2. DEFINITION
Motor neuron disease (MND) refers to a heterogeneous
group of conditions characterized by degeneration of lower
motor neurons (those that have cell bodies in the cranial
nerve nuclei or in the anterior horn of the spinal cord and
synapse directly on muscle) and/or upper motor neurons
(those that have cell bodies in the brain and synapse on
lower motor neurons). [1]
1. ROWLAND LP , SCHNEIDER N : Amyotrophic lateral sclerosis . New. Engl J. Med. ( 2002) 344 ( 22 ) : 1691 - 1700
3. SPECTRUM OF MOTOR NEURON DISEASE
Amyotrophic lateral sclerosis (ALS) is one of multiple
degenerative motor neuron diseases that are clinically defined,
based on the involvement of upper and/or lower motor neurons
ALS is the most common form and includes upper motor neuron
(UMN) and lower motor neuron (LMN) pathology
6. ALS PLUS syndrome
ALS is considered a degenerative disorder of the upper and lower
motor neurons.
However, some patients have all of the clinical features of ALS along
with features of other disorders such as
• Frontotemporal dementia
• Autonomic insufficiency
• Parkinsonism, supranuclear gaze paresis and/or sensory loss.
Such patients are considered to have ALS plus syndrome
7. Also known as LOU GEHRIG’S DISEASE
Degeneration of UMN and LMN
8. 1869 - First described in publication by Dr. Jean-Martin Charcot, in Paris
1881 - Lectures translated into English
9. A-myo-trophic Lateral Sclerosis
Amyotrophic: no muscle
nourishment
Lateral: refers to the the
areas in a person's spinal
cord where portions of the
nerve cells that signal and
control the muscles are
located
Sclerosis: scarring of the
affected nerves
10. INCIDENCE AND PREVALENCE
•Incidence rates for ALS in Europe and North America range
between 1.5 and 2.7 per 100,000/year.[2]
•Prevalence rates range between 2.7 and 7.4 per 100,000 [2] .
•Incidence of ALS may be lower among African, Asian, and
Hispanic ethnic groups than among Caucasians [3].
•The male to female ratio is about 1.3 to 1.5 for sporadic ALS,
although the ratio becomes closer to unity in the age group
over 70 years.
• ALS is most commonly sporadic. Genetic or familial ALS
represents only 10 percent of all ALS
• In the United States, about 7000 new cases of ALS are
diagnosed each year motor neuron disorder;a review of recent studies.j neuro sci 2001;191.
2. Worms, pm .the epidemiology of
3. Cronin s, hardiman o,traynor BJ ethnic variation in the incidence of als ; a systemic review.neurology 2007;68;1002.
11. GEOGRAPHIC CLUSTERS
High prevalence clusters of ALS are found in three regions of
the western Pacific including Guam, West New Guinea, and
the Kii Peninsula in Japan. The first cluster described was
found in the indigenous people of Guam [5] .
The frequent association of ALS with parkinsonism and
Alzheimer disease in this population has led to the designation
of this entity as the amyotrophic lateral sclerosis-parkinsonism
dementia complex (ALS-PDC)
Neurotoxicity was mediated by the local dietary consumption
of Cycad (Cycas circinalis) . Cycad is rich in beta-N-
methylamino-L-alanine (BMAA), an excitatory amino acid .
5-Kurland, LT, Mulder, DW. Epidemiologic investigations of amyotrophic lateral sclerosis. I. Preliminary report on geographic
distribution, with special reference to the Mariana Islands, including clinical and pathologic observations. Neurology 1954; 4:355
12. RISK FACTORS
•The only established risk factors for ALS are age and family
history.
•Increased risk for developing ALS has been suggested for
cigarette smokers, labourers engaged in agricultural work,
factory work, heavy manual labour, exposure to welding or
soldering, and work in the plastics industry .
•Repetitive muscle use, athleticism, playing professional
soccer, trauma, and electrical shock have also been
proposed as risk factors.
•A large case-control study found no association between
physical activity and the risk of developing ALS, but did find
that increased leisure time physical activity was associated
with a younger age of onset in patients with ALS [4].
4- Physical activity and the association with sporadic ALS. AU - Veldink JH; Kalmijn S; Groeneveld GJ; Titulaer MJ; Wokke JH; van
den Berg LH SO - Neurology 2005 Jan 25;64(2):241-5.
