DR.Rudrashis Samal            JUNIOR RESIDENTP. G. Department of Medicine
DEFINITION    Motor neuron disease (MND) refers to a heterogeneous    group of conditions characterized by degeneration o...
SPECTRUM OF MOTOR NEURON DISEASEAmyotrophic lateral sclerosis (ALS) is one of multipledegenerative motor neuron diseases t...
 Primary   Lateral sclerosis Hereditary   spastic paraplegia HTLV-1   associated myelopathy Adrenomyeloneuropathy Lat...
 Poliomyelitis MultifocalMotor Neuropathy Benign Focal Amyotrophy Hopkins’ syndrome: Acute post-asthmatic  amyotrophy...
ALS PLUS syndromeALS is considered a degenerative disorder of the upper and lowermotor neurons.However, some patients have...
Also known as LOU GEHRIG’S DISEASEDegeneration of UMN and LMN
1869 - First described in publication by Dr. Jean-Martin Charcot, in Paris1881 - Lectures translated into English
A-myo-trophic Lateral Sclerosis                  Amyotrophic: no muscle                  nourishment                  Late...
INCIDENCE AND PREVALENCE•Incidence rates for ALS in Europe and North America rangebetween 1.5 and 2.7 per 100,000/year.[2]...
GEOGRAPHIC CLUSTERSHigh prevalence clusters of ALS are found in three regions ofthe western Pacific including Guam, West N...
RISK FACTORS  •The only established risk factors for ALS are age and family  history.  •Increased risk for developing ALS ...
GENERAL: HEREDITARY VS SPORADIC ALS                                       Sporadic                      Hereditary ALSFeat...
INDIAN SCENARIOThe classical motor neuron disease seen in India is similar tothat in the west in the clinical picture and ...
The second type, the Madras pattern of motor neurondisease was first described by Meenakshisundaram et alfrom South India ...
PATHOLOGY•ALS is characterized by motor neuron degeneration and deathwith gliosis replacing lost neurons.•Cortical motor c...
•Intracellular inclusions — Intracellular inclusions inDegenerating neurons and glia are frequent neuropathologicalfinding...
PATHOGENESIS
GENETICS OF ALS
TOXIC MECHANISMS IN ALS
SOD1-MEDIATED TOXICITY• Superoxide dismutase type 1 (SOD1) is a metalloenzyme thatcatalyzes the conversion of toxic supero...
THE MITOCHONDRION AS A TARGET OF MUTANT SOD1MitochondrialPermeability  Transition                                  Translo...
Protein misfolding — Another hypothesis is that mutantSOD1 induces protein aggregates that are potentially toxic tomotor n...
Excitotoxicity — The excitotoxicity hypothesis postulates that excessive levels of the excitatory neurotransmitter glutama...
Cytoskeletal and axonal transport defect•Deranged neurofilaments could disrupt axonal transport andCause axonal strangulat...
Mitochondrial dysfunctionThe cause of the mitochondrial dysfunction is accumulation ofaggregated proteins (such as mSOD1) ...
ApoptosisApoptosis or programmed cell death cascades have beenimplicated in several studies .These reports have shown a nu...
CLINICAL FEATURES:LOWER MOTOR SYMPTOMS Loss of muscle strength Atrophy Fasciculations Muscle cramps Difficulty in che...
CLINICAL FEATURES:UPPER MOTOR SYMPTOMS Loss of dexterity Slowed movements Loss of muscle strength Stiffness Emotional...
DIAGNOSIS OF ALS• No biological marker has been identified yet.• Series of clinical and neurological exams.• MRI• Myelogra...
EL ESCORIAL DIAGNOSTIC CRITERIA
   Other Motor Neuron Diseases                      Neurodegenerative Diseases       Primary lateral sclerosis (UMN onl...
RiluzoleRiluzole — Three separate mechanisms of riluzole are thoughtto reduce glutamate-induced excitotoxicity:• inhibitio...
RecommendationsThe American Academy of Neurology has issued a practiceadvisory on the treatment of ALS with Riluzole.Patie...
SIDE EFFECTSVery CommonAsthenia.Nausea.CommonAlterations in liver function tests.Headache.Abdominal pain.Pain.Vomiting.Diz...
