Motor neuron disease

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the anterior horn cells of the spinal cord and the motor cranial nuclei that leads to progressive muscle weakness and atrophy. Although major recent advances have shed light on its etiology, the key mechanisms in both familial and sporadic ALS remain unknown. No cure is known. This chapter reviews the major breakthroughs in ALS research, the clinical aspects of the disease, and current therapeutic options. An outline of new and promising technology and its application to the understanding of ALS is presented.

  • Definition of the Disease

ALS has two meanings. In one sense, it refers to several adult-onset conditions characterized by progressive degeneration of motor neurons (Figure 1). In the United Kingdom, the term motor neuron disease is used for these disorders. In the second sense, ALS refers to one specific form of motor neuron disease in which there are both upper and lower motor neuron signs.

Figure 1. Motor Neurons Selectively Affected in ALS. (Click to magnify figure)

Degeneration of motor neurons in the motor cortex leads to clinically apparent signs of upper motor neuron abnormalities: overactive tendon reflexes, Hoffmann signs, Babinski signs, and clonus. Degeneration of motor neurons in the brain stem and spinal cord causes muscle atrophy, weakness, and fasciculation.

“Amyotrophic” refers to the muscle atrophy, weakness, and fasciculation that signify disease of the lower motor neurons. “Lateral sclerosis” refers to the hardness to palpation of the lateral columns of the spinal cord in autopsy specimens, where gliosis follows degeneration of the corticospinal tracts. The clinical results are upper motor neuron signs: overactive tendon reflexes, Hoffmann signs, clonus, and Babinski signs.

If lower motor neuron signs alone are evident, the condition is called progressive spinal muscular atrophy. In primary lateral sclerosis, only upper motor neuron signs are seen. These syndromes are considered variants of ALS because, at autopsy, there are likely to be abnormalities in both upper and lower motor neurons. Together, the syndromes account for only 10 percent of all cases of adult-onset motor neuron disease. In patients with typical ALS, the symptoms are primarily those of weakness, which may start in the hands or legs or be manifested by slurred speech and dysphagia. On examination there are almost always lower motor neuron signs together with upper motor neuron signs. The disease is progressive; the mean duration of survival is three to five years.

Pathophysiology: ALS primarily involves anterior horn cells in the spinal cord and cranial motor nerves. Patients may have weakness of bulbar muscles or of single or multiple limb muscle groups. Presentation is not always bilateral or symmetrical. A predominantly bulbar form usually leads to more rapid deterioration and death. Limb weakness is predominantly distal. Weakness and atrophy of the intrinsic hand muscles are prominent. Weakness progresses to involve the forearms and shoulder girdle muscles and the lower extremities.

Involvement of both upper and lower motor neurons is characteristic. Patients develop variable hyperreflexia, clonus, spasticity, extensor plantar responses, and limb or tongue fasciculations. Wallerian degeneration of corticospinal and corticobulbar tracts may be demonstrated by MRI (high-intensity T2 lesions in frontal lobes) or in postmortem examination. Extraocular muscles and bladder and anal sphincter muscles typically are spared.

ALS rarely affects cognitive functions. Electromyogram (EMG) shows signs of diffuse denervation with generally preserved nerve conduction velocities. Although an inflammatory process may be present, new evidence points toward multiple mechanisms that promote neuronal cell death in the CNS as the underlying basis for ALS. The recent demonstration of superoxide dismutase 1 (SOD1) mutations in human familial ALS and in murine ALS models supports the view that oxidative stress, mitochondrial dysfunction, and excitotoxicity pathways may be involved in the process of neuronal cell death.

A lack of trophic factor support has been hypothesized, as some authors have reported decreased insulinlike growth factor 1 (IGF-1) in patients with ALS. Recent reports also claim a beneficial effect of recombinant human IGF-1 in the treatment of ALS. Aberrant RNA processing in sporadic ALS is thought to lead to abnormal expression of glutamate transporter (EAAT2) variants in the spinal cord. Despite multiple searches for infectious causative agents, no definitive viral or bacterial etiology has been identified.

ALS can be part of a complex with parkinsonism and dementia (ALS/PDC complex). This variant can be seen in patients from southern Guam. An ALS-like motor neuron disease also can be seen as a paraneoplastic syndrome in patients with cancer.

Autoimmunity may play a role in ALS. T cells, activated microglia, and immunoglobulin G (IgG) within the spinal cord lesions may be the primary event that leads to tissue destruction. Supporting this hypothesis, IgG derived from ALS patient sera may affect the conductance of neuronal voltage-activated calcium channels and may induce an excessive release of glutamate from nerve endings. The presence of immune complex formation in spinal cords of patients with ALS also has been demonstrated.

The El Escorial World Federation of Neurology criteria are helpful in diagnosis. Careful clinical history-taking is essential in making the correct diagnosis. For instance, Lyme neuroborreliosis on rare occasions may mimic an ALS-like syndrome. Intravenous cyclophosphamide treatment has resulted in only temporary and mild amelioration of symptoms.

Patients with ALS may benefit from riluzole, a glutamate antagonist medication that modestly prolongs tracheostomy-free survival. Techniques that aim to elucidate altered pathways of gene expression (ie, gene chip technology) and ALS animal model research may reveal the cause of neuronal cell death. These may also expedite the identification of abnormal pathway-modifying pharmaceutical agents.

Frequency:

  • In the US: Taking into account the most comprehensive studies (by Kurtzke), the frequency is approximately 5 cases per 100,000 population.

Mortality/Morbidity:

  • ALS leads to death within a decade, and in most cases, within 5 years.

  • Some patients with familial, juvenile-onset ALS have been reported to survive for longer periods (2-3 decades).

