Which term describes a dimness of vision or the partial loss of sight without detectable disease of the eye?

Helen the Monkey

Much of the blindsight literature describes cases of partial blindness – that is, humans or animals with complete or incomplete homonymous hemianopsias, with some form of residual vision in the blind half of the visual field. Rather than starting with the hemianopic situation, I prefer to describe in some detail the best studied case of an adolescent monkey after almost complete surgical removal of the striate cortex (V1).

The monkey was called Helen by Humphrey and co-workers. Following her death 8 years after operation, her brain was studied. Pathologic analysis showed that the striate cortex was removed bilaterally, with the exception of a small island of left calcarine cortex that would correspond to a small portion of the far peripheral right upper visual field. If this visual island was functional, it was nowhere near the part of visual field involved in high acuity form vision.

Helen was carefully studied behaviorally and psychophysically. For the initial 19 months following operation, only light perception vision was apparent. Thereafter, the first visual function to recover was the ability to turn her head or eyes toward a moving object. After training, she could reach out for objects. Ultimately, she could recognize black objects against a light background, best done if the objects were presented in her central visual field. At this time, she appeared to have tunnel vision for stationary objects, but full-field movement perception. Reaching behavior was always preceded by fixating eye movements, and she did not reach for objects presented eccentrically without looking directly at them first. This was in contrast to normal monkeys who easily reach for eccentric objects without looking directly at them.

Approximately 5 years after operation, she was taken outdoors for walks. Initially, she collided with obstacles, but ambulatory vision improved almost daily. Soon she was recognizing trees and reaching out for branches with apparent judgment of depth. In the laboratory, her ability to recognize small objects (currants or pieces of chocolate) on a white floor became acute, but she grasped these objects with her palm rather than with her fingers. When she picked up objects, she was almost always ambulating, leading Humphrey to speculate that her judgment of distances was facilitated by self-motion and dynamic visual information rather than static visual information. She could move in and around three-dimensional objects placed around the room without difficulty. However, when a black piece of tape was placed on the floor surrounded by three-dimensional obstacles and she was allowed to roam the room, she would return to, and persist in trying to pick up, the same piece of tape even after multiple attempts.

She never learned to differentiate shapes. In other experiments, this was demonstrated by her inability to discriminate between a triangle and a circle surrounding a central black spot. Similarly, she could not discriminate between two circles of same size with only one having the central black spot. However, she could easily and accurately choose between a lone black spot and a circle with a black spot at its center. Other experiments were done with light stimuli of different luminances and color stimuli. All and all, it seemed that Helen’s focal, or central, vision had been significantly altered by removal of the striate cortex with preservation to large extent of her peripheral or ambulatory vision.

Visual Impairment

As discussed previously, increased ICP may translate into clinically evident papilledema. If left untreated, this may in lead to optic atrophy resulting in complete or partial blindness. In cases of unilateral coronal craniosynostosis, divergent or convergent nonparalytic strabismus may occur due to either orbital dystopia or abnormalities of the ocular muscles themselves. Some forms of craniosynostosis may involve orbital hypertelorism and may lead to compromised visual acuity and restricted binocular vision. Forms of craniosynostosis, causing restriction of forehead growth or recession of the supraorbital rims (unilateral coronal synostosis, Crouzon disease, and Apert syndrome), may cause an apparent exotropia requiring correction. Without correction, it places the patient at risk for corneal exposure and direct ocular trauma.17

Introduction

The occipital lobe encompasses the posterior portion of the human cerebral cortex and is primarily responsible for vision. The surface area of the human occipital lobe is approximately 12% of the total surface area of the neocortex of the brain. Direct electrical stimulation of the occipital lobe produces visual sensations. Damage to the occipital lobe results in complete or partial blindness or visual agnosia depending on the location and severity of the damage.

