1) Recent advances in understanding the pathophysiology of motor neuron disease include insights into excitotoxicity, oxidative stress, mitochondrial defects, impaired axonal transport, protein aggregation, inflammation, and neurotrophic factor deficits. 2) Riluzole remains the only FDA-approved drug shown to modestly prolong survival for patients with ALS, though Edaravone may also provide benefits for certain subgroups. Experimental therapies targeting genes, antioxidants, neurotrophic factors, and other mechanisms are under investigation. 3) Making an accurate diagnosis involves evaluating the patient's history, physical exam, electrodiagnostic testing, imaging, and sometimes genetic or biomarker analysis to differentiate ALS from other conditions.

1. RECENT ADVANCES AND MANAGEMENT
OF MOTOR NEURON DISEASE WITH
SPECIAL EMPHASIS ON EDAVARONE
“Story of the
helpless body but
thoughtful mind”
DR SWAPNIL SAMADHIYA
SR NEUROLOGY
GMC KOTA

2. CONTENT
Recent advances
• Pathophysiology understanding
• Management (1)Diagnosis
(2)Treatment

3. PATHOPHYSIOLOGICAL PROCESSES IN ALS
• Excitotoxicity - Excessive glutamate induced stimulation of
NMDA & AMPA → massive calcium influx → nitric acid
formation and neuronal death .
• Oxidative stress - increased sensitivity to oxidative damage
- accumulation of free oxygen species → cell death.

4. • Mitochondrial defect - Abnormalities of mitochondrial
morphology and biochemistry ,sporadic MND patients, in
SOD1 transgenic mice, and in cellular models .
• Impaired axonal transport - reported in transgenic mice.

5. • Abnormal Neurofilament aggregation
• Protein aggregation - Intracellular inclusions have been
observed in MND.
• Inflammatory dysfunction - Evidence suggests the
possibility of an inflammatory process.

6. • Deficits in neurotrophic factors and dysfunction of signaling
pathway
Deficits in levels of neurotrophic factors, e.g., IGF-1, have
been reported in MND.
• Apoptosis - final process, markers of apoptosis detected.

7. • To date, more than 25 MND genes have been discovered,
explaining 10% of sporadic and 65% of familial disease.
• The C9orf72 repeat expansion is the most common genetic
cause of MND.

8. Proposed disease mechanisms for ALS and
the genes associated with them

11. Diagnosis
• History and physical examination
• In 2008, the Awaji ALS criteria proposed,approximately 21
percent of patients die from ALS without El Escorial criteria
• Recent Awaji - Shima algorithm for neurophysiological
diagnosis of suspected ALS stresses the importance of
Fasciculation potentials ,denervation.

12. • 2012 systematic review and meta-analysis of eight studies
evaluating the accuracy of the Awaji criteria for the
diagnosis of ALS.
• The pooled sensitivity was higher with the Awaji criteria vs
revised El Escorial criteria (81 versus 62
percent),specificities for both 98 percent.

14. • Electrodiagnostic examination(NCV,EMG)
• Transcranial magnetic stimulation(experimental technique)
External stimulation magnet
Motor Cortex, Cervical Spine, Lumbosacral Spine
CMAP recorded from surface.

16. • Latency difference, cranial versus cervical or cranial versus
lumbosacral stimulation ,central motor conduction time
reflect integrity.
• Slowing central motor conduction ,ALS.
• Cortical hyperexcitability , early and specific feature of ALS
• Sensitivity and specificity (73 and 81 percent, respectively)

17. • Elevated levels of CSF neurofilaments (Neurofilament Light
(NF-L) and phosphorylated Heavy (pNF-H) chain)
• Positive correlation of both neurofilaments (NFs),disease
progression
• Genetic testing

18. • Neuromuscular ultrasound-prospective unblinded report
81 patients with sporadic ALS
• Fasciculations detected at a significantly higher rate by
ultrasound compared with needle electromyography (EMG)
• Tongue (60 versus 0 percent), Biceps Brachii (88 versus 66
percent), Tibialis Anterior (83 versus 45 percent)

20. Neuroimaging
• Conventional MRI is usually normal
• Increased signal in the corticospinal tracts on T2-WI , FLAIR
and hypointensity of the motor cortex on T2-WI

21. Garland sign Motor band sign

22. • Experimental imaging techniques to detect upper motor
neuron disease in ALS include
1. Magnetic resonance spectroscopy (reduced NAA levels or
lower ratios of NAA:Cr , NAA:Cho, or NAA:Cr+Cho in the
motor cortex and corticospinal tract of patients with ALS).
2. Diffusion-tensor imaging

23. • Diffusion-tensor imaging, structural neuroimaging
technique ,measures extent and direction of water
diffusion.
• Patients with ALS have been shown to have decreased
fractional anisotropy and increased mean diffusivity

25. TREATMENT
RILUZOLE
• Only known drug to have any impact on survival in
ALS
• Two multicenter randomized trials

26. • Prospective, double-blind, placebo-controlled trial 155 ALS,
survival at 12 months ,significantly higher ,riluzole (100
mg/day) compared with controls (74 versus 58percent).
• For bulbar-onset ALS, survival at 12 months ,riluzole
group(73 versus 35 percent).