Race: In the US, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.

Sex: The ratio of ALS-affected males to females is 1.5:1.

Age: Onset occurs in the fourth to seventh decades of life. However, exceptions to this do exist.

PROBABLE CAUSES OF ALS

  • Genetic Causes

    • Familial Motor Neuron Diseases

Heritable diseases are the only motor neuron diseases whose causes are known. [14] Five to 10 percent of cases of ALS are familial; the others are believed to be sporadic. In 1993, Rosen et al. [15] described mutations in the gene encoding superoxide dismutase 1 (SOD1) that account for 20 percent of cases of familial ALS. The remaining 80 percent are caused by mutations in other genes. Five percent of people with apparently sporadic ALS also have SOD1 mutations. More than 90 SOD1 mutations involve 40 of the 153 amino acid residues. All SOD1 mutations are dominant, except for the substitution of alanine for aspartate at position 90 (D90A), which can be either recessive16 or dominant. [17] The substitution of valine for alanine at position 4 (A4V) is the most common SOD1 mutation.

Different SOD1 mutations cause distinct syndromes [18,19] that differ with respect to penetrance (penetrance is usually 100 percent but is sometimes less), SOD1 activity of erythrocytes (activity is usually normal but is sometimes depressed), age at onset (onset is usually after the age of 40 but sometimes occurs at a younger age), survival (survival ranges from 1 to 20 years), and clinical manifestations (the initial symptoms may be spinal or bulbar in nature). The histopathological findings also vary. In patients with the A4V mutation in SOD1, the corticospinal tracts are largely spared.18 Neuronal inclusions are not always present; for example, they may be present in some family members and absent in others.

Another autosomal dominant form of ALS progresses slowly and begins before the age of 25 years20; the gene has been mapped to chromosome 9q34. [21] The gene for ALS with frontotemporal dementia has been mapped to 9q21–22. [22] Autosomal recessive juvenile-onset ALS has been linked to chromosomes 2q3323 and 15q15–22. [24]

  • Genetic Susceptibility

ALS and other neurodegenerative disorders sometimes appear in the same family. Majoor-Krakauer et al. [25] found dementia significantly more often in the first-degree relatives of patients with ALS than in relatives of control subjects. They found a trend toward an association between ALS and parkinsonism. Cruz et al. [26] found no such associations, but some persons and families have both ALS and parkinsonism. [27,28] The occurrence of the two disorders together could be due to chance or to multisystem diseases. Amyotrophy is found with dementia and parkinsonism in patients with the chromosome 17–linked disease with mutations in the gene for tau, an intermediate filament important in the cytostructure of neurons. [29] ALS and dementia also occur together in the disease whose chromosomal location was mapped to 9q21–22. [22]

Age and a family history of ALS are the only established risk factors for ALS. Apparent clusters of disease are attributed to chance, but a founder effect may be responsible in some areas with clusters of autosomal dominant familial ALS. [30]

  • Environmental Causes

    • Epidemiologic Features

The incidence and prevalence of ALS vary little worldwide, with notable pockets of higher prevalence, especially in Guam. During World War II, neuropathologist Harry Zimmerman noted an unusual frequency of ALS, parkinsonism, and dementia in Guam. Epidemiologic studies indicated that the prevalence of ALS in Guam was 50 times the prevalence anywhere else. [31] Both the parkinsonism–dementia–ALS complex and ALS alone remain prevalent in Guam.

The cause of Guamanian ALS with parkinsonism and dementia is unknown. Heredity was discounted because the spouses of many patients were also affected, and no environmental cause or virus was found. [32]

  • Exposure to Heavy Metals

Many neurologists order tests for the measurement of mercury, lead, and arsenic in blood and urine. However, there is doubt that mercury or arsenic has ever caused ALS. Lead intoxication once caused a syndrome involving both upper and lower motor neurons, but the syndrome disappeared once occupational exposure to lead began to be monitored. There has not been a convincing report of lead-induced motor neuron disease for 25 years.

  • Viral Infection and Prion Disease as Causes

Persistent viral infection might cause sporadic ALS. Berger et al. detected enterovirus RNA in the spinal cords of patients with ALS, [33] but that observation was not confirmed, [34] and the role of enteroviruses, including poliovirus, has not been established. [35] Motor neuron disease has also been reported in a small number of patients infected with the human immunodeficiency virus (HIV) or human T-cell lymphotropic virus type I, but the existence of these few cases does not prove that retroviral infection causes motor neuron disease. In exceptional cases, anti-HIV therapy has reversed the motor neuron syndrome. Lyme disease in rare cases causes a syndrome with both upper and lower motor neuron signs, but it does not cause typical ALS. [36]

There was once thought to be an amyotrophic form of Creutzfeldt–Jakob disease. In 1983, however, Salazar et al. [37] reported that the injection of brain tissue from 33 patients who had ALS with dementia did not transmit the disease to monkeys, except in the case of 2 patients with “atypical” features. Prion disease seemed an unlikely cause of ALS. Later, however, it was recognized that 3 of the 33 cases were transmitted, and the atypical features were compatible with the features of amyotrophy in patients with Creutzfeldt–Jakob disease. [38] In 50 cases of proven prion disease, lower motor neuron signs were recorded. [38]

Figure 2. Mechanisms That May Contribute to the Degeneration of Motor Neurons in ALS. (Click to magnify figure)

  • Alternative Theories

Autoimmunity may have a role in pathogenesis. [39] Activated microglia and T cells have been found in the spinal cords of patients with ALS who have IgG antibodies against motor neurons. [40] In patients with sporadic ALS, antibodies against voltage-gated calcium channels may interfere with the regulation of intracellular calcium, leading to the degeneration of motor neurons. [40] This process has been verified by electron-microscopical findings. [41]