Vision begins with the spatial, temporal, and chromatic components of light falling on the photoreceptors of the retina and ends in the perception of the world around us. The occipital lobe contains the bulk of machinery that enables this process. However, the perception of the world is also affected by expectations and attention. Indeed, through extensive feedback to the occipital lobe and other lobes of the brain, especially the parietal and temporal lobes, general cognitive processes influence visual perception.

Pathogenesis of Diabetic Foot Ulcer

Certain foot deformities, past history of lower limb complications, reduced skin oxygenation and foot perfusion, poor vision, greater body mass and both sensory and autonomic neuropathy independently influence foot ulcer risk, thereby providing support for a multi-factorial etiology for diabetic foot ulceration.19

Many further factors in the causation of diabetic foot ulceration have been elucidated by numerous observational studies, such as peripheral sensory neuropathy, peripheral vascular disease (PVD), structural foot deformity, prolonged and elevated pressures due to compression, trauma, improperly fitted shoes, callus, history of prior ulcers/amputations, limited joint mobility, uncontrolled hyperglycemia, duration of diabetes, blindness/partial sight, chronic renal disease, older age etc.

Peripheral sensory neuropathy in the absence of perceived trauma is the primary factor leading to diabetic foot ulcerations.14 Approximately 45–60% of all diabetic ulcerations are purely neuropathic, while up to 45% have neuropathic and ischemic components.20 Other forms of neuropathy may also play a role in foot ulceration. Motor neuropathy can lead to foot deformities such as foot drop, equinus, hammer toes, and prominent plantar metatarsal heads.21 Autonomic neuropathy may commonly result in dry skin with cracking and fissuring, thus creating a portal of entry for bacteria.22 The alterations can subsequently be implicated in the pathogenesis of ulceration. Figure 15.1 represents an ulcer in dorsum with deformity.

PVD is defined as disease of any blood vessel that is not part of the heart or brain. It is most commonly reported in the lower extremities, and hence is also termed Lower Extremity Arterial Disease (LEAD). In a study of T2DM subjects, 4% had PVD, these included 15.1% with gangrene and 17.6% who had undergone amputations.18 Newly detected type 2 diabetics have 11% prevalence of PVD. Its revalence was 36% in patients with clinical proteinuria.23 Attempts to resolve any infection will be impaired due to lack of oxygenation and difficulty in delivering antibiotics to the site of infection. Early recognition and aggressive treatment of lower extremity ischemia is therefore vital for lower limb salvage. Trauma to the foot in the presence of peripheral sensory neuropathy is an important component cause of ulcerations. Shoe-related trauma has been identified as a frequent precursor to foot ulceration.20 Other factors often associated with heightened risk of ulceration include: nephropathy, poor diabetes control, blindness, advanced age, and poor nutrition.24

Transplantation of stem cells: where do we stand?

Permission to carry out a clinical trial in human volunteers or patients always requires substantial experimental evidence on how the therapy affects experimental animals both in terms of safety and effectiveness. The animals used for these experiments preferably have symptoms of the disease or condition to be treated (Fig. 7.9). The most commonly used experimental animals are mice because there are many different strains of mice with mutations in their DNA that are similar to those causing human disease. They are also fairly easy to handle and are relatively inexpensive to keep. Sufficient experience is available with respect to humane treatment of the animals, even when they do have particular diseases. In fact, some diseases in mice have very mild symptoms compared to, say, humans or even larger animals like dogs. This type of research in animals is called preclinical research. Many stem cell therapies in development are already at this stage which shows promise with respect to future clinical application. Below we provide examples of the status of some of these preclinical studies, the outcome of which essentially determines the chance at real clinical applications.

