Review Amyotrophic lateral sclerosis: A 40-year personal perspective Andrew Eisen * Neurology, University of British Columbia, 2862 Highbury Street, Vancouver, British Columbia, V6R 3T6, Canada a r t i c l e i n f o Article history: Received 25 April 2008 Accepted 29 July 2008 Keywords: Amyotrophic lateral sclerosis Motor neuron disease Neurodegeneration a b s t r a c t Amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) shares with other neurodegenetrative disorders of the aging nervous system a polygenic, multifactorial aetiology. Less than 10% are familial and these too probably are associated with several interactive genes. The onset of ALS predates development of clinical symptoms by an unknown interval which may extend several years. The cause of neurodegen- eration remains unknown but a common end-point is protein misfolding which in turn causes cell func- tion failure. The complex nature of ALS has hindered therapeutic advances. In recent years longer survival is attributable largely to institution of non-invasive ventilation with BiPAP and timely implementation of percutaneous endoscopic gastrostomy (PEG) feeding. Symptomatic treatment has advanced improving quality of life. Several encouraging avenues of therapy for ALS are beginning to be emerge raising hope for real benefit. They include protective autoimmunity, vaccines against misfolded protein epitopes and other deleterious species, new drug delivery systems employing nanotechnology and the potential of stem cell therapy. �� 2008 Elsevier Ltd. All rights reserved. 1. Introduction When fully developed, classic Charcot amyotrophic lateral scle- rosis (ALS) used in this review, or motor neuron disease (MND), the term more commonly used in Europe, Australia and New Zealand and Asia, is readily diagnosed. A cognitively normal, 55-year-old patient with multi-myotomal muscle weakness and wasting asso- ciated with diffuse and profuse fasciculations, including the ton- gue, brisk reflexes in the weak, wasted limbs, but normal sensation and intact sphincter function almost certainly has ALS. These clinical features described by Charcot over 150 years ago1,2 are reiterated in most text books and in the introduction of many articles as follows: ������Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the cortex, brainstem, and spinal cord. Patients have progressive wasting and weakness of limb, bulbar, and respi- ratory muscles, and die on average within 3 years of symptom on- set, usually because of respiratory failure. Although ALS can occur at any time during adulthood, the median age of onset is in the mid-fifties. The only therapy to slow progression of ALS is currently riluzole, which delays disease development by 3���6 months. Global incidence of ALS is about 1���2 per 100 000 and risk of ALS is esti- mated to be 1/600���1/2000, which makes it the most common mo- tor neuron disease.���3 As will be shown, this definition is too restrictive and needs broadening, and it is far from clear that ALS represents one disease. The diagnosis of ALS remains essentially a clinical diagnosis made through an experienced neurologist familiar with the disease. Most family physicians see one or two patients with ALS in a lifetime and community neurologists may see fewer than 5 to 7 patients annually, insufficient to become comfortable with the condition and its variables. The co-existence of upper and lower motor neu- ron signs in a distribution that cannot be explained by any pathol- ogy other than ALS requires experience and skill. Electrophysiology has not removed the need for careful evaluation of the history and thorough clinical examination, but it is difficult to make the diag- nosis of ALS with any confidence in the absence of electromyo- graphic (EMG) abnormalities. Ideally the ALS neurologist is also an experienced electromyographer. The present lack of an identifying biomarker makes it impossi- ble to diagnose sporadic ALS in a pre-clinical stage when there is opportunity of normalizing dysfunctional neuronal elements be- fore irreversible cell death occurs.4,5 Early diagnosis raises the fun- damental question ��� when does ALS begin? Based on evidence from other neurodegenerative disorders, in particular Alzheimer���s, Parkinson���s and Huntington���s diseases, there is probably a lengthy pre-clinical period spanning years and maybe decades (Fig. 1). Certainly when muscle weakness and wasting are apparent there has already been loss of as many as 80% of the anterior horn cells in the involved motor neuron pool. Unfortunately there is a worldwide average time delay of about 14 months between symp- tom onset and referral to an ALS specialist.6 Because of the rarity of 0967-5868/$ - see front matter �� 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.07.072 * Tel.: +1 604 2281897 fax: +1 604 6775974. E-mail address: Eisen@interchange.ubc.ca Journal of Clinical Neuroscience 16 (2009) 505���512 Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn

the disease it may be difficult to shorten this interval until a good biological disease marker is developed. There is evidence that supports that cortical hyperexcitability, which subsequently induces dysfunction and demise of the lower motor neuron, is an early feature of ALS so that a biomarker should be cortically, not spinal cord, directed.7,8 Possible early clinical fea- tures may include sleep disturbance and loss of smell. Neurodegenerative disorders involve death of cell bodies, ax- ons, dendrites and synapses, but it is surprisingly difficult to deter- mine the spatiotemporal sequence of events and the causal relationships among these events. Neuronal compartments often crucially depend upon one another for survival, and molecular de- fects in one compartment can trigger cellular degeneration in dis- tant parts of the neuron. Although ALS appears to preferentially affect motor neurons in the cortex, brainstem and spinal cord, many other cell types are involved. They include glia, interneurons, vascular endothelium and cells involved in controlling immune- mediated processes. It is likely that these cells interact in complex two-way and three-way interactions. 2. The clinical spectrum ALS presents with a variety of clinical deficits (Table 1). About 70% are primarily associated with lower motor neuron failure. Dysarthria is typically spastic (upper motor neuron in nature) progressing slowly so that initially those familiar with the patient may be unaware there is anything wrong. A little later family and friends (and police) are suspicious of alcohol abuse. Within 6 to 9 months speech often becomes unintelligible and alternative forms of communication are required. Dysarthria and eventual anarthria may persist for many months without other neurological deficit. Initially, and for some time following, dysarthric patients with ALS usually have no problems eating and swallowing and frequently are able to continue actively in sports. Paucity of tongue movement, a brisk jaw jerk and release of the mandibular-corneal reflex and subtle evidence of long tract signs are characteristic. MRI is required to rule out vascular disease. In ALS the MRI may show bilateral sym- metrical hyperintensities in the corticospinal tract in an ������hour- glass��� distribution (Fig. 2). In recent years there have been a variety of modifications of standard MRI, in particular diffusion tensor tech- niques which are better able to detect abnormalities of the cortico- spinal tracts.9,10 Lower motor neuron speech difficulty is nasal in quality and in ALS is always associated with dysphagia and fre- quently with widespread muscle wasting and weakness. Unilateral painless loss of fine manipulative hand control is a common presentation in ALS. It needs to be differentiated from the many causes of hand weakness and wasting most of which are associated with sensory loss. Careful examination reveals that the wasting of the small muscles of the involved hand in ALS is dominantly the thenar hand, involving the thenar complex and first dorsal interosseus with sparing or only minimal involvement of the hypothenar muscle complex (Fig. 3). This ������split hand��� distribution is possibly unique to ALS and is certainly an important clinical clue.11,12 Evidence suggests this distribution results from the loss of motor cortical input. Certainly the loss of fine movement of the involved hand is much greater that would occur with a pure lower motor neuron weakness. Also the hand dysfunction is usually asso- ciated with brisk finger flexion and a positive Hoffman���s sign. The wasting associated with a C8 radiculopathy is limited to the first dorsal interosseus, whereas isolated painless thenar wasting occurs in carpal tunnel syndrome of the elderly (because of its slow pro- gression) and true neurogenic thoracic outlet syndrome. Less commonly upper limb weakness commences proximally. This presentation can be confused with cervical disc degeneration, which is common in the same age group as ALS. In ALS the wasting associated with the weakness is more marked than usually occurs with a radiculopathy and fasiculations are more profuse. Reflexes are maintained and often brisk in the weak wasted limb. A partic- ular form of upper limb presentation in ALS is the flail (floppy) arm syndrome.13���15 It is characterized by a constellation of symmetric, predominantly proximal wasting and weakness of both arms Table 1 Presenting symptoms of 1535 patients with amyotrophic lateral sclerosis Symptom Percentage of patients Dysarthria 32.8% Hand dysfunction 19.7% Shoulder dysfunction 13.6% Foot drop 12.5% Fasciculation/cramps 11.4% Spastic gait 4% Respiratory failure 4% Frontal dementia 2% Fig. 2. Coronal T2-weighted fluid-attenuated inversion recovery (FLAIR) of a patient presenting with spastic dysarthria. There is an ������hour-glass��� hyperintensity bilat- erally and symmetrically through the corticospinal tracts (arrows). Fig. 1. Theoretical timeline of events in amyotrophic lateral sclerosis (ALS). In the pre-clinical period there is presently no marker to detect the sporadic disease. This is a period when protective therapy would be most beneficial. Shortly before the disease becomes overt it might be detectable by imaging, as well as physiological and molecular markers. 506 A. Eisen / Journal of Clinical Neuroscience 16 (2009) 505���512