Multiple sclerosis: natural history, diagnosis and changes in the brain

This article describes the general symptoms, diagnosis and changes in the nervous system in multiple sclerosis. A second article will describe the specific visual symptoms which are believed to be characteristic of the disease.

Ophthalmological manifestations of multiple sclerosis

Optic neuritis, as a result of the formation of demyelination plaques in the optic nerve, is one of the commonest early symptoms of multiple sclerosis. Hence, it is important that optometrists are aware of the symptoms of optic neuritis and of the conditions with which it can be confused. However, only a proportion of patients with optic neuritis will develop the symptoms of multiple sclerosis. The first part of the article describes the symptoms and differential diagnosis of optic neuritis and its relationship with multiple sclerosis. In the second part of the article, the variety of visual changes and symptoms which can be observed in multiple sclerosis patients will be described.

Oligodendrocyte pathology in neurodegenerative disease

Oligodendrocytes have multiple functions in the central nervous system including mechanical support of neurons, production of myelin sheaths, and uptake and inactivation of chemical neurotransmitters released by neurons. Consequently, oligodendrocytes could be involved in the pathology of a number of neurodegenerative diseases. Although, the molecular mechanisms involved require further elucidation, it is likely that oligodendrocyte dysfunction is important in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In addition, abnormal protein aggregates in the form of oligodendrocyte inclusions (OI) have been observed in several other disorders, most notable in multiple system atrophy (MSA), in which the glial cytoplasmic inclusion (GCI) is the ‘signature’ pathology of the disease. OI have also been identified in argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) (Armstrong et al 2007), and various forms of frontotemporal lobar degeneration (FTLD) (Armstrong et al 2010), although their role in the pathology of these disorders is less clear. It is likely that future research will expand the range of disorders in which oligodendrocytes play a significant role in neurodegeneration.

Recent advances in the development of tissue transglutaminase (TG2) inhibitors

Tissue transglutaminase (TG2) is a Ca2+-dependent enzyme and probably the most ubiquitously expressed member of the mammalian transglutaminase family. TG2 plays a number of important roles in a variety of biological processes. Via its transamidating function, it is responsible for the cross-linking of proteins by forming isopeptide bonds between glutamine and lysine residues. Intracellularly, Ca2+ activation of the enzyme is normally tightly regulated by the binding of GTP. However, upregulated levels of TG2 are associated with many disease states like celiac sprue, certain types of cancer, fibrosis, cystic fibrosis, multiple sclerosis, Alzheimer's, Huntington's and Parkinson's disease. Selective inhibitors for TG2 both cell penetrating and non-cell penetrating would therefore serve as novel therapeutic tools for the treatment of these disease states. Moreover, they would provide useful tools to fully elucidate the cellular mechanisms TG2 is involved in and help comprehend how the enzyme is regulated at the cellular level. The current paper is intended to give an update on the recently discovered classes of TG2 inhibitors along with their structure-activity relationships. The biological properties of these derivatives, in terms of both activity and selectivity, will also be reported in order to translate their potential for future therapeutic developments. © 2011 Springer-Verlag.

Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.

Reducing suffering in experimental autoimmune encephalomyelitis (EAE)

This report is based on discussions and submissions from an expert working group consisting of veterinarians, animal care staff and scientists with expert knowledge relevant to the field. It aims to facilitate the implementation of the Three Rs (replacement, reduction and refinement) in the use of animal models or procedures involving experimental autoimmune encephalomyelitis (EAE), an experimental model used in multiple sclerosis research. The emphasis is on refinement since this has the greatest potential for immediate implementation. Specific welfare issues are identified and discussed, and practical measures are proposed to reduce animal use and suffering. Some general issues for refinement are summarised to help achieve this, with more detail provided on a range of specific measures to reduce suffering. © 2013 Elsevier Inc.

Spatial topography of the neurofibrillary tangles in cortical and subcortical regions in progressive supranuclear palsy

Objective: To study the topography of neurofibrillary tangles (NFT) in cortical and subcortical areas in progressive supranuclear palsy (PSP). Methods: Pattern analysis was carried out on tau-positive NFT in eight PSP cases. Results: Of the areas studied, NFT were randomly distributed in 68%, regularly distributed in 3%, and clustered in 29%. A regular distribution of clusters was more frequent in cortical than subcortical areas. Conclusion: NFT topography in subcortical areas was similar to inclusions in the synucleinopathy multiple system atrophy (MSA) but in cortical areas was comparable to other tauopathies. © 2006 Elsevier Ltd. All rights reserved.