13. GENERAL: HEREDITARY VS SPORADIC ALS
Sporadic
Hereditary ALS
Feature ALS
Males:Females 1:1 1.7:1
Onset
Age distribution More younger More older
Mean age 46 years 56 to 63 years
Juvenile ALS 2, 4, 5 Rare
Bulbar features 20% to 30% Unusual
Involvement of Legs Common Occasional
14. INDIAN SCENARIO
The classical motor neuron disease seen in India is similar to
that in the west in the clinical picture and frequency of
occurrence. However, the onset of the illness is about a
decade earlier and the proportion of patients below the age of
30 is considerably high.
In addition to these forms of motor neuron disease in the
young, two specific types have been identified. Single limb
involvement variously described as
•Juvenile muscular atrophy of upper extremity
•Monomelic amyotrophy
•Wasted leg syndrome
•Benign focal amyotrophy.
15. The second type, the Madras pattern of motor neuron
disease was first described by Meenakshisundaram et al
from South India in 1970.
Essential features-
• sensorineural deafness
• Involvement of lower cranial nerve nuclei.
• Persistent asymmetry in the distribution of weakness.
There was no positive family history, all being sporadic in
occurrence
A characteristic biochemical finding of persistently low
citrate and elevated pyruvate level has been described in
patients with MMND.
16. PATHOLOGY
•ALS is characterized by motor neuron degeneration and death
with gliosis replacing lost neurons.
•Cortical motor cells (pyramidal and Betz cells) disappear
leading to retrograde axonal loss and gliosis in the
corticospinal tract.
• This gliosis results in the bilateral white matter changes
sometimes seen in the brain magnetic resonance imaging (MRI)
of patients with ALS.
• The spinal cord becomes atrophic. The ventral roots become
thin, and there is a loss of large myelinated fibers in motor
nerves.
• The affected muscles show denervation atrophy.
17. •Intracellular inclusions — Intracellular inclusions in
Degenerating neurons and glia are frequent neuropathological
findings of ALS.
Bunina bodies are unique to ALS and consist of eosinophilic
aggregates that are positive for cystatin C, a cysteine protease
inhibitor.
• Ubiquinated inclusions are seen in ALS .
TDP-43 protein — The TAR DNA binding protein 43 (TDP-43) has
been identified as a major component of ubiquinated inclusions
in sporadic ALS.
21. SOD1-MEDIATED TOXICITY
• Superoxide dismutase type 1 (SOD1) is a metalloenzyme that
catalyzes the conversion of toxic superoxide radicals to
oxygen (O2) and hydrogen peroxide (H2O2).
• Mutations in the SOD1 gene are associated with some cases
of familial ALS suggested that free radical toxicity may play a
role in the process of neuronal cell death or apoptosis [6] .
• SOD1 mutations have been found in 0.7 to 4% patients with
"sporadic" ALS [6] .
• SOD1 has pro-oxidant as well as anti-oxidant activity, and
mutated SOD1 could lead to oxidative injury by an increase
in pro-oxidant pathways, including generation of hydroxyl
radicals and nitration of tyrosine.
6-ANDERSEN PM : Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.
Curr. Neurol. Neurosci. Rep. ( 2006 ) 6 ( 1 ) : 37 - 46 .
22. THE MITOCHONDRION AS A TARGET OF MUTANT SOD1
Mitochondrial
Permeability
Transition
Translocator Outer
Membrane
Complex
23. Protein misfolding — Another hypothesis is that mutant
SOD1 induces protein aggregates that are potentially toxic to
motor neurons [7].
Microglial activation — Microglia are immune-modulating
cells of the CNS.
Their presence was observed in ALS tissue .
•Once activated, microglia elaborate a host of factors, including
nitric oxide, oxygen radicals, glutamate, and others that may
play roles in part of the cascade leading to motor neuron cell
death .
•Mutant SOD1 appears to increase the production of damaging
reactive oxygen species by activated microglia , thereby
accelerating motor neuron injury [8] .
7-WANG J , XU G , SLUNT HH : Coincident thresholds of mutant protein for paralytic disease and protein aggregation
caused by restrictively expressed superoxide dismutase cDNA. Neurobiol. Dis. ( 2005 ) 20 :943 - 952
8-MOISSE K , STRONG M : Innate immunity in amyotrophic lateral sclerosis. Biochimica et Biophysica Acta ( 2006 )
1762: 1083 - 1093
24. Excitotoxicity — The excitotoxicity hypothesis postulates
that excessive levels of the excitatory neurotransmitter
glutamate may initiate a cascade resulting in cellular death
of motor neurons in ALS.[9].