27. • Larger follow-up trial, 959 patients with clinically probable
or definite ALS of less than five years duration were
randomly assigned treatment with riluzole (50 mg, 100 mg,
or 200 mg daily) or placebo.
• Follow-up of 18 months, survival without tracheostomy,
riluzole-treated group (100mg/day) compared with controls
(57 versus 50 percent).
• Functional measures did not differ

28. Mechanism of action
• Reduce glutamate-induced excitotoxicity:
1. Inhibition of glutamic acid release,
2. Noncompetitive block of N-methyl-d-aspartate (NMDA)
receptor mediated responses,
3. Direct action on the voltage-dependent sodium channel

29. • Patients most likely to benefit from treatment with Riluzole
include
1. Definite or probable ALS by El Escorial criteria, in whom
other causes of progressive muscle atrophy have been
ruled out
2. Symptoms present for less than five years
3. Vital capacity (VC) greater than 60 percent of predicted
4. No tracheostomy

30. • Available preparations include tablet, suspension,
and an orally disintegrating film.
• COST 7000-12000 rs /mnth

31. EDARAVONE
• Free radical scavenger that is thought to reduce oxidative
stress.
• Approved in 2015 for the treatment of ALS in JAPAN and
KOREA
• US food and drug administration (FDA) approval for all
people with ALS in may 2017 ,ALS in the United States

33. • An earlier 24-week trial 206 subjects with ALS who had a
disease duration of three years, lived independently , and
had forced vital capacity (FVC) of ≥70 percent .
• The primary outcome measure was the change in the
revised ALS functional rating scale (ALSFRS-R) score, in
which higher scores indicate better function.

35. • After the 24-week treatment period, no statistically
significant benefit for function on the ALSFRS-R score with
edaravone treatment compared with placebo (-5.7 versus -
6.35,mean difference 0.65, 95% CI -0.90 to 2.19).

36. • A post hoc analysis showed a greater treatment effect in
the subgroup of subjects with
1. Definite or probable ALS at entry who had scores of 2 or
more on all items of the ALSFRS-R
2. An FVC of at least 80 percent at baseline
3. A disease duration of two years or less

37. • A subsequent controlled trial enrolled 137 Japanese
subjects with early stage ALS who were selected to match
the subset of patients defined by the post hoc analysis of
the previous trial
1. Definite or probable ALS by the el escorial criteria
2. A disease duration of two years or less
3. Independent living status
4. Scores of 2 or more on all items of ALSFRS-R
5. FVC of ≥80 percent) .

38. • Subjects were randomly assigned to treatment with
edaravone or placebo.
• At 24 weeks, there was a smaller decline in function,
measured by the ALSFRS-R, for the edaravone group
compared with the placebo group (-5.01 versus -7.50,
difference 2.49, 95% CI 0.99-3.98).
• This change was considered clinically significant, with a
slowing of approximately 33 percent.

41. Edaravone dosing and adverse effects
• Edaravone 60 mg intravenous infusion over 60 minutes.
Treatment is started with daily infusion for 14 days,
followed by 14 days off treatment.
• Subsequent treatment cycles involve daily edaravone 60
mg infusions on 10 days within a 14-day period, followed
by 14 days off treatment.
• The estimated yearly cost of edaravone in the United
States is approximately $146,000.

42. • Injection-site contusion, gait disturbance, and headache.
• Edaravone contains sodium bisulfite, which may cause
allergic reactions including asthmatic episodes in
susceptible individuals.
• 5 percent of patients with asthma, whereas individuals
without asthma are rarely affected.
• Regular LFT ,RFT follow up

43. EXPERIMENT AL THERAPY
Number of agents are under investigation for the treatment of
ALS
• Antisense oligonucleotide therapy for genetic forms of ALS.
• AMX0035
• Arimoclomol
• Skeletal muscle activators (eg, levosimendan, reldesemtiv)
• Masitinib
• Memantine
• Mexiletine
• Neurotrophic factor (NTF)-secreting mesenchymal stromal
cells (MSC-NTF cells) and other stem cell treatments.
• Retigabine
• Tamoxifen
• Tocilizumab

44. 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 SOD1
gene mutations may contribute to reduced antiapoptotic
capability

45. • A trial of arimoclomol in 38 people with SOD1-mutant ALS
found that a dose of 200 mg three times daily was safe and
well tolerated for up to 12 months.
• Secondary efficacy outcomes suggested possible clinical
benefit; however ,confidence intervals were wide due to
the small number of patients enrolled.
• A larger study in patients with sporadic ALS has been
initiated.