CONTRAINDICATIONS•Hepatic disease or baseline transaminases greater than 3 times theupper limit of normal or raised biliru...
Ceftriaxone  •A cephalosporin antibiotic.  •It increases expression of EAAT2/GLT1 and prolongs  survival in MND patients. ...
•IV ceftriaxone, 4 gm/day, four sequential days weekly in early 2004.•Patient improvement was rapidly evident.•Objective m...
EdavaroneHas multiple ALS-relevant                             mechanisms              of      action,including• free radi...
• 20 subjects with ALS received either 30 mg (5 ) or 60 mg (15) ofedaravone via intravenous drip once per day.•Two weeks o...
Tamoxifen• Used to treat breast cancer.• Acts as an anti-inflammatory through inhibition of PKC. In aPhase II study of pat...
•Two-year study of 60 people with (ALS)who took varying dosages oftamoxifen.•Participants who took more than 20 milligrams...
Arimoclomol  •Heat shock proteins are involved in protein repair, and  thus are cytoprotective.  •Motor neurons appear to ...
Lithium•An antiapoptotic agent that promotes autophagy , andmay therefore have neuroprotective effects.• An open-label ALS...
Stem cellsThere are a number of ways in which stem cells could bebeneficial in ALS. These include•Replacement of dying mot...
ANTISENSE OLIGONUCLEOTIDE•Another approach to gene therapy employs antisenseoligonucleotides•To downregulate or silence mu...
COMPOUNDS            ALS Research Stage MECHANISMCo-enzyme q10        Phase II          Antioxidant.                      ...
 Spasticity  Baclofen 5 to 10 mg twice daily to three   times daily.  Tizanidine 2 to 4 mg by mouth twice   daily up to...
 Non-pharmacologic     management    Suction machine (not usually helpful for thick     mucus, but helpful with sialorrh...
 Also  known as: pseudobulbar palsy,  emotional incontinence, pathologic  crying/laughing The emotional lability is NOT ...
 Amitriptyline 100-150mg QHS Fluvoxamine 100-200mg QD Alternatively may try Lithium or L-Dopa
 Speech  therapy often helpful early Computer technology offer many options to  assist with patient communication
 Urinary   frequency/urgency    In the absence of UTI, often due to spasticity that     responds well to Oxybutinin Per...
 Steven Hawking Proved Einsteins Theory  of Relativity He currently uses an  electric wheelchair to  get around A comp...
1. ROWLAND LP , SCHNEIDER N : Amyotrophic lateral sclerosis . New. Engl J. Med. ( 2002) 344 ( 22 ) : 1691 – 17002. Worms, ...
12. SMITH RA , MILLER TM ,YAMANAKA K et al. : Antisense oligonucleotide therapy forneurodegenerative disease. J. Clin.Inve...
Motor neuron disease
Motor neuron disease
Motor neuron disease
Motor neuron disease
Motor neuron disease
Motor neuron disease
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Motor neuron disease

  1. 1. DR.Rudrashis Samal JUNIOR RESIDENTP. G. Department of Medicine
  2. 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. 3. SPECTRUM OF MOTOR NEURON DISEASEAmyotrophic lateral sclerosis (ALS) is one of multipledegenerative 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
  4. 4.  Primary Lateral sclerosis Hereditary spastic paraplegia HTLV-1 associated myelopathy Adrenomyeloneuropathy Lathyrism
  5. 5.  Poliomyelitis MultifocalMotor Neuropathy Benign Focal Amyotrophy Hopkins’ syndrome: Acute post-asthmatic amyotrophy Spinal Muscular Atrophy Bulbo-Spinal Muscular Atrophy (BSMA; Kennedys Syndrome; X-linked) Primary Muscular Atrophy (PMA)
  6. 6. ALS PLUS syndromeALS is considered a degenerative disorder of the upper and lowermotor neurons.However, some patients have all of the clinical features of ALS alongwith 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. 7. Also known as LOU GEHRIG’S DISEASEDegeneration of UMN and LMN
  8. 8. 1869 - First described in publication by Dr. Jean-Martin Charcot, in Paris1881 - Lectures translated into English
  9. 9. A-myo-trophic Lateral Sclerosis Amyotrophic: no muscle nourishment Lateral: refers to the the areas in a persons spinal cord where portions of the nerve cells that signal and control the muscles are located Sclerosis: scarring of the affected nerves
  10. 10. INCIDENCE AND PREVALENCE•Incidence rates for ALS in Europe and North America rangebetween 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, andHispanic 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 groupover 70 years.• ALS is most commonly sporadic. Genetic or familial ALSrepresents only 10 percent of all ALS• In the United States, about 7000 new cases of ALS arediagnosed each year motor neuron disorder;a review of recent studies.j neuro sci 2001;191.2. Worms, pm .the epidemiology of3. Cronin s, hardiman o,traynor BJ ethnic variation in the incidence of als ; a systemic review.neurology 2007;68;1002.