Excessive activation of glutamate receptors may lead to
increased entry of calcium into cells. In turn, intracellular
calcium may trigger a cascade of events that causes
neuronal cell death via
• Lipid peroxidation
• Nucleic acid damage
• and mitochondrial disruption.
9-VAN DEN BOSCH L , VAN DAMME P , BOGAERT E , ROBBERECHT W : The role of excitotoxicity in the pathogenesis
of amyotrophic lateral sclerosis. biochimica et Biophysica Acta ( 2006 ) 1762: 1068 - 1082
25. Cytoskeletal and axonal transport defect
•Deranged neurofilaments could disrupt axonal transport and
Cause axonal strangulation .
•Mutations in the neurofilament gene peripherin have been
found in sporadic and familial forms of ALS.
•Inhibition of axonal transport may be a cause of motor neuron
degeneration.
•Defects in the dynein-dynactin complex, a molecular motor
responsible for axonal transport along microtubules, have been
linked with motor degeneration.[10]
10-BOILLEE S , VANDE VELDE C , CLEVELAND D : ALS: a disease of motor neurons and their nonneuronal neighbors .
Neuron ( 2006 ) 52 :39 - 59 .
26. Mitochondrial dysfunction
The cause of the mitochondrial dysfunction is accumulation of
aggregated proteins (such as mSOD1) within the mitochondria
where
• they may clog protein translocation machinery.
• tie up antiapoptotic proteins such as Bcl-2 [11] .
Dysfunctional mitochondria may result in
.
•Impaired calcium buffering within neurons.
•Impaired energy production
•Spillage of reactive oxygen species into the cytoplasm.
•Release of cytohome C into the cytoplasm, which may
activate the apoptosis cascade
11-MANFREDI G , BEAL M : Mitochondrial dysfunction and energy metabolism in amyotrophic lateral sclerosis.In:
Amyotrophic Lateral Sclerosis.Brown RH, Swash M, Pasinelli P (Eds) ,Informa Healthcare, London, UK( 2006 ); 323-
331
27. Apoptosis
Apoptosis or programmed cell death cascades have been
implicated in several studies .
These reports have shown a number of the hallmarks of
apoptosis including
•DNA fragmentation
•caspase activation
•altered expression of the antiapoptotic protein Bcl-2 [16]
16-LI M , ONA VO , GUEGAN C et al. : Functional role of caspase 1 and 3 in ALS. Science ( 2000 ) 288 :335 - 339
28. CLINICAL FEATURES:
LOWER MOTOR SYMPTOMS
Loss of muscle strength
Atrophy
Fasciculations
Muscle cramps
Difficulty in chewing, swallowing & movement of
face and tongue
29. CLINICAL FEATURES:
UPPER MOTOR SYMPTOMS
Loss of dexterity
Slowed movements
Loss of muscle strength
Stiffness
Emotional lability
30.
31. DIAGNOSIS OF ALS
• No biological marker has been identified yet.
• Series of clinical and neurological exams.
• MRI
• Myelogram of cervical spine (an x-ray analysis that allows
the detection of lesions in selected area of the spinal cord)
• Muscle and/or nerve biopsy
• Electromyography (EMG) and nerve conduction velocity
(NCV) to measure muscle response to nervous stimulation.
33. Other Motor Neuron Diseases Neurodegenerative Diseases
Primary lateral sclerosis (UMN only) Parkinson’s, Progressive Supranuclear
Palsy, Multiple sclerosis.
Progressive muscular atrophy (LMN only)
Progressive bulbar palsy
Malignancy
Primary/metastasis to CNS
Structural lesions Motor neuron syndromes with MM,
cervical spondylosis Lymphoma, lung, breast.
parasaggital/foramen magnum tumor
spinal cord AV malformation Toxic Exposure
alcohol, heavy metals.
Neuropathies
CIDP
Endocrine
hyperthyroidism
Myopathies hyperparathyroidism.
PM, inclusion body myositis
Infectious
HIV, CMV
NM Junction
Myasthenia gravis
34.
35. Riluzole
Riluzole — Three separate mechanisms of riluzole are thought
to reduce glutamate-induced excitotoxicity:
• inhibition of glutamic acid release
• noncompetitive block of NMDA receptor mediated responses
• direct action on the voltage-dependent sodium channel
Dose and side effects — The recommended dose of Riluzole is
100 mg per day.
36. Recommendations
The American Academy of Neurology has issued a practice
advisory on the treatment of ALS with Riluzole.