However, immunotherapy has not been effective in patients with ALS. Corticosteroids, plasmapheresis, intravenous immune globulin, cyclophosphamide, and whole-body radiation have all failed. The theory of an autoimmune cause of ALS is controversial. [42]

Paraneoplastic motor neuron disease could be an autoimmune disorder. Epidemiologic studies have not shown an unexpectedly high number of malignant tumors among patients with ALS, but the neurologic syndrome in these patients sometimes abates after the removal of a tumor of lung or kidney. Some patients with cancer and ALS were found to have antineuronal antibodies. [43,44,45,46]

The incidence of lymphoproliferative diseases among patients with motor neuron diseases may be higher than expected. [47,48,49] Of the 65 reported cases of ALS with lymphoproliferative disease, half involved both upper and lower motor neuron signs. Eighty percent had Hodgkin’s or non-Hodgkin’s lymphoma, and the other 20 percent had myeloma or macroglobulinemia. Among these patients, few had a neurologic response to immunotherapy and most died of the neuronal disease. Many patients with ALS have a monoclonal gammopathy whether or not they have a lymphoproliferative disease, but the nature of the association is not known. Both motor neuron disease and lymphoproliferative disease could arise from a persistent viral infection, as is the case in wild mice with a spontaneous retroviral infection that causes both leukemia and motor neuron disease.

Table 1. Classification of hereditary ALS. (Click to view table 1a) (Click to view table 1b)

HISTOPATHOLOGICAL FEATURES AND PATHOGENESIS

The pathological hallmarks of ALS are the degeneration and loss of motor neurons with astrocytic gliosis. Intraneuronal inclusions are seen in degenerating neurons and glia [50,51]. The finding of similar inclusion bodies in patients with ALS and in those with ALS dementia led Ince et al. [52] to posit the existence of a spectrum of disease ranging from pure frontotemporal dementia to pure motor neuron disease and syndromes of combined ALS and dementia.

Mitochondrial abnormalities have been found in patients with ALS and transgenic mice with mutant SOD1. [53,54] Only two cases of motor neuron disease have been associated with mutations in mitochondrial DNA. [55,56] Some patients also have fragmentation of the Golgi apparatus. [57]

  • Pathogenesis

Although the precise molecular pathways that cause the death of motor neurons in ALS remain unknown, [58,59] possible primary mechanisms include the toxic effects of mutant SOD1, including abnormal protein aggregation; the disorganization of intermediate filaments; and glutamate-mediated excitotoxicity and other abnormalities of intracellular calcium regulation in a process that may involve mitochondrial abnormalities and apoptosis (Figure 2).

  • SOD1-Induced Toxicity

Sporadic and familial ALS are clinically and pathologically similar, suggesting a common pathogenesis. Although only 2 percent of patients with ALS have a mutation in SOD1, the discovery of these mutations [15] was a landmark in ALS research because it provided the first molecular insights into the pathogenesis of the disease.

SOD1, an enzyme that requires copper, catalyzes the conversion of toxic superoxide radicals to hydrogen peroxide and oxygen. A copper atom at the active site mediates catalysis. SOD1 also has pro-oxidant activities, including peroxidation, the generation of hydroxyl radicals, and the nitration of tyrosine (Figure 3).

Figure 3. Copper-Mediated Oxidative Reactions Catalyzed by Superoxide Dismutase 1. (Click to magnify figure)

Superoxide dismutase 1 (SOD1) normally catalyzes the conversion of toxic superoxide anions (O2•) to hydrogen peroxide (H2O2) (top). Mutations in the gene for superoxide dismutase 1 may reverse this reaction, leading to the production of toxic hydroxyl radicals (OH•) (middle), or promote the use of other abnormal substrates such as peroxynitrite (ONOO–), ultimately leading to the aberrant nitration of tyrosine residues (Tyr) in proteins (bottom).

Mutations in SOD1 that impair the antioxidant functions of the enzyme could lead to toxic accumulation of superoxide. [60,61] This loss-of-function hypothesis was disproved, because the overexpression of mutant SOD1 (in which alanine had been substituted for glycine at position 93 of SOD1 [G93A]) in mice caused motor neuron disease despite the presence of elevated SOD1 activity. [62] Moreover, the total elimination of SOD1 did not cause motor neuron disease in mice in which SOD1 has been inactivated, or “knocked out.” [63] Therefore, SOD1 mutations must cause disease by a toxic gain of function, not by the loss of the scavenging activity of SOD1.

Table 2. ALS syndromes: Correlations with specific SOD mutations

ALS syndromes: Correlations with specific SOD mutations

1- Exon 1; Ala4Val
  Most common mutation
  Rapid onset & progression (1.0 yrs)
  Frequently only lower motor neuron signs

2- Exon 2; His46Arg
  @ Cu binding site of SOD
  Onset late; in legs
  Bulbar unusual
  Slow progression (17 yrs)

l Exon 4; Leu84Val
  Lower motor neuron only
  Rapid progression (1.5 yrs)
  ?Earlier onset in males

3- Exon 4; Asp90Ala
  Onset: 20 to 94 yrs; Legs; Preparetic phase
    Leg cramps; Myalgia; Painful paresthesia
  Bladder dysfunction
  Progression: Slow; Legs ® Arms
  Inheritance

    Recessive: Finnish (2.5% carriers)
    Dominant: Other patients

4- Exon 4; Ile104Phe
  Variable intrafamilial clinical features
    Age of Onset: 6 yrs – asymptomatic
    Course: 2 to 14 yrs until bulbar signs
    Limb onset: arms or legs

