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February 2007

 
Clinical Update: Neuro-Ophthalmology
Hemianopia: A Treatment Attracts Turmoil, Part One
By Denny Smith, Senior Editor
 
 

Vision commands the attention of the central nervous system like no other sense. From tear film on a clear cornea to the vanishing ends of the ventral stream, vision-dedicated structures constitute what may be the most elaborate functional system of the conscious mind.

With so many neurologic riches, the visual system might naturally be expected to profit from the potential of the brain to repair from or at least adapt to injury to itself. And that is exactly what one small company is suggesting: neurogenic visual field defects once thought to be irreversible can indeed, with its treatment, be reversed.

But the limits of neuroplasticity, and the efficacy of that treatment, have fallen under the scrutiny of some neuro-ophthalmologists who say they doubt the device works and want to see proof of the company’s assertions.

Venturing Into the Void

The Florida-based company NovaVision is now marketing Vision Restoration Therapy (VRT), which it describes as a noninvasive therapy “intended for the diagnosis and improvement of visual functions in patients with impaired vision that may have resulted from stroke, trauma, inflammation, surgical removal of brain tumors or brain surgery.”

VRT is based on a straightforward idea. A patient with homonymous hemianopia, for example, sits at a VRT monitor and responds to a perimetry program tailored to present stimuli to the patient’s transition zone, the borderline of their defect. The patient’s course of treatment, which costs around $6,000, is done at home, and the hour-long exercise is repeated six times a week for six to seven months. The aim is to reinvigorate the frontier between impaired and still-functioning cells, on the assumption that neurons which survived the original injury can, with encouragement, make new connections with neighboring cells to produce compensatory visual information.

Misha L. Pless, MD, associate professor of neurology at Harvard University and member of NovaVision’s scientific and medical advisory board, explained, “The cells at the border zone of injury are working at ‘half-mast,’ and will themselves become unusable without stimulation. Examples of this have been well-reported for the motor cortex, in particular.” Dr. Pless acknowledges that a response to injury by the growth of new connections between “bystander” neurons is not universally accepted. “My own take on it is that among these cells there are old but viable connections not currently in use, and they may be called back into service by constant and focused stimulation.”

NovaVision’s Web site tells patients that “VRT is a clinically proven, FDA-cleared technology designed to improve the quality of life of stroke and brain injury patients by restoring some of your lost vision. The therapy does not require surgery or medication of any kind. Over 800 patients have been treated with VRT, and in a recent retrospective study more than 65 percent of patients who completed VRT showed measurable improvements in their vision, which enhanced their quality of life.” (Note: FDA clearance is not the same as FDA approval, a topic that will be discussed next month in Part Two.)

Parsing the Promises

NovaVision’s optimistic assertions have raised some eyebrows in the neuro-ophthalmology community, according to Peter J. Savino, MD, director of the neuro-ophthalmology service at Wills Eye Hospital and chairman of ophthalmology at Graduate Hospital in Philadelphia. To begin with, he said that the description of VRT as “clinically proven” is a stretch, because it implies that a rigorous, controlled study was conducted and demonstrated a significant recovery of visual fields.

That is not currently the case. NovaVision has published some studies describing visual field improvement, but the patients were tested with the same perimetry software that was used for their treatment, rather than with standardized perimetry, which is considered a reliable control for fixation.

That was a mistake in methodology, according to Michael Wall, MD, professor of neurology and ophthalmology at the University of Iowa. “If you’re trying to find out if a treatment works, you should use an independent method to test it. And an independent measure for fixation that all could agree on would be standard automated perimetry.”

Two studies show no objective improvement. In fact, the few published trials of VRT in which fixation was carefully controlled did not yield positive results. One was commissioned by the German health service and conducted by, among others, Bernhard A. Sabel, PhD, the founder of NovaVision and a professor and chairman of medical psychology at the University of Magdeburg, and Susanne Trauzettel-Klosinski, MD, an internationally recognized visual field expert at University Eye Hospital in Tübingen. The participants in that study were treated for homonymous hemianopia with VRT, and were then tested by Dr. Trauzettel-Klosinski with a scanning laser ophthalmoscope. No objective improvement in the visual field was measured. This small study was published in 2005 in the British Journal of Ophthalmology, and has become the nexus of a flurry of opinions published there1,2 and elsewhere.3

Another study, published in Neurology and also conducted by Tübingen researchers, including Dr. Trauzettel-Klosinski, tested patients with threshold-oriented, slightly supraliminal, static automated grid perimetry, using the Tübingen Automated Perimeter 30° test, and found that VRT had little effect on results.4