Patients most likely to benefit from treatment include those
who have:
• Definite or probable ALS by El-Escorial criteria , in whom other
causes of progressive muscle atrophy have been ruled out
• Symptoms present for less than five years
• Vital capacity (VC) greater than 60 percent of predicted
• No tracheostomy
37. SIDE EFFECTS
Very Common
Asthenia.
Nausea.
Common
Alterations in liver function tests.
Headache.
Abdominal pain.
Pain.
Vomiting.
Dizziness.
Tachycardia.
Somnolence.
Oral Paraesthesia.
Uncommon
Anaemia.
Anaphylactoid reaction.
Neutropenia.
Angioedema.
Pancreatitis
38. CONTRAINDICATIONS
•Hepatic disease or baseline transaminases greater than 3 times the
upper limit of normal or raised bilirubin.
•Pregnancy and breastfeeding
MONITORING
•Regular hepatic function blood tests (baseline then every month for 3
months, then every 3 months for a further 9 months and annually thereafter)
are recommended to monitor tolerability.
• ALT levels should be measured more frequently in patients who develop
elevated ALT levels >2x upper limit of normal.
• If patient presents with febrile illness then monitoring white blood cell
count for neutropenia is strongly recommended.
STOP TREATMENT IF
• Liver function tests – ALT greater than 5 times the upper limit of normal .
• Blood disorders - absolute neutrophil count less than 500/mm3 .
39. Ceftriaxone
•A cephalosporin antibiotic.
•It increases expression of EAAT2/GLT1 and prolongs
survival in MND patients.
•Has good brain penetration and has a good short-
term safety record.
•However, intravenous administration is required.
13-ROTHSTEIN JD, PATEL S, REGAN MR et al. : β-lactam antibiotics offer neuroprotection by
increasing glutamate transporter expression. Nature ( 2005 ) 433: 73 - 77 .
40. •IV ceftriaxone, 4 gm/day, four sequential days weekly in early 2004.
•Patient improvement was rapidly evident.
•Objective muscle strength was significantly improved and muscle
atrophy was visibly diminishing.
•After 12 weeks of assistance was no longer required for mobility, and
squats became possible for the first time since presentation.
•Ceftriaxone cessation after 12 weeks resulted in partial return of
signs and symptoms typical of als but with improvement on re-
infusion.
41. Edavarone
Has multiple ALS-relevant mechanisms of action,
including
• free radical scavenging.
• blocking the mitochondrial transition pore and
upregulating bcl-2 expression.
• there was a suggestion of slowed disease progression as
measured by the ALS Functional Rating Scale .[14]
14-YOSHINO H , KIMURA A :Investigation of the therapeutic effects of edaravone, a free radical
scavenger, on amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 :241 - 245
42. • 20 subjects with ALS received either 30 mg (5 ) or 60 mg (15) of
edaravone via intravenous drip once per day.
•Two weeks of administration was followed by a two-week
observation period. This four-week cycle was repeated six times.
•There was the change in the revised ALS functional rating scale
(ALSFRS-R) score.[14]
43. Tamoxifen
• Used to treat breast cancer.
• Acts as an anti-inflammatory through inhibition of PKC. In a
Phase II study of patients with ALS, it was safe and well
tolerated; furthermore, there was a suggestion of efficacy
with increased survival at certain dosages [18] .
•Tamoxifen has been extensively used in humans and has a
good safety profile.
18-TRAYNOR BJ , BRUIJN L , CONWIT F et al. : Neuroprotective agents for clinical trials in ALS: a systematic
assessment. Neurology ( 2006 ) 67 :20 - 27 .
44. •Two-year study of 60 people with (ALS)who took varying dosages of
tamoxifen.
•Participants who took more than 20 milligrams a day had a better
survival rate than those who took fewer than 10 milligrams a day.
•After two years, 27 out of 37 (73 percent) of the participants in the
high-dose tamoxifen group had survived, while only 11 of 23 (48
percent) of those in the low-dose groups were still living.
45. Arimoclomol
•Heat shock proteins are involved in protein repair, and
thus are cytoprotective.
•Motor neurons appear to have a high threshold for
activation of the heat shock protein pathway, and
mutant SOD1 may contribute to reduced anti-apoptotic
capability.