Progressive supranuclear palsy (PSP): general pathology and visual signs and symptoms

Progressive supranuclear palsy (PSP) is a rare, degenerative disorder of the brain believed to affect between 1.39 and 6.6 individuals per 100,000 of the population. The disorder is likely to be more common than suggested by these data due to difficulties in diagnosis and especially in distinguishing PSP from other conditions with similar symptoms such as multiple system atrophy (MSA), corticobasal degeneration (CBD), and Parkinson’s disease (PD). PSP was first described in 1964 by Steele, Richardson and Olszewski and originally called Steele-Richardson-Olszewski syndrome. The disorder is the second commonest syndrome in which the patient exhibits ‘parkinsonism’, viz., a range of problems involving movement most typically manifest in PD itself but also seen in PSP, MSA and CBD. Although primarily a brain disorder, patients with PSP exhibit a range of visual clinical signs and symptoms that may be useful in differential diagnosis. Hence, the present article describes the general clinical and pathological features of PSP, its specific visual signs and symptoms, discusses the usefulness of these signs in differential diagnosis, and considers the various treatment options.

Visual signs and symptoms of progressive supranuclear palsy

Progressive supranuclear palsy is a rare, degenerative brain disorder and the second most common syndrome in which the patient exhibits 'parkinsonism', that is, a variety of symptoms involving problems with movement. General symptoms include difficulties with gait and balance; the patient walking clumsily and often falling backwards. The syndrome can be difficult to diagnose and visual signs and symptoms can help to separate it from closely related movement disorders such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies and corticobasal degeneration. A combination of the presence of vertical supranuclear gaze palsy, fixation instability, lid retraction, blepharospasm and apraxia of eyelid opening and closing may be useful visual signs in the identification of progressive supranuclear palsy. As primary eye-care practitioners, optometrists should be able to identify the visual problems of patients with this disorder and be expected to work with patients and their carers to manage their visual welfare.

General features of Multiple System Atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of a group of neurodegenerative diseases referred to collectively as the ‘parkinsonian syndromes’. Characteristic of these syndromes is that the patient exhibits symptoms of ‘parkinsonism’, viz., a range of problems involving movement, most typically manifest in Parkinson’s disease (PD) itself1, but also seen in progressive supranuclear palsy (PSP), and to some extent in dementia with Lewy bodies (DLB). MSA is a relatively ‘new’ descriptive term and is derived from three previously described diseases, viz., olivopontocerebellar atrophy, striato-nigral degeneration, and Shy-Drager syndrome. The classical symptoms of MSA include parkinsonism, ataxia, and autonomic dysfunction.6 Ataxia describes a gross lack of coordination of muscle movements while autonomic dysfunction involves a variety of systems that regulate unconscious bodily functions such as heart rate, blood pressure, bladder function, and digestion. Although primarily a neurological disorder, patients with MSA may also develop visual signs and symptoms that could be useful in differential diagnosis. The most important visual signs may include oculomotor dysfunction and problems in pupil reactivity but are less likely to involve aspects of primary vision such as visual acuity, colour vision, and visual fields. In addition, the eye-care practitioner can contribute to the management of the visual problems of MSA and therefore, help to improve quality of life of the patient. Hence, this first article in a two-part series describes the general features of MSA including its prevalence, signs and symptoms, diagnosis, pathology, and possible causes.

Visual signs and symptoms of Multiple System Atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of a group of neurodegenerative diseases, which include Parkinson’s disease (PD) and progressive supranuclear palsy (PSP), and referred to as the ‘parkinsonian syndromes’. Although primarily a neurological disorder, patients with MSA may also develop visual signs and symptoms that could be useful in differential diagnosis. In addition, the eye-care practitioner may contribute to the management of visual problems of MSA patients and therefore, help to improve quality of life. This second article in the series considers the visual signs and symptoms of MSA with special reference to those features most useful in differential diagnosis of the parkinsonian syndromes.

Visual signs and symptoms of multiple system atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of the 'parkinsonian syndromes', which also include Parkinson's disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB) and corticobasal degeneration (CBD). Multiple system atrophy is a complex syndrome, in which patients exhibit a variety of signs and symptoms, including parkinsonism, ataxia and autonomic dysfunction. It can be difficult to separate MSA from the other parkinsonian syndromes but if ocular signs and symptoms are present, they may aid differential diagnosis. Typical ocular features of MSA include blepharospasm, excessive square-wave jerks, mild to moderate hypometria of saccades, impaired vestibular-ocular reflex (VOR), nystagmus and impaired event-related evoked potentials. Less typical features include slowing of saccadic eye movements, the presence of vertical gaze palsy, visual hallucinations and an impaired electroretinogram (ERG). Aspects of primary vision such as visual acuity, colour vision or visual fields are usually unaffected. Management of the disease to deal with problems of walking, movement, daily tasks and speech problems is important in MSA. Optometrists can work in collaboration with the patient and health-care providers to identify and manage the patient's visual deficits. A more specific role for the optometrist is to correct vision to prevent falls and to monitor the anterior eye to prevent dry eye and control blepharospasm.