Amyotrophic Lateral Sclerosis (ALS): The Diagnosis and Treatment of this Debilitating Disease

In 1869, french neurologist Jean-Martin Charcot first described a rapidly progressive, fatal neuromuscular disease. This disease, amyotrophic lateral sclerosis, or Lou-Gehrig's disease, is a neurodegenerative disorder that affects the patient's motor neurons; typically the patient is paralyzed or deceased within 2 to 5 years of the initial diagnosis. Currently, approximately 3000 Canadians suffer from this tragic disease.

Andrew Eisen MD, FRCPC
Professor and Head, Division of
Neurology, University of British Columbia,
Head of the Neuromuscular Diseases Unit,
Vancouver General Hospital

Amyotrophic lateral sclerosis (ALS) is a prototypic neurodegeneration of the aging nervous system. It has a worldwide incidence of about 2 per 100,000 members of the population and a prevalence of 4&endash;7 per 100,000. As is true of both Parkinson's and Alzheimer's disease, the incidence of ALS is increasing proportional to the increasing longevity of the population. Information regarding the specific incidence of ALS in the elderly (aged 75 years and older) is sparse. The apparent decrease in incidence of this disease in patients older than 70 years reflects mortality from competing diseases in later life.

The etiopathogenesis of ALS is complex and multi-factorial.

Long-term Care of Your Parkinson’s Patient

Sharon Yardley, RN Clinical
Coordinator, Vancouver Hospital
Movement Disorders Clinic

Co-author
Susan Calne, RN
Coordinator Neurodegenerative
Disorders Centre

Introduction
I work at the Neurodegenerative Disorder Centre at the University of British Columbia, where we currently care for more than 1,500 patients with Parkinson's disease (PD). I work with four neurologists, all of whom have subspecialty training in PD, and on a part-time basis I also have the help of one other nurse. My role as the clinic co-ordinator, is to provide counselling and education to new patients, and as their disease progresses, to continue counselling these patients on an outpatient basis. By providing the patients with knowledge and support, we seek to optimize their quality of life and their independence.¹

The clinical co-ordinator focuses primarily on the patients, and provides them with information about PD, the emotional and employment issues that may arise during the course of the illness, and changes that will occur in their lifestyle. Another important function is to provide the patients with education about pharmaceutical treatment and monitoring services, and to support them as they begin antiparkinson therapy, documenting changes in their symptoms and any problems that occur between visits.

Antiglutamate Agents Hold Promise for Control of Hallucinations in PD

Interview with Dr. Michel Panisset

Dr. Michel Panisset is the Director of the Movement Disorder Clinic at the McGill Centre for Studies in Aging, and an Assistant Professor in the Department of Neurology and Neurosurgery at McGill University. He specializes in neurology and movement disorders and is particularly interested in Parkinson's Disease. He is also a member of the Parkinson Study Group. Dr. Panisset kindly agreed to share his knowledge and views on the best methods to control hallucinations in patients suffering from PD.

Q: Do hallucinations constitute a big problem for your patients who suffer from Parkinson's disease? How do these hallucinations affect a patient's wellbeing and daily functioning? Do they affect a patient's compliance with medication?

A: Approximately 20 to 40% of patients with Parkinson's Disease experience hallucinations. When we look at our own data, we find that this number is closer to 40%. So, it is a very significant problem. Hallucinations usually start in patients suffering from a more advanced stage of the disease, who have greater problems with cognition and require more medications. We do not see a strong effect on compliance in this particular subpopulation of patients. Typically, when a patient suffers from cognitive or psychiatric problems, medications are administered with the help of a caregiver.

New Model for Neuronal Cell Death in Inherited Neurodegerative Diseases

There appear to be different biochemical mechanisms that underlie neuro-degeneration in a variety of different diseases including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and amyotrophic lateral sclerosis (ALS). AD, PD and HD, are all characterized by the accumulation of protein aggregates, although the genes that produce the offending proteins are different, whereas in ALS there are alterations in the morphology of neuronal axons and in the expression of genes that encode neurofilaments.

A study that was recently published in the journal Nature suggests that although the essential biochemistry of these diseases may be different, they may have a common mechanism of neuronal cell death. Previously it was postulated that this common mechanism may be the process known as the 'cumulative-damage' hypothesis, which holds that the accumulation of damage to macromolecules, or toxic substances, eventually leads to the demise of the affected neuronal population. Over time, this would lead to an increase in the probability that a cell will die. If this theory were incorrect, one would expect that the probability of cell death would either remain constant, or would decline.

Clarke et al. investigated the kinetics of neuronal death in several neuro-degenerative diseases, in an effort to test the cumulative-damage hypothesis. Twelve different models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, and mouse models of cerebellar degeneration and Parkinson's and Huntington's disease, all showed patterns of death that are more consistent with a mathematical model in which the risk of cell death remains constant, or decreases exponentially with age. The authors propose that affected neurons are in an abnormal state, which they refer to as a 'mutant steady state', in which there is an increase in the probability that a single, rare catastrophic event will lead to cell death.