5- Exon 4; Ile113Thr
  Reported in ? sporadic ALS
  Relatively common
  Late Onset: Mean 59 years
  Rapid progression

6 Exon 5; Codon 126
  2 base pair deletion
  Rapid Progression
Mutant protein not detectable in brain

l- General syndrome features

  • Lower motor neuron predominant

    • A4V, Leu84Val, D101N

     

  • Slow progression
    • Gly37Arg (18 yrs); Gly41Asp (11 yrs);
      Gly93Cys; Leu144Ser;
      Leu144Phe (9 yrs)

     

  • Rapid progression
    • Ala4Thr (1.5 yrs);
      Asn86Ser Homozygous (5 months);
      Leu106Val (1.2 yrs); Val148Gly (2 yrs)
      126 2bp del

     

  • Late onset
    • Gly85Arg (55 yrs), His46Arg

     

  • Early onset (~ 29 years)
    • Gly37Arg; Leu38Val; ?Leu106Val

     

  • More common in females
    • Gly41Asp

     

  • Bulbar onset reported
    • Asp76Tyr; Homozygous Asp90Ala;
      Val148Ile; Ile151Thr

     

  • Low penetrance
    • Asp90Ala; Ile113Thr; A89V

     

  • SOD Mutations in “sporadic” ALS
    • Most common: Asp90Ala; Ile113Thr
    • Other: V14G; G16S; E21K; G72S;
      D101N; V118InsAAAAC; E133delGAA

  • Peroxynitrite and Zinc

According to one gain-of-function theory, a mutation in SOD1 alters the enzyme in a way that enhances its reactivity with abnormal substrates. For example, abnormal tyrosine nitration could damage proteins if the radical peroxynitrite is used as a substrate of SOD1. [64] Spinal cord levels of free nitrotyrosine are elevated in patients with sporadic ALS and in those with familial ALS, [65] as well as in SOD1-knockout mice, [66] but specific targets of nitration have not been identified.

Mutations in SOD1 may cause oxidative damage by impairing the ability of the enzyme to bind zinc. [67] Deprived of zinc, both mutant and wild-type SOD1 are less efficient superoxide scavengers, and the rate of tyrosine nitration increases. [68] Mutations in SOD1 decrease the enzyme’s affinity for zinc, [68] so that the mutant protein is more likely to assume a toxic, zinc-deficient state. It has also been theorized that in patients with sporadic ALS, normal SOD1 might also somehow be stripped of zinc to become toxic.

  • Copper and SOD1 Aggregates

Zinc-deficient SOD1 still requires copper at the active site even though its activity is abnormal. Two chelators remove copper from zinc-deficient SOD1 but not from normal SOD1 (replete with both copper and zinc). [67] Both chelators protected cultured motor neurons from zinc-deficient SOD [167] and might be beneficial in treating human ALS.

Despite this finding, it is uncertain whether SOD1-induced toxicity requires any enzymatic activity — normal or abnormal. A copper chaperone protein for SOD1 incorporates copper ions into both wild-type and mutant SOD1. [69] In mice, targeted disruption of the gene for this chaperone protein markedly reduced but did not eliminate SOD1 activity in the central nervous system. [70] If copper loading could be eliminated in a mouse with a mutation in SOD1, it would be possible to determine whether copper-mediated catalysis is required for the toxic effect.

SOD1-mediated oxidative abnormalities may not be a primary cause of toxicity. Instead, the proposed toxic gain-of-function mechanism may involve misfolding of mutant SOD1 to form abnormal protein aggregates, [71,72] as occurs in age-related neurodegenerative disorders.

  • Disorganization of Intermediate Filaments

    • Neurofilaments

Possible targets of SOD1-induced toxicity include the neurofilament proteins, which are composed of heavy, medium, and light subunits. They have a role in axonal transport and in determining the shape of cells and the caliber of axons. Large-caliber, neurofilament-rich motor axons are preferentially affected in human ALS, and the level of neurofilaments may be important in selective neuronal vulnerability.

In both patients with sporadic ALS and those with familial ALS, [73,74] as well as in SOD1-knockout mice, [75,76] neurofilaments accumulate in the cells and proximal axons of motor neurons. Abnormalities in neurofilaments could be either causal or a byproduct of neuronal degeneration. [77]

The direct involvement of neurofilaments in pathogenesis was suggested by the finding that overexpression of mutant [78] or wild-type [79,80] subunits in mice caused the dysfunction of motor neurons and the degeneration of axons and resulted in neurofilament swellings that were similar to those seen in patients with ALS. Also, mutations in the gene for the heavy subunit of neurofilaments are found in patients with sporadic ALS and in those with familial ALS. [81,82] A mutation in the gene for the light subunit of neurofilaments was found in another motor neuron disorder, the neuronal form of Charcot–Marie–Tooth disease. [83]

The way in which the aberrant expression of neurofilaments causes the degeneration of motor neurons is unclear. Disorganized neurofilaments could impede the axonal transport of molecules necessary for the maintenance of axons (referred to as “axonal strangulation”) (Figure 2). [84,85] Such abnormalities in neurofilaments may result from the toxic effects of mutant SOD1. In mice with a mutation in SOD1, elimination of the expression of the light subunit of neurofilaments [86] or overexpression of the heavy subunit of neurofilaments [87] ameliorated the motor neuron disease. Axonal neurofilaments may be targets of the toxic effects of mutant SOD1, which could explain why reducing the number of axonal neurofilaments is protective. Alternatively, the accumulation of neurofilaments in motor neuron cells could protect against SOD1-mediated injury by buffering calcium [88] or diminishing zinc binding.

