A. Characteristics [8]
[Figure] "Cross Section of the Spinal Cord"

1. Progressive degenerative disease of motor neurons
   1. Motor Neuron involvement with sensory sparing
   2. All motor neurons affected, from cortex to anterior horn of spinal cord
   3. Limb and facial motor weakness, atrophy, spacticity and death
   4. Onset may be bulbar or limb (cervical and/or lumbar)
2. Occurs in sporadic (~90%), familial (<10%), and Western Pacific forms
3. Usually occurs in persons >50 years old with median ae of onset 65 years old [8]
4. Males > Females
5. Median lifespan 3 years following diagnosis [2]

B. Symptoms and Signs

1. Presentation: muscle weakness (60%), bulbar symptoms (20%), muscle atrophy (10%) [8]
2. Paresis (muscle weakness)
   1. Must have >1 muscle group involved
   2. Both upper and lower motor neuron signs
   3. Babinski sign (upgoing toes), clonus, weakness
3. Bulbar onset with slurring of speach (dysarthria), diffulty swallowing (dysphagia), or both
4. Progressive muscular atrophy (wasting)
   1. Progression to tracheostomy requirement due to respiratory muscle failure
   2. Death within 2-5 years
5. Preservation of mood and intellect and sensory neurons
6. Electromyogram (EMG)
   1. Fasciculations, fibrillations
   2. Spontaneous hyperactivity (due to sprouting of axons)
   3. Large motor units affected
   4. Demonstration of denervation in at least 3 limbs confirms lower motoro neuron disease
7. Dementia may occur, but only as a familial ALS syndrome (see below)

C. Pathophysiology [2]

1. Degeneration of motor neurons throughout neuraxis [8]
   1. Motor cortex
   2. Cranial nerve nuclei (particularly CN XII)
   3. Corticospinal tracts
   4. Ventral horns of spinal cord (ventral root degeneration with normal dorsal roots)
2. Pathology
   1. Motor neuron degeneration with astrocytic gliosis is hallmark
   2. Neuronal loss appears mainly through apoptosis [3]
   3. Variety of neuronal inclusions found in ALS
   4. Only Bunina bodies are specific for ALS
3. Biochemical Changes
   1. Accumulation of phosphorylated cell body filaments (normally only in axon)
   2. Enlarged proximal axon; atrophic distal axon
   3. Impaired Axonal Transport
   4. Disorganized neurofilament proteins may be final pathway
4. Glutamate Accumulation
   1. Glutamate is a primary excitatory brain neurotransmitter
   2. Causes death of neurons, probably through N-methyl-D-aspartate (NMDA) receptors
   3. NMDA links to a calcium dependent pathway
   4. Calcium plays a key role in cell toxicity and death
   5. Abnormal glutamate metabolism is found in ALS
5. Superoxide Dismutase (SOD) [4,10]
   1. Two forms of this enzyme: coper-zinc (cytoplasmic, SOD1) and manganese (mitochondrial)
   2. Responsible for conversion of toxic superoxide less toxic peroxides
   3. In 10-15% of familial ALS, the SOD1 gene is mutated leading to increased superoxide
   4. Expression of mutant SOD1 human genes in mice leads to paralytic disease
   5. SOD levels in serum of patients with ALS are normal
   6. However, spinal cord and/or brain levels may not be normal
   7. Reduced local SOD activity would exacerbate glutamate toxicity
   8. Elevated levels of apoptosis associated with caspase 1 activation have been noted
   9. Caspase 9 activation, cytochrome c release, and proapoptotic bcl-2 members upregulated
6. Insulin-Like Growth Factor 1 (IGF-1) [5]
   1. IGF-1 is a key neuron growth and survival factor
   2. IGF-1 is bound by various binding proteins, IGFBPs 1-6
   3. Total IGF-1 levels in spinal cord ventral horn similar in ALS patients and controls
   4. Free IGF-1 levels reduced ~50% in patients versus controls
   5. IGFBP2, -5, -6 all elevated in patients versus controls
   6. Elevated IGFBP causes reduced free IGF-1 levels
7. Genetic Mutations Linked to Sporadic ALS
   1. Angiogenin (chr 14q11.2)
   2. Vascular endothelial growth factor (VEGF; chr 6p12)
   3. Survival motor neuron (SMN, chr 5q12.2)
   4. Neurofilament protein (chr 22q)
   5. Charged multivesicular body protein 2B (chr 2pq11.2)
   6. A variety of novel genetic associations in sporadic ALS have been reported [11]
8. Autoimmunity
   1. May also play a role
   2. IgG from some ALS patients abnormally affects neurons in culture
9. Familal Forms of ALS (5-10%)
   1. Inheritance of adult forms: autosomal dominant (more common) or X-linked
   2. Inheritance of juvenille forms: autosomal recessive or dominant
   3. SOD mutations in 10-20% of autosomal dominant form (chromosome 21q22.1)
   4. Both upper and lower motor neuron signs prominent
   5. Other auotsomal dominant linkages: chr 18q21, chr 9q34 (senataxin), chr 16q12.1, chr 20pter, chr 20q13.3 (VAPB protein), chr 2p13 dynactin 1 gene [2]
   6. Autosomal recessive linkages: chr 2q33, chr 15q15.1

