reports. Setting: University of Rochester Medical Center, Rochester, New York. Patients: A 61-year-old man with late-onset episodic ataxia, an 83-year-old woman with mutation-positive Andersen-Tawil syndrome, and a 21-year-old woman with mutation-positive episodic ataxia 2, all of whom had a history of severe skin rash with the use of sulfonamides for treatment of infection. Results: The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved sub-stantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction. Conclusions: These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide. Nonantibiotic sulfonamides are used for treatment of diseases such as type 2 diabetes mellitus, hypertension, and ion channelopathies. However, patients who might benefit from these medications have often been prohibited from taking them owing to fear of cross-reactivity between antibiotic and nonantibiotic sulfonamides. In patients with severe allergic responses to sulfonamide antibiotics, the risk of severe reaction with other sulfa-containing drugs such as acetazolamide was thought to outweigh potential benefits. However, recent studies of the chemical structure and mechanisms of immune response to these drugs suggest that cross-reactivity is unlikely. Furthermore, there is little clinical evidence supporting allergic cross-reactivity, and several case studies have found them safe in patients allergic to sulfonamide antibiotics. The authors report the successful treatment of 3 patients with a reported sulfonamide allergy who had channelopathies meriting treatment with acetazolamide. When treating patients with idiopathic intracranial hypertension (IIH), we are often limited when the patient has an allergy to sulfonamides. It usually restricts many of us from using acetazolamide, methazolamide, topiramate, and most diuretics. This report of 3 patients without allergic reaction to acetazolamide despite history of allergic skin reactions to sulfonamide antibiotics is encouraging. The article reviews the literature and suggests that the reactions to the antibiotics may be specific to their structure as sulfonylarylamines and may not predict allergy to the carbonic anhydrase inhibitors. I will be more comfortable carefully trying acetazolamide in the future for IIH based on this and other reports. -Mark L. Moster, MD About a decade ago, Strom et al (1) reported that patients with sulfa antibiotic allergy experienced more aller-gic reactions to sulfa diuretics than controls without an allergy. However, the sulfa antibiotic allergic individuals were also more likely to be allergic to other medications as well. This suggests that patients with allergy to one med-ication (e.g., sulfa antibiotic) are more apt to have an allergy to any other medication. Therefore, I tell IIH patients with a sulfa antibiotic allergy that they are at higher risk of developing an allergy to sulfa diuretics, but it does not represent cross-reactivity. It is because they are just "more allergic" than patients with no known drug allergies. -Michael S. Lee, MD 1. Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, Bilker WB, Pettitt D. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med. 2003;349:1628-1635. Moster and Lee: J Neuro-Ophthalmol 2012; 32: 288-291 291 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