  • Peripherin

Peripherin — another intermediate filament — is found with neurofilaments in the neuronal inclusions of patients with sporadic ALS [89] and mice with SOD1 mutations. [90] Peripherin is normally expressed in motor neurons, [91,92] but levels of peripherin increase in response to cellular injury [91] or inflammatory cytokines. [93] Overexpression of peripherin in mice induced selective degeneration of motor axons. [94] The levels of messenger RNA (mRNA) of the light subunit of neurofilaments are abnormally low in the neurons of patients with sporadic ALS. [95] In mice that lack these light subunits and also overexpress peripherin, the selective death of motor neurons is a prominent characteristic.

Therefore, increased expression of peripherin after neuronal injury or inflammation could cause motor neuron disease through an interaction with the medium and heavy subunits of neurofilaments in the absence of the light subunits, [96] leading to the formation of toxic aggregates. This could explain why the overexpression of peripherin kills only motor neurons, which contain high levels of neurofilaments, and not sensory neurons, [94] which do not express neurofilaments.

  • Calcium Homeostasis and Excitotoxicity

    • Calcium-Binding Proteins

There is much evidence to indicate that ALS involves a derangement of intracellular free calcium. Abnormal calcium homeostasis activates a train of events that ultimately triggers cell death. In patients with ALS and in mice with mutant SOD1, [97] the resistance of particular motor neurons (e.g., oculomotor neurons) may be related to the presence of calcium-binding proteins that protect against the toxic effects of high intracellular calcium levels. [98,99]

  • Glutamate Receptors and Transporters

The mechanism of excitotoxic injury of neurons involves excessive entry of extracellular calcium through the inappropriate activation of glutamate receptors. Glutamate, the chief excitatory neurotransmitter in the central nervous system, acts through two classes of receptors: the G protein–coupled receptor, which, when activated, leads to the release of intracellular calcium stores, and the glutamate-gated ion channels, which are distinguished by their sensitivity (or insensitivity) to N-methyl-d-aspartic acid (NMDA).

The NMDA-receptor channel is calcium-permeable, whereas the permeability of the non–NMDA-receptor channel (activated by the selective agonists kainate and -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA]) varies with the subunit composition of the receptor. If a particular subunit (named GluR2) is present, the channel is impermeable to calcium. In contrast, AMPA receptors that lack GluR2 are calcium-permeable. This activity of the GluR2 subunit depends on post-transcriptional editing of GluR2 mRNA. [100] The selective vulnerability of motor neurons to AMPA [101] could be explained either by the fact that the expression of GluR2 in motor neurons is normally lower than in other neurons102 or by an impairment in the editing of GluR2 mRNA in patients with ALS. [103] Either mechanism would lead to the expression of calcium-permeable AMPA receptors.

The possibility of glutamate excitotoxicity in patients with ALS [104,105] was suggested by the finding of increased glutamate levels in cerebrospinal fluid in patients with sporadic ALS. [106,107] High levels of glutamate could be excitotoxic, increasing levels of free calcium through the direct activation of calcium-permeable receptors or voltage-gated calcium channels.

The increased levels of glutamate in cerebrospinal fluid could also result from impaired glutamate transport in the central nervous system. The synaptic activity of glutamate is normally terminated by reuptake of the neurotransmitter by excitatory amino acid transporters (EAATs), predominantly [108] the EAAT1 and EAAT2 proteins on perisynaptic astrocytes. Rothstein [109] proposed that the selective loss of EAAT2 in patients with sporadic ALS impairs glutamate transport. This loss of EAAT2 was attributed to aberrant splicing of EAAT2 mRNA in affected regions of the central nervous system. [110] The presence of disease-specific and region-specific errors in the processing of EAAT2 mRNA, however, has not been confirmed. [111,112,113]

In patients with familial ALS, mutant SOD1 could lead to excitotoxic neuronal injury by catalyzing the inactivation of EAAT2, as it does in the presence of hydrogen peroxide. [114] This process would represent another link between familial and sporadic ALS.

Mutant SOD1 may also affect intracellular calcium levels through a direct toxic effect on mitochondria, which are essential for calcium homeostasis. [115,116] The high metabolic load of motor neurons and the consequent dependence of these cells on oxidative phosphorylation may make them particularly vulnerable to the loss of mitochondrial function.

  • Apoptosis

The many possible triggers of ALS could perturb diverse cellular functions essential for the survival of motor neurons. In SOD1-mediated ALS, motor neurons most likely die as a result of apoptosis, [117] although this point is disputed.118 Apoptosis involves the activation of the caspase proteases [119] in response to signals integrated by Bcl-2 proteins. [120] In mice with the G93A mutation in SOD1, the expression of anti-apoptotic Bcl-2 delayed the onset of motor neuron disease and prolonged life. [121] An inhibitor of the caspase, interleukin-1–converting enzyme, also slowed progression and extended survival, [122] as did the intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor. [123] Although apoptosis is a late event in the degeneration of motor neurons, inhibition of programmed cell death might ameliorate ALS.

Multiple theories have been proposed to explain the molecular pathogenesis of ALS. It is likely that more than one of these mechanisms contributes to human ALS. How these pathways interact remains to be explained.

CLINICAL PICTURE

History:

  • ALS begins insidiously as weakness, atrophy, or fasciculations in 1 or more limbs.

    • The manifestations are usually distal but gradually progress to involve the more proximal muscles.

    • Fasciculations and atrophy of the tongue may be noted.

    • Respiratory insufficiency is usually a late event.

Physical:

  • Physical examination reveals weakness and atrophy of the intrinsic hand muscles, hyperreflexia with extensor plantar responses, and clonus.

    • Thigh fasciculations are common.

    • Hyperreflexia can be variable and in some cases may be absent.

  • Sensory involvement, if any, is minimal.