To date, most preclinical research with human pluripotent stem cells has been performed in mice. In addition, rats and pigs have also been used, with the advantage that these larger animals more closely reflect human physiology. One of the most interesting types of preclinical experiments has been the transplantation of differentiated stem cells to rats that were paralyzed and unable to walk because of an experimentally induced spinal cord lesion. Under anesthesia, the nerves of the spinal cord were either completely severed or crushed. After injection of embryonic stem cells that had been differentiated in the laboratory to oligodendrocytes (Fig. 7.10) the rats regained much of the ability to walk. Spectacular as films of these animals are to see, extrapolation to humans can only be made to a limited extent in terms of effectiveness. This is because in these rodents the spinal cord not only contains nerve extensions, as in humans, but also complete nerve cells. This suggests that electrical signaling from the brain with associated movement of the legs in these animals is organized differently compared to humans, implying that the therapeutic requirements for restoring nerves are also likely to be different. Moreover, the mechanism by which paralysis in the animals improved was unclear from the experiments: did the transplanted cells replace damaged cells, or did they just deliver a factor, that somehow induced repair of the damaged resident cells? Despite this reservation, expectations are understandably high. Whilst several trials have stopped because of insufficient resources, research toward clinical trials is ongoing primarily in China and Japan.

Parkinson’s disease, as we have also mentioned earlier in this chapter, is another potential candidate for stem cell therapy. Clinical experience has already been acquired in patients through transplantation of cells from the brains of aborted human fetuses into the brains of patients. Clinical results from a Swedish trial were initially promising, and symptoms like uncontrolled movements improved significantly in a number of patients. Unfortunately, during a later clinical trial in the United States, patients were observed where there seemed to be a cell “overdose,” leading to a disastrous increase in uncontrolled movements and inevitable stopping the trial. This event emphasized the extreme care that is required to introduce brain cell therapy in the clinic, but also highlighted the ethical issues associated with using human fetal abortion material. At one point, wealthy American patients were traveling to China to receive fetal brain cell transplants without evidence that the abortions were entirely voluntary, and it could not be excluded that pregnancies were established “for sale.” This issue would of course be redundant if established pluripotent stem cell lines were the source of cells for transplantation. Cells from these stem cell lines can be differentiated efficiently to nerve cells producing the molecule dopamine, which is produced in insufficient amounts by brain cells of patients with Parkinson’s disease. Transplantation of these cells into mice with a form of Parkinson’s indeed did alleviate some of the symptoms and the cells survived well in the mouse brain. In rats similar positive results were obtained. Most strikingly, nerve reflexes were partially restored so that rats could pick something up with a front paw after touching it with their whiskers. However, when the brains of these rats were analyzed, few surviving cells were detected (Fig. 7.11). This again raises questions on the mechanism underlying the improvement in paw reaction: could it be possible that the transplanted cells indirectly helped restore function, for example, by secreting one or more specific factors which stimulated the regenerative capability of the resident brain cells?

One of the most important discoveries of late though has been the realization that in the first patient studies, the right type of neurons might not have been transplanted, which caused a side effect known as kinesis. This is continuous and exhausting involuntary movement. In fact, the earlier prestudies on pluripotent stem cells tested in mice and rats may also not have used the right neurons. Evidence suggests that this may now have been solved and research toward a clinical trial has been financed in New York, with decisions pending in Lund (Sweden) and Cambridge (United Kingdom) (see Box 7.16).

We anticipate that the experiments described here are only the beginning of an era in which the benefit of stem cells will be explored for many more diseases. Clinical trials for stem cell treatment of Parkinson’s disease, macular degeneration, and diabetes are all close to commencement or have begun, as described earlier. Scientists are still discussing what Regenerative Medicine 2.0 will look like. Intestine? Lung? Liver? Inner ear?

Box 7.13

Stem cell therapy for macular degeneration

Macular degeneration is a common cause of partial blindness in the elderly. They lose their central field of vision, because of degeneration of the retina cells in the macular region of the eye (Figure B7.13.1). Although some vision remains, reading, for example, becomes nearly impossible for these patients, except with a magnifying glass. Therapy options are still very limited. Macular degeneration is often referred to as age-related blindness.