  11. 11. GEOGRAPHIC CLUSTERSHigh prevalence clusters of ALS are found in three regions ofthe western Pacific including Guam, West New Guinea, andthe Kii Peninsula in Japan. The first cluster described wasfound in the indigenous people of Guam [5] . The frequent association of ALS with parkinsonism andAlzheimer disease in this population has led to the designationof this entity as the amyotrophic lateral sclerosis-parkinsonismdementia complex (ALS-PDC) Neurotoxicity was mediated by the local dietary consumptionof 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 geographicdistribution, with special reference to the Mariana Islands, including clinical and pathologic observations. Neurology 1954; 4:355
  12. 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; vanden Berg LH SO - Neurology 2005 Jan 25;64(2):241-5.
  13. 13. GENERAL: HEREDITARY VS SPORADIC ALS Sporadic Hereditary ALSFeature ALSMales:Females 1:1 1.7:1Onset 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% UnusualInvolvement of Legs Common Occasional
  14. 14. INDIAN SCENARIOThe classical motor neuron disease seen in India is similar tothat in the west in the clinical picture and frequency ofoccurrence. However, the onset of the illness is about adecade earlier and the proportion of patients below the age of30 is considerably high.In addition to these forms of motor neuron disease in theyoung, two specific types have been identified. Single limbinvolvement variously described as•Juvenile muscular atrophy of upper extremity•Monomelic amyotrophy•Wasted leg syndrome•Benign focal amyotrophy.
  15. 15. The second type, the Madras pattern of motor neurondisease was first described by Meenakshisundaram et alfrom 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 inoccurrenceA characteristic biochemical finding of persistently lowcitrate and elevated pyruvate level has been described inpatients with MMND.
  16. 16. PATHOLOGY•ALS is characterized by motor neuron degeneration and deathwith gliosis replacing lost neurons.•Cortical motor cells (pyramidal and Betz cells) disappearleading to retrograde axonal loss and gliosis in thecorticospinal tract.• This gliosis results in the bilateral white matter changessometimes seen in the brain magnetic resonance imaging (MRI)of patients with ALS.• The spinal cord becomes atrophic. The ventral roots becomethin, and there is a loss of large myelinated fibers in motornerves.• The affected muscles show denervation atrophy.
  17. 17. •Intracellular inclusions — Intracellular inclusions inDegenerating neurons and glia are frequent neuropathologicalfindings of ALS.Bunina bodies are unique to ALS and consist of eosinophilicaggregates that are positive for cystatin C, a cysteine proteaseinhibitor.• Ubiquinated inclusions are seen in ALS .TDP-43 protein — The TAR DNA binding protein 43 (TDP-43) hasbeen identified as a major component of ubiquinated inclusionsin sporadic ALS.