46. Gene therapy
• Research in a transgenic mouse model found that insulin-
like growth factor 1 (IGF-1) can be delivered directly to
respiratory and motor limb muscles to target the affected
motor neurons by using the retrograde transport ability of
adeno-associated virus (AAV).
• Delays disease onset and prolongs survival by 30 percent in
the preclinical model and 18 percent in the
postsymptomatic model in the SOD1-mutant mouse model.

47. • Glial cell line-derived neurotrophic factor (GDNF) gene was
injected into lower-extremity muscles of a G93A transgenic
mouse using a replication defective adenoviral vector.
• Larger motor neurons were seen in the injected muscles,
suggesting gene therapy may delay progression in ALS.
• Lumbar injection of neural progenitor cells expressing
GDNF (CNS10-NPC-GDNF) in patients with ALS has
completed enrollment.

48. • 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.

49. • In a preliminary study , continuous intraventricular infusion
of antisense oligonucleotides to SOD1 reduced both SOD1
protein and mRNA levels throughout the rat brain and
spinal cord.
• In addition, this treatment significantly slowed disease
progression when initiated prior to disease onset in a rat
model of ALS caused by an SOD1 mutation.

50. • A preliminary human trial of an antisense oligonucleotide
to SOD1 (ISIS 333611) found that the drug was well
tolerated and achieved predicted levels in cerebrospinal
fluid and plasma.
• A larger study is planned.

51. • Additional studies are ongoing, including a phase 1
multicenter study of intrathecal antisense oligonucleotides
in patients with C9ORF72-associated ALS.

52. OTHER STRATEGIES
Neurotrophic factors
• Trials utilizing IGF-1 and other neurotrophic factors
unsuccessful
• The limitations and shortcomings unfavorable
pharmacokinetics, bioavailability and dose-limiting
toxicities, antibody inactivation.
• However , alternative methods gene therapy or
mesenchymal derived cells modified to deliver growth
factor experimental.

53. Antioxidants
• Oxidative stress has been implicated in the pathogenesis of
ALS
• The production of oxygen free radicals resulting in
1. Lipid peroxidation
2. Cytoskeletal disruption
3. Damage to the mitochondria

54. • Randomized controlled trials have not shown benefit for
other antioxidants.
• At least two trials have failed to demonstrate significant
benefit of vitamin E as add on therapy to Riluzole in ALS.
• In study , subjects were randomly assigned to vitamin E 500
mg twice daily or placebo; there was no significant
difference in disease progression at 12 months.

55. • In another randomized controlled trial testing the free
radical scavenger Nacetylcysteine (NAC), there was no
significant difference in delay of progression of the disease
between the treatment and placebo groups
• However , there was a beneficial trend in survival for the
patients with limb-onset disease.

56. CONCLUSION
• Disease-modifying treatment (ALS) are limited. Riluzole is
the only drug to have any impact on survival, slowing ALS
progression to a modest degree.
• Riluzole 50 mg twice daily. Patients benefit from those with
definite or probable ALS with symptoms present for less
than five years, a forced vital capacity (FVC) >60 percent of
predicted, and no tracheostomy .

57. • For patients with ALS who have a disease duration of two
years or less, are living independently , and have an FVC
≥80 percent, we suggest treatment with EDARAVONE
• We also suggest EDARAVONE for patients with more
advanced ALS
• While few disease-modifying drugs are available for ALS, a
number of agents are under investigation

58. REFERENCES
• Bradley’s Neurology in clinical practice 7th edition
• Adams & Victor’s Principles of Neurology 10th edition
• Edaravone in Amyotrophic Lateral Sclerosis—Lessons from the
Clinical Development Program and the Importance of a Strategic
Clinical Trial Design Said R Beydoun and Jeffrey Rosenfeld;DOI:
https://doi.org/10.17925/USN.2018.14.1.47
• White Matter Microstructure Breakdown in the Motor Neuron
Disease Spectrum: Recent AdvancesUsing Diffusion Magnetic
Resonance Imaging; doi: 10.3389/fneur.2019.00193
• UPTODATE.COM

59. THANK YOU