  • Patients may present with an inability to write due to weakness. Gait function may be preserved.

Video 1. Fasciculations and prominent muscle atrophy of the small muscle of the hands in a patient suffering from amyotrophic lateral sclerosis (ALS)

 

Causes:

  • Nearly 10% of ALS cases are familial; the disease is transmitted in an autosomal dominant fashion.

    • The copper/zinc SOD1 gene is mutated in 10-20% of these familial cases.

    • Although the primary mechanism of SOD1-mediated neural injury is currently unknown, apoptosis, excitotoxicity, and oxidative stress are thought to play major roles in pathogenesis.

  • Sporadic ALS shares clinical features with familial ALS. However, no SOD1 mutations or polymorphisms have been identified in these patients. Common pathways of disease pathogenesis may play a role, with different molecular abnormalities that lead to similar phenotypes.

  • Several studies have shown an inflammatory component to the affected spinal cord regions, with the presence of activated microglia, reactive astrocytes, and IgG deposition. Whether this reaction precedes or accompanies the molecular events that promote neuronal cell death is unknown.

  • ALS animal models

    • The SOD1 transgenic model of ALS has provided important insights into potential pathogenetic mechanisms in human ALS.

    • These investigations suggest that SOD1 mutations act through a gain of function and involve free radical generation.

    • Disease onset in these animals correlates with a massive increase in degenerating mitochondria.

    • The murine SOD1 mutant also shows a proliferation of astrocytes and microglia within the brain and spinal cord, suggesting the presence of a reactive inflammatory component.

    • Knockout mice for SOD1 exhibit typical progressive muscle atrophy and weakness with selective damage to motor neurons that closely resembles human ALS.

    • In the wobbler mouse (a motor neuron disease model), administration of recombinant IGF-1 delays the deterioration of grip strength.

    • Mice that overexpress the human neurofilament (NF) heavy gene accumulate neurofilaments in the spinal cord, leading to an ALS-like disease. Disruption of normal axonal transport in motor neurons is believed to trigger the phenotype of this ALS model.

    • A motor neuron disease that resembles ALS can be generated in rabbits by sciatic subperineural administration of aluminum. Retrograde transport of aluminum results in anterior horn cell neurofilament accumulation and fragmentation of endoplasmic reticulum.

INVESTIGATION

Lab Studies:

  • Serum protein immunoelectrophoresis should be done to rule out a possible monoclonal gammopathy syndrome.

  • Lyme disease serology

    • If Lyme disease is suspected, enzyme-linked immunosorbent assay (ELISA) for Borrelia burgdorferi should be done.

    • This should be followed by IgG and immunoglobulin M (IgM) Western blots.

    • These tests are done to rule out ALS-mimicking neuroborreliosis (if history of exposure is obtained).

  • HIV testing

    • HIV testing in appropriate only if the history is highly suggestive of exposure.

    • A chronic, inflammatory, demyelinating polyradiculoneuropathy (CIDP) syndrome in HIV-infected patients can resemble ALS.

    • However, a clinical history of sensory signs is helpful in excluding this possibility.

  • Hexosaminidase A in urine is warranted when adult Tay-Sachs is suspected strongly.

Imaging Studies:

  • Brain or cervical spine MRI should be done to rule out dysmyelinative lesions (eg, in family history of Tay-Sachs disease) or to rule out cervical myelopathy.

  • The cervical spinal cord is often normal in appearance in ALS. Cord atrophy is generally a late manifestation of this disease. The most common finding noted in ALS is signal hyperintensity on T2-weighted images in the posterior limbs of the internal capsule and extending into the adjacent frontoparietal white matter. The phenomenon is caused by secondary degenerative changes related to the neuronal abnormality in the anterior horn cells of the spinal cord. Low signal intensity in a gyral distribution in the posterior frontal and anterior parietal lobes-already described with AD-has also been observed with ALS.

Figure 4. The most common finding noted in ALS is signal hyperintensity on T2-weighted images in the posterior limbs of the internal capsule and extending into the adjacent frontoparietal white matter. The phenomenon is caused by secondary degenerative changes related to the neuronal abnormality in the anterior horn cells of the spinal cord. Notice moderate central atrophy. (Click to magnify figure)

Figure 5. A, Left corticospinal tract degeneration in a patient with ALS. Axial proton density–weighted FSE MR image demonstrates a single round hyperintense focus within the posterior limb of the internal capsule on the left. B, Bilateral corticospinal tract degeneration in a patient with ALS. Coronal T2-weighted FSE MR image demonstrates linear hyperintensity extending from the subcortical white matter of both cerebral hemispheres through the internal capsule to the cerebral peduncles. (Click to magnify figure)

Other Tests:

  • Needle EMG and nerve conduction studies are the tests of choice for confirming the diagnosis of ALS.

    • The confirmation of ALS is facilitated by demonstrating diffuse denervation signs, decreased amplitude of compound muscle action potentials, and normal conduction velocities.

    • However, for a more detailed confirmation of ALS, more strict electrophysiologic criteria have been developed by a subcommittee of the World Federation of Neurology and are referred to as the “El Escorial” criteria for motor neuron disease.

  • Electrophysiological studies in the diagnosis of ALS – El Escorial criteria

    • ALS may be identified most reliably when the clinical and electrophysiological manifestations involve enough regions so that other possible causes of similar EMG abnormalities are highly unlikely. The electrodiagnostic examination is thus an extension of the clinical examination used to identify lower motor neuron (LMN) dysfunction. The electrophysiological features of LMN dysfunction include the following:

      • Conventional EMG studies: Features of LMN dysfunction in a particular muscle are defined by EMG concentric needle examination, which provides evidence of active and chronic denervation. Nerve conduction studies also are required to exclude motor neuropathy. Signs of active denervation include fibrillation potentials and positive sharp waves. Signs of chronic denervation include large motor unit potentials of increased duration with an increased proportion of polyphasic potentials, often of increased amplitude; reduced interference pattern with firing rates higher than 10 Hz, unless a significant UMN component is involved, in which case the firing rate may be lower than 10 Hz; and unstable motor unit potentials. The combination of active denervation findings and chronic denervation findings is required, but the relative proportion may vary from muscle to muscle.