  18. 18. PATHOGENESIS
  19. 19. GENETICS OF ALS
  20. 20. TOXIC MECHANISMS IN ALS
  21. 21. SOD1-MEDIATED TOXICITY• Superoxide dismutase type 1 (SOD1) is a metalloenzyme thatcatalyzes the conversion of toxic superoxide radicals tooxygen (O2) and hydrogen peroxide (H2O2).• Mutations in the SOD1 gene are associated with some casesof familial ALS suggested that free radical toxicity may play arole 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, andmutated SOD1 could lead to oxidative injury by an increasein pro-oxidant pathways, including generation of hydroxylradicals 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. 22. THE MITOCHONDRION AS A TARGET OF MUTANT SOD1MitochondrialPermeability Transition Translocator Outer Membrane Complex
  23. 23. Protein misfolding — Another hypothesis is that mutantSOD1 induces protein aggregates that are potentially toxic tomotor neurons [7].Microglial activation — Microglia are immune-modulatingcells of the CNS.Their presence was observed in ALS tissue .•Once activated, microglia elaborate a host of factors, includingnitric oxide, oxygen radicals, glutamate, and others that mayplay roles in part of the cascade leading to motor neuron celldeath .•Mutant SOD1 appears to increase the production of damagingreactive oxygen species by activated microglia , therebyaccelerating motor neuron injury [8] .7-WANG J , XU G , SLUNT HH : Coincident thresholds of mutant protein for paralytic disease and protein aggregationcaused by restrictively expressed superoxide dismutase cDNA. Neurobiol. Dis. ( 2005 ) 20 :943 - 9528-MOISSE K , STRONG M : Innate immunity in amyotrophic lateral sclerosis. Biochimica et Biophysica Acta ( 2006 )1762: 1083 - 1093
  24. 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 pathogenesisof amyotrophic lateral sclerosis. biochimica et Biophysica Acta ( 2006 ) 1762: 1068 - 1082
  25. 25. Cytoskeletal and axonal transport defect•Deranged neurofilaments could disrupt axonal transport andCause axonal strangulation .•Mutations in the neurofilament gene peripherin have beenfound in sporadic and familial forms of ALS.•Inhibition of axonal transport may be a cause of motor neurondegeneration.•Defects in the dynein-dynactin complex, a molecular motorresponsible for axonal transport along microtubules, have beenlinked 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. 26. Mitochondrial dysfunctionThe cause of the mitochondrial dysfunction is accumulation ofaggregated proteins (such as mSOD1) within the mitochondriawhere• 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 mayactivate the apoptosis cascade11-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. 27. ApoptosisApoptosis or programmed cell death cascades have beenimplicated in several studies .These reports have shown a number of the hallmarks ofapoptosis 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. 28. CLINICAL FEATURES:LOWER MOTOR SYMPTOMS Loss of muscle strength Atrophy Fasciculations Muscle cramps Difficulty in chewing, swallowing & movement of face and tongue
  29. 29. CLINICAL FEATURES:UPPER MOTOR SYMPTOMS Loss of dexterity Slowed movements Loss of muscle strength Stiffness Emotional lability
  30. 30. 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 allowsthe 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.
  31. 31. EL ESCORIAL DIAGNOSTIC CRITERIA
  32. 32.  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
  33. 33. RiluzoleRiluzole — Three separate mechanisms of riluzole are thoughtto reduce glutamate-induced excitotoxicity:• inhibition of glutamic acid release• noncompetitive block of NMDA receptor mediated responses• direct action on the voltage-dependent sodium channelDose and side effects — The recommended dose of Riluzole is100 mg per day.
  34. 34. RecommendationsThe American Academy of Neurology has issued a practiceadvisory on the treatment of ALS with Riluzole.Patients most likely to benefit from treatment include thosewho have:• Definite or probable ALS by El-Escorial criteria , in whom othercauses 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
  35. 35. SIDE EFFECTSVery CommonAsthenia.Nausea.CommonAlterations in liver function tests.Headache.Abdominal pain.Pain.Vomiting.Dizziness.Tachycardia.Somnolence.Oral Paraesthesia.UncommonAnaemia.Anaphylactoid reaction.Neutropenia.Angioedema.Pancreatitis
  36. 36. CONTRAINDICATIONS•Hepatic disease or baseline transaminases greater than 3 times theupper limit of normal or raised bilirubin.•Pregnancy and breastfeedingMONITORING•Regular hepatic function blood tests (baseline then every month for 3months, 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 developelevated ALT levels >2x upper limit of normal.• If patient presents with febrile illness then monitoring white blood cellcount 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 .
  37. 37. 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 byincreasing glutamate transporter expression. Nature ( 2005 ) 433: 73 - 77 .
  38. 38. •IV ceftriaxone, 4 gm/day, four sequential days weekly in early 2004.•Patient improvement was rapidly evident.•Objective muscle strength was significantly improved and muscleatrophy was visibly diminishing.•After 12 weeks of assistance was no longer required for mobility, andsquats became possible for the first time since presentation.•Ceftriaxone cessation after 12 weeks resulted in partial return ofsigns and symptoms typical of als but with improvement on re-infusion.
