Motor neuron disease

Motor neuron disease

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

9. 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 .

10. 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.

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

12. 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)

13. 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

14. 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)

15. 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

16. Garland sign Motor band sign

17. Experimental imaging techniques to detect upper motor neuron disease in ALS include 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). Diffusion-tensor imaging

18. 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

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

20. 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).

21. 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

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

23. Patients most likely to benefit from treatment with Riluzole include 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

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

25. 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

26. 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.

27. 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).

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

29. 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 Definite or probable ALS by the el escorial criteria A disease duration of two years or less Independent living status Scores of 2 or more on all items of ALSFRS-R FVC of ≥80 percent) .

30. 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.

31. 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.

32. 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

33. 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

34. 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

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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 .

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

42. 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.

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

44. 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.

45. 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 .

46. 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 .

47. 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

48. REFERENCES Bradley’s Neurology in clinical practice 7 th edition Adams & Victor’s Principles of Neurology 10 th 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

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