In March 2010 the FDA announced it had granted “orphan status” to a human embryonic stem cell therapy directed at providing a cure for a special rare form of macular degeneration in younger patients, called Stargardt’s macular dystrophy (SMD). This means that, because the disease is rare, it can be given what is called an “orphan” (or exceptional) status and can be developed for clinical application faster. The therapy first started being developed by a commercial company, called Advanced Cell Technology, and was already documented by several research groups to work in mouse and rat animal models for macular degeneration. Human embryonic stem cells or induced pluripotent stem cells differentiated to retinal pigment epithelial cells were placed by a surgical procedure underneath the retinal cell layer in the eye, and took over the function of the lost retinal cells in supporting the survival of the photoreceptors that lie on top of the epithelium. It requires exceptional surgical skills to place new epithelium under the photoreceptors. In 2012 a report was published in the Lancet, a medical journal, of the first clinical treatment of two patients with macular degeneration; one had the Stargardt’s form of macular degeneration and the other had the age-related form. The two patients also received drugs to prevent rejection of the transplanted cells. Although the goal of the study was to investigate safety of the treatment and very few retinal cells were actually delivered, the study raised hopes that once larger numbers of cells can be tested, vision may indeed improve. Within the short, 4-month follow-up time no side effects were detected and most importantly, no signs of teratoma (tumor) formation were found.

By 2019 more than 90 patients with the “dry” form of macular degeneration or SMD had been treated in one eye with a low cell dose as part of safety trials. Many had improved visual acuity (they could once more count an investigator’s fingers and see letters, something they had lost during the progress of the disease) in the treated eye whilst the other eye had continued to deteriorate. Japan has concentrated on the use of human induced pluripotent stem cells for the same purpose and in 2013 obtained permission from the regulatory authorities to treat the first patients. The next developments will include using stem cells to replace the photoreceptors that have been irreversibly lost, to extend the treatment to a broader group. Many millions of the elderly with macular degeneration eagerly await the outcome of these early trials for with this distressing condition. The “wet” form of the disease, however, remains untreatable (Figure B7.13.2).

2 Features of Migraine

Migraines comprise four phases: premonitory phase (also commonly referred to as the prodrome), aura, headache, and postdrome2,3 (Fig. 1). Studies have estimated that the number of patients with migraine who experience premonitory symptoms may range from as low as 37% to as high as 80%.4,5 The premonitory phase occurs hours to days before the actual headache and can be a reliable predictor of an upcoming migraine for some patients.4 This phase consists of symptoms that range in severity such as excessive yawning, food cravings, mood changes, fatigue, sore neck, and confusion among others.4–6 Following the premonitory phase is the aura phase that takes place up to an hour prior to the headache phase, but is only experienced by 15–30% of migraineurs. Aura involves sensory disturbances, often visual, with moving and intensifying regions of flashing lights or scintillations accompanied by partial vision loss or scotomas (areas of decreased acuity in the visual field). Scotomas are reported as typically originating in the center of a patient's visual field and progressing toward the edges.7 Aura may present other somatosensory symptoms that can affect normal motor function, perception of language, or even production of discernible language. The next phase is headache which must, by definition, be a minimum of 4 h but can last up to 72 h without medical intervention.7–9 It is described as moderate to severe throbbing pain, initially localized to one side of the head.7 The headache can be aggravated by repositioning of the head, by normal physical activity, or by changes in intracranial pressure, e.g., coughing or sneezing. Common symptoms that accompany the throbbing pain include sensitivity to light, sounds, and smells, also commonly referred to as photophobia, phonophobia, and osmophobia, respectively, although the first two are more correctly described by the terms photo- and phonoallodynia as these stimuli cause pain. Additionally, nausea and vomiting are common during the headache phase. After the headache has resolved, it can often be followed by a postdrome phase where the patient still does not feel recovered or entirely back to normal. The postdrome can typically last from 18 to 24 h and often consists of exhaustion, irritability, and an inability to concentrate.7

Migraine currently lacks a known cause or source that can be identified as the driver of the disorder. Nonetheless, individual patients may be susceptible to distinct stimuli that are capable of evoking a migraine. These stimuli, referred to as triggers (Fig. 1), can vary between individuals and yet they share the commonality of eliciting a migraine attack. However, it should be noted that these triggers do not exhibit a noxious effect in nonmigraine sufferers and therefore are not the true source of the condition. Sensitivity to triggers in migraine patients suggests the presence of maladaptive plasticity in the nervous system (discussed below) that contributes to the development of attacks in response to stimuli that are innocuous in normal individuals.