•Treatment with Arimoclomol, a co-inducer of heat
shock proteins, delayed disease progression and
improved survival.[19]
19. CUDKOWICZ M , SHEFNER M , SIMPSON E et al. : A multicenter, dose ranking safety and
pharmacokinetic study of arimoclomol in ALS. Amyotrophic Lateral Sclerosis ( 2006 ) 7 ( S1 ) : 113
46. Lithium
•An antiapoptotic agent that promotes autophagy , and
may therefore have neuroprotective effects.
• An open-label ALS clinical trial compared 16 patients
treated with Riluzole plus Lithium to 28 patients treated
with Riluzole alone [20] .
• At the end of the 15 month follow-up period, all
patients in the Lithium group were alive, while mortality
in the Riluzole monotherapy group was 29 percent.
• In addition, disease progression, as measured by
Functional Rating Scales and pulmonary function was
slower in patients, treated with lithium.
20-Lithium induces autophagy by inhibiting inositol monophosphatase. AU - Sarkar S; Floto RA; Berger Z; Imarisio S;
Cordenier A; Pasco M; Cook LJ; Rubinsztein DCSO - J Cell Biol. 2005 Sep 26;170(7):1101-11
47. Stem cells
There are a number of ways in which stem cells could be
beneficial in ALS. These include
•Replacement of dying motor neurons.
•Replacement of defective glial cells.
•Sources of growth factor production.
•‘sinks’ for excitotoxins such as glutamate.
Even more recently, eight patients with ALS were given
intrathecal injections of autologous mesenchymal stem cells,
along with intravenous erythropoietin.
Transient benefits on strength, and a trend toward a reduced
slope of decline in ALS Functional Rating Scale was reported.
15. BRUIJN L , CUDKOWICZ M :Therapeutic targets for amyotrophic lateral sclerosis: current treatments
and prospects for more effective therapies expert rev.neorotherapeutics(2006) 6(3): 417-428.
17. KIM S , KIM H , KOH S et al. :Effectiveness of recombinant human erythropoietin therapy in
amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 ( S1 ) : 9.
48. ANTISENSE OLIGONUCLEOTIDE
•Another approach to gene therapy employs antisense
oligonucleotides
•To downregulate or silence mutant genes.
•The antisense strategy targets specific RNA sequences by
constructing complementary oligonucleotides that bind to the
native mRNA sequences and reduce their translation and
subsequent protein expression.
•In a preliminary study, continuous intraventricular infusion of
antisense oligonucleotides to SOD1 reduced both SOD1 protein
and mRNA levels.
•This treatment significantly slowed disease progression when
initiated near disease onset.
12. SMITH RA , MILLER TM ,YAMANAKA K et al. : Antisense oligonucleotide therapy for
neurodegenerative disease. J. Clin.Invest. ( 2006 ) 116 ( 8 ) : 290 - 2297 .
49. COMPOUNDS ALS Research Stage MECHANISM
Co-enzyme q10 Phase II Antioxidant.
Facilitates
mitochondrial
respiration.
Creatinine. Phase II Antioxidant.
Facilitates
mitochondrial
respiration.
Glatirmer acetate. Phase II Evokes
neuroprotective
T.cell response.
Minocycline. Phase III Prevents microglial
activation.
Prevents caspase
activation.
Dex-pramipexole Phase II Antioxidant.
50.
51. Spasticity
Baclofen 5 to 10 mg twice daily to three
times daily.
Tizanidine 2 to 4 mg by mouth twice
daily up to a total dose of 24 mg daily.
Memantine starting at 5 mg daily,
increasing by 5 mg a week to a
maximum of 20 mg twice a day.
Tetrazepam 50 mg at bedtime,
increasing by 25 mg a day to a maximum
dose of 150 mg taken two to three times
a day.
52.
53. Non-pharmacologic management
Suction machine (not usually helpful for thick
mucus, but helpful with sialorrhea)
Mechanical insufflation-exsufflation (In-
Exsufflator cough machine)
Manually assisted coughing techniques
54.
55.
56. Also known as: pseudobulbar palsy,
emotional incontinence, pathologic
crying/laughing
The emotional lability is NOT a mood
disorder, but is an uncontrolled outburst
and is a very troubling symptom for
patients.
It is an abnormal affective display that
can be seen in about 50% of ALS patients.
