Monday, 29 April 2013

4-aminopyridine improves visual function

4AP or 4-aminopyridine helps MSers visual function. #MSBlog #MSResearch

"As you are aware MS often affects the optic nerves and may cause long standing visual dysfunction. Before getting to this studies results you need to understand about the tests we use to assess visual function."

"Visual acuity (VA) is what we measure using a wall chart; it simply tells us how good your vision is relative to normals. For example a visual acuity of 6/12 means that what you can see at 6m a normal person can see at 12m; in some parts of the world neurologists still use imperial charts that are in feet, i.e. 6/12 (meters) is 20/36 (feet)."


Visual acuity chart; this one is calibrated in feet.

"To assess how quickly the optic nerve conducts electrical impulses we use visual evoked potentials (VEPs). VEPs report several measures; with the P100 being the most common index used. The P100 stands for positive wave that occurs around 100 milliseconds in normal subjects. If you have had optic neuritis the P100 is delayed and you get a reading that is typically more than 108 milliseconds. If you have a drug that improves conduction velocity it will reduce the P100, i.e.improve conduction speed."



"OCT or optical coherence tomography is a relatively new way of assessing the retina or layers of nerves at the back of the eye. OCT uses light to measure the thickness of the nerve fibre layer. A typical attack of optic neuritis results in a loss of approximately 20% of the nerve fibres."



"This study shows that 4-aminopyridine or 4AP  improves visual function and conduction in eyes previously damaged by optic neuritis. 4AP is a drug that has been around for decades and was typically produced by compounding pharmacies, as it was never formally licensed for any indication. More recently it has been formulated as a slow-release formulation that is called fampridine. Fampridine has been licensed to improve walking speeds for MSers with walking difficulties. Once a drug becomes licensed it becomes illegal under EU law to continue formulating it therefore we can't prescribe 4AP in the EU, but only fampridine.  Fampridine costs a lot more than 4AP does and this has caused problems in many countries, notably The Netherlands and Switzerland. In these countries formulating pharmacies have apparently been threatened with legal action if they did not stop formulating the 4AP. This is an example of legislation that has been designed to protect innovators, by preventing other drugs or copies been made."

"This study, and others, has led to additional clinical trials in MSers with visual dysfunction post optic neuritis; some MSers are quite disabled by intermittent visual blurring as a result of temperature changes and fatigue. Watch this space."

Epub: Horton et al. Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy. Neurology. 2013.

OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled, crossover study was to examine if MSers with optic neuropathy would derive a therapeutic benefit from 4-aminopyridine (4-AP) treatment. Furthermore, the study was intended to determine if MSers with certain P100 latencies or retinal nerve fiber layer (RNFL) measures would be more likely to respond to therapy.

METHODS: MSers were enrolled in a randomized, placebo-controlled, double-blind, crossover study of 10 weeks duration. MSers underwent visual evoked potentials (VEP), optical coherence tomography (OCT), and visual acuity before starting 5 weeks of either placebo or 4-AP. After 5 weeks, they completed a second evaluation (VEP, OCT, and visual acuity) and were crossed over between treatment arms. Five weeks later, they had their final evaluation. All investigators were blinded to treatment arm until after data analysis.

RESULTS: On average, MSers had faster P100s on 4-AP when compared to placebo. A subset of MSers had distinct responses to 4-AP as measured by improvements in visual acuity. Finally, eyes with an RNFL measure between 60 and 80 µm had the highest response rate.

CONCLUSIONS: 4-Aminopyridine is useful for improving vision in MSers with demyelinating optic neuropathy. Future clinical trials may be able to enrich a MSer population for potential responders using OCT and VEP measures. Selecting MSers for future trials should use RNFL measures as part of inclusion/exclusion criteria.

CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence supporting the use of 4-AP in certain MSers with optic neuropathy to improve visual function (MSers with RNFL between 60 and 80 µm).

Clinical trial of Ampyra for Optic Neuritis in MS, ClinicalTrials.gov Identifier: NCT01337986

2 comments:

  1. The use of ampyra in the U.S. for walking improvement by blocking a subset of K channels is not new. It is not surprising that other beneficial effects would occur. Why is the use of phenytoin and amiloride Na channel blockers not expedited? Ion imbalance in demyelination is nothing new. Wish the FDA would stop dragging their feet too.

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  2. I thought Fampridine is licensed to improve walking, not vision so would use of 4-AP for vision still be a possibility until fampridine is licensed for optic nerve problems?

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