One extremely common trigger in those susceptible to migraine is stress. In fact, studies demonstrate that anywhere from 59% to over 80% of patients indicate that stress is their primary trigger for migraine,10–12 thus making stress the most commonly reported trigger. The effect of stress exposure may be cumulative. Stress appears to have a greater influence with two consecutive days of moderate or greater stress in a row. On the other hand, low stress followed by a day with moderate or greater stress on the subsequent day is associated with less risk.9 Conversely, this study also found that if stress is moderate or greater on the first day, but low on the following day the migraine risk is still increased, thus suggesting a complex relationship between stress and migraine. Recent reports also show that the peak susceptibility to migraine is in the 18–24 h after a stressful event,13 further supporting the complex nature of the contribution of stress to migraine. It is hypothesized that stress itself may not be the trigger; however, it may evoke changes in normal behaviors such as sleep or food intake that can aggravate the condition.14 Patients able to identify their triggers can benefit and potentially reduce migraine attacks by minimizing their encounters with that particular stimulus (or stimuli).15 Other common triggers include foods (and alcohol), environmental irritants (cigarette smoke, odors), exercise, changes in the environment (barometric pressure), too much/lack of sleep, hormone fluctuations, sensory stimuli (such as intense light), and skipping meals. Notably, drugs such as nitric oxide donors (e.g., nitroglycerin) are capable of eliciting headaches reliably among migraineurs,16 an important observation since NO donors are often used to experimentally trigger attacks in clinical studies.

Compressive optic neuropathy

The optic nerves can be compressed by various pathologies. Compression initially leads to venous occlusion, nerve fiber edema, and partial vision loss that are potentially reversible with early surgical decompression. Prolonged pressure can cause arterial occlusion, optic nerve infarction, and permanent vision loss.40 Typically, patients present with subacute to chronic vision loss with optic nerve atrophy. Patients tend to present early when the lesions involve the optic canal. Contrast-enhanced MR imaging is the modality of choice to evaluate the underlying cause (Fig. 9). Common causes of compressive neuropathy are discussed below.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune inflammatory disease secondary to excessive thyroid-stimulating hormone receptor antibodies, which cross-react with extraocular muscles and retrobulbar soft tissue.41 TAO may occur before, during, or after hyperthyroidism.42 Occasionally, patients with euthyroid may also be affected. CT and MR imaging are valuable in the diagnosis and treatment assessment. On imaging, eyelids, lacrimal glands, and bellies of the extraocular muscles (inferior > medial > superior > lateral recti) are swollen with sparing of the tendinous insertion.43 Rarely, the disease involves only a single muscle or primarily involves the lateral rectus.1 There is increase in the volume of retrobulbar fat, resulting in proptosis.44 The enlarged muscles can compress the optic nerve at the orbital apex, causing compressive optic neuropathy, which can present in patients with only mild proptosis.44 Intensity of the most affected muscle measured on short tau inversion recovery sequence correlates with clinical disease activity.45 Hypodensity in the muscle bellies seen on CT represents glycoaminoglycans or lymphocyte infiltration (Fig. 10).1 Later the muscles are replaced by fat.