  39. 39. EdavaroneHas multiple ALS-relevant mechanisms of action,including• free radical scavenging.• blocking the mitochondrial transition pore andupregulating bcl-2 expression.• there was a suggestion of slowed disease progression asmeasured by the ALS Functional Rating Scale .[14]14-YOSHINO H , KIMURA A :Investigation of the therapeutic effects of edaravone, a free radicalscavenger, on amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 :241 - 245
  40. 40. • 20 subjects with ALS received either 30 mg (5 ) or 60 mg (15) ofedaravone via intravenous drip once per day.•Two weeks of administration was followed by a two-weekobservation period. This four-week cycle was repeated six times.•There was the change in the revised ALS functional rating scale(ALSFRS-R) score.[14]
  41. 41. Tamoxifen• Used to treat breast cancer.• Acts as an anti-inflammatory through inhibition of PKC. In aPhase II study of patients with ALS, it was safe and welltolerated; furthermore, there was a suggestion of efficacywith increased survival at certain dosages [18] .•Tamoxifen has been extensively used in humans and has agood safety profile.18-TRAYNOR BJ , BRUIJN L , CONWIT F et al. : Neuroprotective agents for clinical trials in ALS: a systematicassessment. Neurology ( 2006 ) 67 :20 - 27 .
  42. 42. •Two-year study of 60 people with (ALS)who took varying dosages oftamoxifen.•Participants who took more than 20 milligrams a day had a bettersurvival rate than those who took fewer than 10 milligrams a day.•After two years, 27 out of 37 (73 percent) of the participants in thehigh-dose tamoxifen group had survived, while only 11 of 23 (48percent) of those in the low-dose groups were still living.
  43. 43. 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 andpharmacokinetic study of arimoclomol in ALS. Amyotrophic Lateral Sclerosis ( 2006 ) 7 ( S1 ) : 113
  44. 44. Lithium•An antiapoptotic agent that promotes autophagy , andmay therefore have neuroprotective effects.• An open-label ALS clinical trial compared 16 patientstreated with Riluzole plus Lithium to 28 patients treatedwith Riluzole alone [20] .• At the end of the 15 month follow-up period, allpatients in the Lithium group were alive, while mortalityin the Riluzole monotherapy group was 29 percent.• In addition, disease progression, as measured byFunctional Rating Scales and pulmonary function wasslower 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
  45. 45. Stem cellsThere are a number of ways in which stem cells could bebeneficial 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 givenintrathecal injections of autologous mesenchymal stem cells,along with intravenous erythropoietin.Transient benefits on strength, and a trend toward a reducedslope of decline in ALS Functional Rating Scale was reported.15. BRUIJN L , CUDKOWICZ M :Therapeutic targets for amyotrophic lateral sclerosis: current treatmentsand 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 inamyotrophic lateral sclerosis. Amyotroph. Lateral Scler. ( 2006 ) 7 ( S1 ) : 9.
  46. 46. ANTISENSE OLIGONUCLEOTIDE•Another approach to gene therapy employs antisenseoligonucleotides•To downregulate or silence mutant genes.•The antisense strategy targets specific RNA sequences byconstructing complementary oligonucleotides that bind to thenative mRNA sequences and reduce their translation andsubsequent protein expression.•In a preliminary study, continuous intraventricular infusion ofantisense oligonucleotides to SOD1 reduced both SOD1 proteinand mRNA levels.•This treatment significantly slowed disease progression wheninitiated near disease onset.12. SMITH RA , MILLER TM ,YAMANAKA K et al. : Antisense oligonucleotide therapy forneurodegenerative disease. J. Clin.Invest. ( 2006 ) 116 ( 8 ) : 290 - 2297 .
  47. 47. COMPOUNDS ALS Research Stage MECHANISMCo-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.
  48. 48.  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.
  49. 49.  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
  50. 50.  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.
  51. 51.  Amitriptyline 100-150mg QHS Fluvoxamine 100-200mg QD Alternatively may try Lithium or L-Dopa
  52. 52.  Speech therapy often helpful early Computer technology offer many options to assist with patient communication
  53. 53.  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
  54. 54.  Steven Hawking Proved Einsteins Theory of Relativity He currently uses an electric wheelchair to get around A computerized voice synthesizer operated by facial muscles in order to speak
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