Particularly important is the fact that this study has implications for therapeutic intervention. The fact that a cell is not necessarily more likely to die with increasing age suggests that it may still be rescued by pharmaceutical intervention, even at a late stage in the disease process.

Source

1. Clarke G. et al. Nature 2000, 406:195-199.

The Other Causes of Parkinsonism

Drugs, Toxins and Pugilism May All Lead to PD-Like Symptoms

D'Arcy L. Little, MD, CCFP
Director of Medical Education
York Community Services,
Toronto, ON

Introduction
Diagnosing a patient with Parkinson's disease might, at first, seem to be straightforward. In some cases, a medical student can make the diagnosis from across a room. However, fully one quarter of the diagnoses of idiopathic Parkinson's, which were made clinically by specialists, were found upon pathological examination to be some other disease.^1,2,3 This figure is even higher in situations where the diagnosis was made in the early stages of the disease, by a non-specialist.³ Given that the list of conditions in the differential diagnosis of Parkinson's is vast, and the diagnosis is essentially a clinical one made by the process of elimination or exclusion, the clinician needs a solid approach when considering a diagnosis of this illness. The purpose of this review is to itemize an approach to the exclusion of cases of secondary parkinsonism, in the diagnosis of idiopathic Parkinson's disease (See Figure 1: Approach to Diagnosis of Parkinsonism). Table 1 lists clues that suggest a diagnosis of secondary parkinsonism.

Movement Disorders: A Potentially Dangerous Outcome of Specific Classes of Drugs

Nadège Chéry, PhD
Medical Writer/Consultant,
Snell Medical Communication Inc.
Montreal, Qc

The prescription of medications is among the most frequent and the most reliable forms of therapeutic strategy that physicians use for the treatment of patients with a variety of medical disorders.¹ Unfortunately, many of these medications also produce side effects, especially in the geriatric population,¹ some of which may be mild and relatively tolerable by most patients, and others, such as dyskinetic reactions, which are considered harmful.^2,10 Drug-induced movement disorders represent an important iatrogenic condition that is occasionally encountered in clinical practice.² These potentially disabling movement disorders are involuntary, they appear to be idiosyncratic extensions of the expected action of the drug and they are known to particularly affect the elderly patient.^2-6 Among the devastating consequences of these disorders are involuntary movements, which may contribute to falls and fractures in the elderly, and social isolation, which can result from the limited mobility of an elderly individual.^4,7

Nonetheless, movement disorders are often reversible; the withdrawal of the offending drug(s) usually leads to the alleviation of symptoms.³ Unfortunately, in some cases, discontinuing the offending drug may not be feasible.

The Fascinating Field of Movement Disorders

Dr. Barry Goldlist
Editor in Chief
Geriatrics & Aging

As I write this editorial, I am looking forward to an important event in Canadian geriatrics. For the first time since its inception, the Canadian Geriatrics Society is meeting independently of the Royal College of Physicians and Surgeons. This is not by chance, and certainly not because the Royal College has asked us to leave. This is a deliberate attempt to make the activities of the society more accessible to family physicians with an interest in geriatrics. Now, physicians will no longer have to pay a registration fee to the Royal College when they are only interested in the section on geriatrics. This year's meeting is in Edmonton, and in addition to our usual scientific sessions and symposia, we are having a CME day that is specifically targeted to primary care physicians. We would certainly welcome as members any physicians who are interested in care of the elderly. The current membership fee is minimal ($50/year) and information can be obtained from our current secretary-treasurer, Dr. Chris MacKnight (e-mail: "cmacknig@is.dal.ca" and mailing address: Camp Hill Veteran's Memorial Building, 5955 Jubilee Road, Halifax, NS, B3H 2E1). Next year's meeting is tentatively scheduled for mid-October in Toronto, in collaboration with a meeting on dementia that is being sponsored by the Tanz Centre for Research in Neurodegenerative Disease at the University of Toronto. I have seen the preliminary program and it is quite impressive.

I believe we have quite an interesting journal for you this month. Extensive research has clearly documented that impaired mobility is the most common cause of functional disability in the elderly. The causes of impaired mobility are numerous. Perhaps the most common is "simple" osteoarthritis but stroke, and fractures secondary to osteoporosis, are also important causes. This issue focuses on the fascinating field of movement disorders. Although it might seem relatively easy to recognize full-blown Parkinson's disease, diagnosis at an early stage can be quite challenging. Dr. Janis Miyasaki discusses the diagnosis of Parkinson's disease and how to differentiate it from other causes of tremor and the other Parkinsonian syndromes. As in other chronic conditions, the long-term management of patients suffering from Parkinson's disease can be extremely challenging. In her article, Sharon Yardley discusses some of the non-pharmacological treatments that are available. Dr. Robert Chen explores the burgeoning field of surgical treatment for Parkinson's disease. The pharmacological armament for treatment of Parkinson's disease has expanded dramatically in the past few years. While this is good news for the patient, as treatment can now be better tailored for the individual, it means physicians need to be provided with more information. In their article on the pharmacological treatment of Parkinson's disease, Doctors Sanjiv and Tsui address this potential information gap. Dr. Nadege Chery's article addresses drug induced Parkinsonism, which can represent a therapeutic challenge if the offending drug is considered essential for the patient. Parkinsonism is not always caused by a primary neurodegenerative disorder, and in his article Dr. D'Arcy Little describes the secondary causes of Parkinsonism, such as trauma or stroke.