      • Fasciculation potentials are a characteristic clinical feature of ALS. Their presence in EMG recordings is helpful in the diagnosis, particularly if they are of long duration and polyphasic of if they are present in muscles that have evidence of active or chronic partial denervation and re-innervation. Their distribution can vary. Their absence raises diagnostic doubts but does not preclude the diagnosis of ALS. Fasciculation potentials of normal morphology occur in healthy subjects (ie, benign fasciculations), and fasciculation potentials of abnormal morphology occur in other denervation disorders (eg, motor neuropathies).

      • Quantitative EMG studies: Signs of chronic partial denervation can be demonstrated by other techniques, including single-fiber EMG, macro EMG, turns/amplitude analysis and decomposition EMG, quantitative motor unit potential analysis, and motor unit number estimates (MUNE).

      • Topography of active and chronic denervation and re-innervation: The EMG signs of LMN dysfunction required to support a diagnosis of ALS should be found in at least 2 of these 4 regions of the CNS: brain stem and cervical, thoracic, and lumbosacral regions of the spinal cord. To be considered affected, each region must meet the following minimum criteria: In the brainstem region, EMG changes in 1 muscle (eg, tongue, facial muscles, jaw muscles) are sufficient. In the thoracic spinal cord region, EMG changes either in the paraspinal muscles at or below the T6 level or in the abdominal muscles are sufficient. In the cervical and lumbosacral spinal cord regions, at least 2 muscles innervated by different roots and peripheral nerves must show EMG changes.

      • Nerve conduction studies: Nerve conduction studies are required for the diagnosis, principally to define and exclude other disorders of the peripheral nerves, neuromuscular junctions, or muscles that may mimic or confound the diagnosis of ALS. These studies generally should be normal or near normal. Motor conduction times should be normal unless the compound muscle potential is small. Sensory nerve conduction studies can be abnormal in the presence of entrapment syndromes and coexisting peripheral nerve disease. Lower extremity sensory nerve responses can be difficult to elicit in the elderly.

    • Electrophysiological features compatible with UMN involvement include the following:

      • Increase of up to 30% in central motor conduction time determined by cortical magnetic stimulation

      • Low firing rates of motor unit potentials on maximal effort

    • Electrophysiological features suggesting other disease processes include the following:

      • Evidence of motor conduction block

      • Motor conduction velocities <70%, and distal motor latencies>30%, of the lower and upper limits of normal values, respectively

      • Sensory nerve conduction studies that are abnormal

      • Difficulty in eliciting sensory nerve action potentials may occur in entrapment syndromes, peripheral neuropathies, or advanced age

      • F-wave or H-wave latencies 30% above established normal values

      • Decrements 20% on repetitive stimulation

      • Somatosensory evoked response latency 20% above established normal values

      • Full interference pattern in a clinically weak muscle

      • Significant abnormalities in autonomic function or electronystagmography

  • These criteria constitute a summarized version of the currently accepted electrophysiologic criteria, which are known as the El Escorial Criteria of the World Federation of Neurology (revised, 1998). For more details on these criteria, including clinical criteria, please consult the internet site of the World Federation of Neurology and the literature reference by Brooks (see Bibliography).

Procedures:

  • Muscle biopsy should be done if the presentation is atypical (eg, very early onset, prominent lower extremity weakness with or without hand muscle involvement). This will confirm the presence of signs of denervation and reinnervation.

Histologic Findings: Muscle biopsy shows small angular fibers that are consistent with neurogenic atrophy (denervation) and fiber type grouping that is consistent with reinnervation.

Figure 6. Picture of the anterior aspect of the spinal cord. The anterior spinal nerve roots appear thin and gray (atrophic) (blue arrows) as compared to the posterior roots with preserved normal thickness. This lesion can be seen in amyotrophic lateral sclerosis and spinal muscular atrophy (motor neuron diseases) (Click to magnify figure)

MANAGEMENT

Medical Care:

  • Medical care in ALS is primarily palliative.

  • Patients should be involved in regular exercise and a physical therapy program.

  • Medications such as baclofen and tizanidine may be used to relieve severe spasticity.

  • Riluzone is an FDA-approved medication for prolonging tracheostomy-free survival.

  • Pharmacotherapy

Riluzole, a glutamate antagonist, is the only drug approved by the Food and Drug Administration for the treatment of ALS (Table 3). In two therapeutic trials, riluzole prolonged survival by three to six months. [124,125] In one of these trials, [124] treatment slightly slowed the decline in the strength of limb muscle; there was no benefit with respect to many measures of function in either trial. In one retrospective analysis, [126] patients who received riluzole remained in a milder stage of disease longer than did controls. For patients, the effects are invisible. The efficacy of riluzole has been taken as evidence in support of the excitotoxic-glutamate theory of the pathogenesis of ALS. But other glutamate antagonists, including branched-chain amino acids, lamotrigine, and dextromethorphan, had no beneficial effects in clinical trials. [127,128]

When tested in transgenic mice with mutant SOD1, gabapentin, like riluzole, extended survival but did not significantly affect the onset of clinical disease. [129] In contrast, vitamin E delayed the onset and the progression of the disease but failed to extend survival. Despite the moderate benefits of these agents in mice, gabapentin and vitamin E were of no benefit in trials of patients with ALS. [130,131]