58. Speech therapy often helpful early
Computer technology offer many options to
assist with patient communication
59. Urinary frequency/urgency
In the absence of UTI, often due to spasticity that
responds well to Oxybutinin
Peripheral edema
Often dependent: elevation, massage, compression
hose (r/o DVOT)
Laryngospasm
Sudden reflex closure of vocal cords due to variety of
stimuli, usually resolves spontaneously
H1 and H2 blocking agents may be helpful
60. Steven Hawking
Proved Einstein's Theory
of Relativity
He currently uses an
electric wheelchair to
get around
A computerized voice
synthesizer operated by
facial muscles in order
to speak
61. 1. ROWLAND LP , SCHNEIDER N : Amyotrophic lateral sclerosis . New. Engl J. Med. ( 2002) 344 ( 22 ) : 1691 – 1700
2. Worms, pm .the epidemiology of motor neuron disorder;a review of recent studies.j neuro sci 2001;191.
3. Cronin s, hardiman o,traynor BJ ethnic variation in the incidence of als ; a systemic review.neurology
2007;68;1002.
4- Physical activity and the association with sporadic ALS. AU - Veldink JH; Kalmijn S; Groeneveld GJ; Titulaer MJ;
Wokke JH; van den Berg LH SO - Neurology 2005 Jan 25;64(2):241-5.
5-Kurland, LT, Mulder, DW. Epidemiologic investigations of amyotrophic lateral sclerosis. I. Preliminary report
on geographic distribution, with special reference to the Mariana Islands, including clinical and pathologic
observations. Neurology 1954; 4:355
6-ANDERSEN PM : Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.
Curr. Neurol. Neurosci. Rep. ( 2006 ) 6 ( 1 ) : 37 - 46 .
7-WANG J , XU G , SLUNT HH : Coincident thresholds of mutant protein for paralytic disease and protein aggregation
caused by restrictively expressed superoxide dismutase cDNA. Neurobiol. Dis. ( 2005 ) 20 :943 - 952
8-MOISSE K , STRONG M : Innate immunity in amyotrophic lateral sclerosis. Biochimica et Biophysica Acta ( 2006 )
1762: 1083 - 1093
9-VAN DEN BOSCH L , VAN DAMME P , BOGAERT E , ROBBERECHT W : The role of excitotoxicity in the pathogenesis
of amyotrophic lateral sclerosis. biochimica et Biophysica Acta ( 2006 ) 1762: 1068 - 1082
10-BOILLEE S , VANDE VELDE C , CLEVELAND D : ALS: a disease of motor neurons and their nonneuronal neighbors .
Neuron ( 2006 ) 52 :39 - 59 .
11-MANFREDI G , BEAL M : Mitochondrial dysfunction and energy metabolism in amyotrophic lateral sclerosis.In:
Amyotrophic Lateral Sclerosis.Brown RH, Swash M, Pasinelli P (Eds) ,Informa Healthcare, London, UK( 2006 ); 323-
331
62. 12. SMITH RA , MILLER TM ,YAMANAKA K et al. : Antisense oligonucleotide therapy for
neurodegenerative disease. J. Clin.Invest. ( 2006 ) 116 ( 8 ) : 290 - 2297 .
13-ROTHSTEIN JD, PATEL S, REGAN MR et al. : β-lactam antibiotics offer neuroprotection by
increasing glutamate transporter expression. Nature ( 2005 ) 433: 73 - 77 .
14-YOSHINO H , KIMURA A :Investigation of the therapeutic effects of edaravone, a free radical
scavenger, on amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 :241 - 245
15. BRUIJN L , CUDKOWICZ M :Therapeutic targets for amyotrophic lateral sclerosis: current treatments
and prospects for more effective therapies expert rev.neorotherapeutics(2006) 6(3): 417-428.
16-LI M , ONA VO , GUEGAN C et al. : Functional role of caspase 1 and 3 in ALS. Science ( 2000 ) 288 :335 - 339
17. KIM S , KIM H , KOH S et al. :Effectiveness of recombinant human erythropoietin therapy in
amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 ( S1 ) : 9.
18-TRAYNOR BJ , BRUIJN L , CONWIT F et al. : Neuroprotective agents for clinical trials in ALS: a systematic
assessment. Neurology ( 2006 ) 67 :20 - 27 .
19. CUDKOWICZ M , SHEFNER M , SIMPSON E et al. : A multicenter, dose ranking safety and
pharmacokinetic study of arimoclomol in ALS. Amyotrophic Lateral Sclerosis ( 2006 ) 7 ( S1 ) : 113
20-Lithium induces autophagy by inhibiting inositol monophosphatase. AU - Sarkar S; Floto RA; Berger Z; Imarisio S;
Cordenier A; Pasco M; Cook LJ; Rubinsztein DCSO - J Cell Biol. 2005 Sep 26;170(7):1101-11