The intracranial optic nerve is in close proximity to the supraclinoid internal carotid artery, anterior cerebral artery, and anterior communicating artery.1 The intraorbital segment is in close relation to the ophthalmic artery. Aneurysms of these arteries can directly compress or rupture into the nerve (Fig. 11).46,47 Vision loss can fluctuate because of changes in size of the aneurysm.1 Acute monocular vision loss with severe headache and neck stiffness strongly suggest aneurysm rupture, prompting emergent neuroimaging and intervention.47

The lateral walls of the sphenoid or posterior ethmoid sinuses (Onodi cell) form the medial wall of the orbit and the optic canal. Mucoceles of these air cells can directly compress the optic nerve.48 The presence of active infection in the mucocele and initial poor vision are important prognostic factors for visual outcome regardless of the origin of the mucoceles.48 Infection can directly spread to involve the optic nerve through a dehiscent wall and nutrient foramina, resulting in optic nerve ischemia.49 Presence of vision loss in patients with sphenoid/ethmoid sinus mucocele mandates early surgical drainage.48 Sinus expansion and wall erosion are common in allergic fungal sinusitis (AFS), which may lead to optic nerve compression (Fig. 12). Direct invasion of fungus in AFS into the optic nerve is found in a series of case studies.40

1 Introduction

Formulation development of novel drug delivery systems in the area of eye are one of the most challenging because eye as an organ is most sensitive to work on. Human eye has a spherical shape with diameter of 23–24 mm and is divided into two major segments that is anterior and posterior segment [1]. The anterior part of the human eye has cornea, iris, aqueous humor, ciliary body, conjunctiva; while the sclera, retina, choroid, optic nerve forms the posterior part of the eye [2]. Anterior segment diseases include glaucoma, cataract, conjunctivitis, anterior uveitis while posterior segment diseases include age related macular dysfunction (AMD), retinitis pigmentosa (RP), diabetic retinopathy. In most of these disease there is a chance of partial vision loss or complete blindness. Presently the different approaches to treat ocular diseases include topical eye drops, oral therapy by tablets, intrascleral and intravitreal injection [3]. Topical and systemic route of administering drugs result in low therapeutic drug levels due to multiple ocular barriers, requiring administration of unnecessarily high concentrations of which leads to toxicity [4]. It was estimated that around 285 million people are suffering from vision problem, in which the population of totally blind affected individuals are around 39 million and approximately 246 million population have low vision [1]. The conventional drug delivery for eye suffers from drawbacks of needing repeated drug administration which leads to patient non-compliance. These issues arise the need to have novel drug delivery systems to provide not only the sustained drug action but also targeted delivery to overcome the drawbacks of the conventional therapy [4].

Among the various novel drug delivery systems, injectable formulations have the most impactful application as they can deliver the right amount of drug in the desired area of the eye. Conventional hypodermic needles are used for giving therapy through intraocular injections. There are various routes through which these intraocular injections are given namely, subconjuctivial, periocular, intravitreal (IVT), intracorneal etc. Considering this, some of the disadvantages associated with intraocular injections are invasive nature, frequent application of injections leads to non-compliance and also less bioavailability [4–6].

Microneedles (MNs) are devices made up of polymer or metal having dimensions in the range of few micrometres to 200 μm. MNs have micro sized projections which makes them minimal invasive in nature. These MNs are able to not only overcome the disadvantages associated with the presently used conventional delivery systems but also are able to cross the ocular barriers to specifically target the drugs at the needed site of action. MNs as a technique is efficient enough for expediting percutaneous drug delivery. Other than the promising role MNs have shown in eye treatment they are also useful in percutaneous delivery across the oral mucosal, GIT and even nail. These micron sized needle have easy insertion on to the eye for various types of applications. As compared to the traditional hypodermic needles these are less painful and may be formulated to release the drug over a period of extended time. Hence, would not be required to be administered repeatedly [7].

This review article reflects the therapeutic applications of MNs in several ocular diseases. There are various obstacles associated with the conventional ocular delivery system, the article provides an insight of how MNs overcome these obstacles and provide effective drug delivery. Among various types of ocular diseases some of them are glaucoma, age-related macular degeneration, uveitis, retinal vascular occlusion and retinitis pigmentosa are majorly discussed. The article gives brief explanation of various studies conducting on the use MNs in these ocular diseases, which is directed to give advantage to the researcher to work on in this area.