Table 3. Therapy for ALS. (Click to view table 3)

More than 60 years ago, Wechsler touted the benefits of vitamin E in a series of patients with ALS. [132] Although Wechsler reported an improvement in the condition of Patient 4, identified on the basis of his initials and age as Lou Gehrig himself, Gehrig nevertheless died within a year. Other treatments have also failed in clinical trials. Agents that are currently being evaluated include xaliproden (which may foster the release of neurotrophic factors), creatine, [133] coenzyme Q10, intrathecally administered (by lumbar puncture) brain-derived neurotrophic factor, and orally administered brain-derived neurotrophic factor. [134] Inhibitors of cyclooxygenase-2 [135] and caspase inhibitors are being considered, and “high-throughput” drug development is on the horizon. [136] Reliable cell-based or other in vitro assays are needed to expedite the process of identifying potential therapies.

Surgical Care:

  • Early consideration for elective tracheostomy should be considered in patients with early signs of respiratory difficulty.

  • Home health aides can be helpful in managing secretions and feeding.

  • Computerized aids for writing and communication also can be helpful.

Consultations:

  • Surgeon or gastroenterologist – To perform elective tracheostomy or G-tube placement

  • Pulmonologist and respiratory therapist – For ventilator assistance and management of intercurrent infections and tracheostomy

  • Physical and respiratory therapists – To enhance muscle function and manage spasticity

  • Secretion management – For chest percussion therapy and suctioning

Diet:

  • Evaluate swallowing to quantify any dysphagia.

  • Modify the patient’s diet to prevent aspiration.

  • Consider a gastrostomy tube when patient cannot swallow fluids or soft foods.

Activity: No activity restriction is necessary. Patients should maintain a regular exercise regimen if the degree of weakness allows.

MEDICATION

Riluzole is the only medication that has shown treatment efficacy for ALS. That it prolongs tracheostomy-free survival compared to placebo has been shown in 2 randomized trials. No statistically significant difference in mortality rates was revealed at the end of these studies, however. In other clinical trials, creatine, human recombinant IGF-1, and ciliary neurotrophic factor (CNTF) also have shown promise.

Drug Category: Glutamate pathway antagonist - Riluzole is thought to counteract the excitatory amino acid (glutaminergic) pathways, but its exact mechanism of action in ALS is unknown.

Drug Name

 Riluzole (Rilutek)- Benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 h; steady state reached within 5 d with multiple dose administration; metabolism occurs in liver (P 450-dependent glucuronidation and hydroxylation); 6 major and a few minor metabolites produced.

Adult Dose

 50 mg PO bid

Pediatric Dose

 Not established

Contraindications

 Documented hypersensitivity, liver disease with elevations in liver function tests

Interactions

 Metabolized primarily by liver isoenzyme CYP1A2; other agents also metabolized via this enzymatic pathway (ie, theophylline, caffeine) may affect rate of elimination

Pregnancy

 C – Safety for use during pregnancy has not been established.

Precautions

 Use caution in patients with concomitant liver or renal insufficiency

Drug Category: Antispastic agents - These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Drug Name

 Baclofen (Lioresal)- Metabolized in liver and excreted primarily in urine; not a DEA-controlled substance.

Adult Dose

 5 mg PO tid; not to exceed 80 mg/d

Pediatric Dose

 Not established

Contraindications

 Documented hypersensitivity

Interactions

 May interact with alcohol, antipsychotics, MAOIs, narcotics, antipsychotics, tricyclic antidepressants, oral hypoglycemics, or insulin

Pregnancy

 C – Safety for use during pregnancy has not been established.

Precautions

 Use with caution in patients with seizure disorder or impaired renal function; serious reactions include somnolence and stupor, cardiovascular collapse, seizures, and respiratory depression; common adverse effects include headaches, dizziness, blurred vision, slurred speech, rash, weight gain, pruritus, constipation, increased perspiration; exercise caution in prescribing to patients already experiencing such symptoms; excessive dosing may lead to weakness

Drug Name

 Tizanidine (Zanaflex)- Centrally acting muscle relaxant metabolized in liver and excreted in urine and feces; used in patients with predominantly UMN involvement; not a DEA-controlled substance.

Adult Dose

 4-8 mg PO q8h prn; not to exceed 36 mg/d

Pediatric Dose

 Not established

Contraindications

 Documented hypersensitivity

Interactions

 May interact with alcohol (to increase somnolence, stupor) and oral contraceptives (to decrease its clearance); can increase hypotensive effects when administered concurrently with diuretics

Pregnancy

 C – Safety for use during pregnancy has not been established.

Precautions

 Use with caution in elderly patients and in patients with impaired renal function; serious reactions include hallucinations, severe bradycardia, and liver toxicity; more common adverse effects include dryness of mouth, somnolence and sedation, dizziness, malaise, constipation, increased spasms, and hypotension

FOLLOW-UP

Complications:

  • Aspiration pneumonia

  • Respiratory insufficiency

  • Progressive inability to perform activities of daily living (ADLs), including handling utensils for self-feeding

  • Deterioration of ambulation

  • Complications from wheelchair-bound or bedridden states, including decubitus ulcers and skin infections

Prognosis:

  • At the time of writing this review, no treatment significantly prolongs survival in ALS.

  • Prognosis is grim, but new medications that counteract neuronal apoptosis, oxidative stress, mitochondrial dysfunction, or excitotoxicity show significant promise.

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  1. Stem Cell therapy of Amyotrophic Lateral Sclerosis « Online newspaper of professor Yasser Metwally said

    May 12, 2009 @ 7:59 pm

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