D. Other Motor Neuron Diseases [1]

1. Adult onset types of motor neuron disease: ~1 in 500 persons
2. ALS with Frontotemporal Dementia ± Parkinsonism
   1. Less than 5% of cases of ALS develop with accompanying dementia
   2. This is a frontotemporal dementia (FTD)
   3. FTD in ALS has been localized to chromsome 9q21-22 [6]
   4. FTD with parkinsonism in ALS linked to Tau mutations chromosome 17p21
3. Related Syndromes
   1. Multifocal Motor Neuropathy
   2. Progressive Muscular Atrophy
   3. Primary Lateral Sclerosis
   4. Bulbopsinal Muscular Atrophy (Kennedy's Syndrome)
   5. Spinal Muscular Atrophy (Juvenile)
4. Multifocal Motor Neuropathy [1]
   1. Lower motor neuron signs dominant
   2. IgM antibodies against GM1 ganglioside in ~50% of these patients
   3. Multiple motor-conduction blocks on EMG
   4. Immunological dysfunction appears causative
   5. Responds to cyclophosphamide or intravenous immune globulin (unlike ALS)
   6. Little effect of agents less toxic than cyclophosphamide (other than IVIg)
5. Progressive Muscular Atrophy
   1. Lower motor neuron syndrome without upper motor neuron signs
   2. Some patients progress slowly, others progress to full ALS
   3. Unclear if this is a distinct syndrome
6. Primary Lateral Sclerosis
   1. Pure upper motor neuron disease, no lower motor neuron invovlement
   2. However, ~50% of patients progress to combined upper and lower motor neuron
   3. Unclear if this is a distinct syndrome
7. Bulbopsinal Muscular Atrophy (Kennedy's Syndrome)
   1. X-linked recessive lower motor neuron syndrome with bulbar invovlement
   2. Tongue wasting and fasciulation
   3. Gynecomastia, testicular atrophy, infertility
   4. Some patients with primary sensory neuronopathy
   5. Chromosome Xq11-12 and associated with CAG repeat in androgen receptor gene
8. Spinal Muscular Atrophy (SMA)
   1. Infantile / Juvenile motor neuron disease
   2. Autosomal recessive disorders which affect mainly lower motor neurons
   3. Mapped to chromosome 5q13 at survival motor neuron (SMN) locus
   4. SMN appears to influence the metabolism of mRNA
   5. Nearly 100% of patients with SMA have mutations in SMN gene
9. Acute Poliomyelitis and Postpolio Syndrome

E. Therapy

1. Anti-glutamate agents are the best validated
2. Riluzole (Rilutek®) [1,7]
   1. Anti-glutamate agent which inhibits glutamate release pre-synaptically
   2. Acts on sodium channels
   3. Appears to slow progression of ALS, better in bulbar than in limb onset disease
   4. Slows progression to tracheostomy requirement; 3-6 month survival advantage
   5. Adverse reactions include asthenia, spasticity, mild transaminase elevations, nausea
   6. Dose is 200mg po qd and overall is well tolerated
   7. In absence of more effective agents, is reasonable therapy
3. IGF-1 (Myotrophin®)
   1. Free IGF-1 levels are reduced in ventral spinal cord of ALS patients versus controls [5]
   2. Exogenous IGF-1 slows progression of ALS in some patients (no survival effect)
   3. Previous trials with serious flaws, thus preventing adequate efficacy evaluation [2]
   4. Studies to evaluate combination with riluzole are planned
4. Experimental
   1. Immunosuppressive regimens are being investigated
   2. Neurotrophic factors have been evaluated and are ineffective thusfar
   3. Gene therapies are being evaluated in familial disease
5. Supportive Care [2]
   1. Fasciculations and Muscle Cramps
   2. Spasticity
   3. Drooling
   4. Pathological Laughing or Crying
6. Fasciculations and Muscle Cramps
   1. Magnesium: 5mmol up to tid
   2. Vitamin E: 400 IU bid
   3. Quinine sulfate: 200mg bid
   4. Carbamazepine: 200mg bid
   5. Phenytoin: 100mg up to tid
7. Spasticity
   1. Baclofen: 10-80mg
   2. Tizanidine: 6-24mg
   3. Memantine (Namenda®): 10-60mg
   4. Tetrazepam: 100-200mg
8. Drooling
   1. Amitriptyline: 10-150mg
   2. Transdermal hyoscine patches: 1-2 patches
   3. Glycopyrrolate: 0.1-0.2mg sc or IM tid
   4. Atropine or benaropine: 0.25-0.75 mg or 1-2 mg
9. Pathological Laughing or Crying
   1. Amitriptyline: 10-150mg
   2. Fluvoxamine: 100-200mg
   3. Lithium carbonate: 400-800mg
   4. Levodopa: 500-600mg
10. Respiratory Support
    1. Respiratory muscle failure usually in 2-3 years but may occur early (within 1 year)
    2. Usually life threatening requiring mechanical ventilation
    3. Patients may benefit from non-invasive or invasive mechanical ventilation
    4. Patients requiring invasive ventilation usually require a tracheostomy
    5. Tolerance of noninvasive positive pressure ventilation is a good prognostic feature [9]
11. Clinical depression, found in ~10% of ALS patients, should be treated
12. End-of-life issues must be addressed [1]

References

1. Rowland LP and Shneider NA. 2001. NEJM. 344(22):1688
2. Mitchell JD and Borasio GD. 2007. Lancet. 369(9578):2031
3. Honig LS and Rosenberg RN. 2000. Am J Med. 108(4):317
4. Babior BM. 2000. Am J Med. 109(1):33
5. Wilczak N, de Vos RAI, De Keyser J. 2003. Lancet. 361(9362):1007
6. Hosler BA, Siddique T, Sapp PC, et al. 2000. JAMA. 284(13):1664
7. Riluzole. 1995. Med Let. 37(963):113
8. O'Neill GN, Gonzalez RG, Cros DP, et al. 2006. NEJM. 355(296):296
9. Aboussouan LS, Khan SU, Meeker DP, et al. 1997. Ann Intern Med. 127(6):450
10. Friedlander RM. 2003. NEJM. 348(14):1365
11. Dunckley T, Huentelman MJ, Craig DW, et al. 2007. NEJM. 357(8):775