Controlled fixation is the only way to ensure that changes in the visual field have truly taken place, and are not artifacts of the patients unintentionally enhancing their blind field by “sneaking” surveillance from their seeing field, said Jonathan C. Horton, MD, professor of ophthalmology at the University of California, San Francisco. Dr. Horton is the author of one of the opinions on VRT published in the BJO.1

But what about subjective improvement? It may be useful to consider the subjective reports of patients who say that their vision has improved with VRT and who feel they are more fully functional in their activities of daily living. NovaVision can provide a number of anecdotal reports from both patients and physicians describing the benefits of VRT. These might be explained as true benefits of VRT or, alternatively, as adaptations unrelated to the treatment’s intent, such as head tilts or more aggressive saccadic sweeps toward the blind hemifield. One report delivered at last year’s meeting of the North American Neuro-Ophthalmology Society (NANOS) noted both possibilities: that hemianopia patients often do improve with such oculomotor adaptations and that constant retraining of neurons close to the border of the blind hemifield—as VRT is designed to do—could possibly, incrementally, extend the seeing hemifield, a process evocatively called “perceptual bootstrapping.”5

Another member of NovaVision’s scientific advisory board, Jose G. Romano, MD, disagrees with the premise that improvement measured by NovaVision’s perimetry is an artifact of eye movement. Dr. Romano, who is an associate professor of neurology at the University of Miami, has given VRT therapy to about 40 patients. He said the fixation stimulus that NovaVision uses is part of a suprathreshold perimetry employing an isoluminant change of color and offers excellent fixation. “If you move your eyes just a few degrees off center, you have a very difficult time registering the change of color,” he said. “And even if you think that eye movement accounts for the improvement, then you would expect to see the entire border between the hemifields shift toward the blind side. But that doesn’t happen. We have many patients who improve in one area of their field, but not another. And that just wouldn’t be explained by errant horizontal saccades.”

From the Dark, Some Light

Visual field loss stems from an interruption of the peri- or postchiasmal visual pathway, and can be caused by stroke, trauma and neoplastic or autoimmune processes. Historically, it has not been considered treatable. Lucky patients may spontaneously recover some vision, but many are consigned to permanent, if partial, blindness.

Ironically, for all the troubling darkness they cast over patients’ lives, field defects open an elegant window onto the decussated anatomy of the visual pathway. The theory that some fibers from each optic nerve cross over at the chiasm and traverse the opposite hemisphere of the brain was first proposed by Isaac Newton and then established in the 19th century by Bernhard von Gudden. For neuro-ophthalmologists, it means that the symmetry, or lack thereof, in hemi- and quadrantanopias offers a virtual blueprint for the location of the lesion or trauma responsible for the defect. Damage to one optic nerve, for example, will cause visual loss only in the eye it serves. But damage at the chiasm can cause bitemporal defects, when crossed fibers are involved, and interruptions beyond the chiasm result in homonymous defects respecting the vertical meridian.

More Data Please

Another persuasive test that NovaVision could do, said Dr. Wall, is a multifocal visual evoked response, which would measure the electrical potential in the visual system. This does not rely on the patient’s attention, and could neutralize the contention over drifting fixation.

In any event, Drs. Savino, Wall and Horton all say that since the Tübingen studies, NovaVision has not produced more compelling, independently verified data, and yet has continued to assert the benefits of VRT at recent meetings of NANOS. “NovaVision continues to claim their patients improved, but how did they improve? Did they improve with real visual fields, or with the laptop apparatus?” Dr. Savino asked.

“At bottom, I don’t think the evidence supporting VRT is adequate, and I just don’t really think it works,” Dr. Horton said. Both he and Dr. Savino say that the only way to determine the value of VRT would be for NovaVision to put marketing on hold and instead ask physicians with no financial interests in VRT to carry out well-powered, controlled, verifiable studies.

Dr. Pless is quick to say he is very much in favor of new, well-designed studies of the effect and benefit of VRT. “We are all very interested in fresh, independent data. I don’t believe any of us in the field of visual sciences is fully satisfied with the results of the German trials.”

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1 Horton, J. C. Br J Ophthalmol 2005;89:1–2.
2 Reinhard, J. et al. Br J Ophthalmol 2005;89:30–35.
3 Sabel, B.A. and Trauzettel-Klosinski, S. J Neuro-Ophthalmol 2005;25(2):143–149.
4 Schreiber, A. et al. Neurology 2006;67:143–145.
5 Huxlin, K. R. The Plasticity of Visual Perception After Permanent Damage to the Adult Visual Cortex, NANOS, 32nd Annual Meeting, 2006, Feb. 26–Mar. 2.

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Dr. Horton has no related financial interests. Drs. Pless and Romano were given option grants for serving on NovaVision’s scientific and medical advisory board, but have no other related interests. Drs. Savino and Wall have no related interests.

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