As well as the focus on movement disorders, we also have our usual pot-pourri of articles on geriatric topics. Our column on ethics examines the ethical issues involved in transplanting foetal brain tissue in patients with Parkinson's disease. Another article discusses the utility of memory clinics for the diagnosis and management of Alzheimer's disease and other dementias. In the cardiology column, we look at the rational diagnosis of leg swelling and also review the application of the results of the HOPE study to clinical practice. There are also articles on the clinical aspects of Lou Gehrig's disease and the benefits of pancreatic transplants, an area in which Canadians are among the world leaders. I hope you enjoy this edition.

Manipulation of Dopaminergic Pathways is Mainstay of Pharmacological Treatment of PD

The history of the use of pharmaceuticals to alleviate the symptoms of Parkinson's disease (PD) began 125 years ago, when belladonna alkaloids were first used in an attempt to control severe drooling in patients suffering from PD. These alkaloids possess anticholinergic activity, and unexpectedly, they alleviated other characteristic symptoms of PD, which include tremor, rigidity, akinesia and postural instability. However, it was not until 1958 that researchers discovered the presence of high levels of dopamine in the striatum of the brain and showed that the dopamine precursor (levodopa or L-dopa) reversed the tranquillization and parkinsonian-like motor impairments induced by treatment with reserpine. This set the stage for the development of the first real pharmacotherapy for treatment of PD.

Sanjiv CC, DM,
Tsui JKC, MD, FRCPC
Neurodegenerative Disorders Centre,
University of British Columbia,
Vancouver, BC, Canada

Dopaminergic Agents
At present, there is no pharmacological cure for Parkinson's disease (PD) and only the symptoms of the disease can be treated. There is no firm evidence to support the notion that any drug has a neuroprotective action in PD; therefore, the mainstay of current drug therapy is the manipulation of the dopaminergic pathways.

Levodopa (L-DOPA)
L-dopa is the most commonly prescribed medication for the treatment of PD.

How to Differentiate Between PD and Other Parkinsonian Syndromes

Janis Miyasaki, MD, FRCPC
Mount Sinai Hospital,
Movement Disorders

Each year Parkinson's disease (PD) affects 4.5-21 people out of every 100,000. The prevalence rate is 200/100,000 members of the population. As the population ages, the prevalence can be expected to increase since the risk of developing PD steadily increases with each decade of life.¹ The cardinal symptoms of PD are tremor, rigidity, akinesia and postural instability.² A patient is diagnosed with Parkinson's disease based on him/her having a history consistent with PD, and showing the clinical signs on examination. Therefore, the physician must be familiar with the classic appearance of each sign of PD and with the alternative diagnoses that are implied by any variance in symptoms.

Tremor
The tremor in PD is classically 3-5 Hz and is described as pill-rolling, due to the rhythmic opposition of the index finger and thumb. Tremor is seen at rest, however, in some cases it may only be seen if the patient is distracted by the use of manoeuvres such as mental arithmetic. While the patient is walking, the affected arm will often shake. Anxiety markedly increases the tremor, whereas it abates during sleep. Tremor may also be seen with postural maintenance or during a physical action. If the postural or kinetic component of the tremor is predominant, the physician should consider an enhanced physiologic tremor or essential tremor as the diagnosis.

Refinements to Surgical Treatment for Parkinson’s Disease

Basal Ganglia Motor Circuit is Target Site for Surgical Intervention

Farooq I. Khan, MD,
Robert Chen, MBBChir, MSc, FRCPC
Movement Disorders Centre,
Division of Neurology,
Toronto Western Hospital,
University of Toronto

Parkinson's Disease (PD) was first described by James Parkinson in 1817, and is a neurodegenerative disease that is characterized by tremor, bradykinesia, rigidity and postural instability. It results from the degeneration of the dopaminergic neurons in the substantia nigra (pars compacta) causing alterations in the basal ganglia circuitry; this circuitry is responsible for modulating and facilitating motor function through the cerebral cortex. The evolution of the treatment for PD has relied on both pharmacological and surgical approaches, arguably the most important of which was the discovery of levodopa in the early 1960s. Since then a number of other pharmacological agents such as monoamine oxidase (MAO) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, and dopamine agonists, have played a vital role in the amelioration of disability arising from this disease. Unfortunately, long term pharmacotherapy, especially with levodopa, has caused problems of its own, namely the occurrence of fluctuation and dyskinesia. For these and other reasons that will be discussed, surgery has offered a ray of hope to combat this eventually crippling disease.