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  • today we talk about ALS. disease of weakness. we will talk fo about the first 30 minutes. the most important thing is for us to talk to one of her patietns. that is how important it is to this gorup of patietns think about this disease, research this disease and find a cure. everything on the exam is in the slides. if she doesnt make it through them all, read them and study them.\n
  • nerve cells quit functioning and die. this is the motor neuron. both the upper motor neuron down to the anterior horn cell, both are affected. it causes progressive weakness. each person presents differently. can be in the respiratory muscles, neck muscles, swallowing and speech muscles, foot for foot drop. these people go to general med or orthopedic medicine first. delay in diagnosis is one of our biggest problems. the anatmoy is important. what we are talking about involves the motor neuron in motor cortex that comes down to motor nuclei in the brainstem, tongue nuclei. thisi s the upper motor neuron process. lower motor neuron goes to \n
  • lower motor neurongoes to muscle. both are involved in ALS\n
  • we are seeing higher prevalence of ALS. it does appear there is increased prevalence occuring. occurs in mid to late life. she has a teenage, 19 year old, 20 year old andn 29. slight male predominance. the average life expectance is 3-5 years. mechanical ventilation, they can live indefinietly. the only association is smoking. thre is some environmental trigger- military, gulf war, physically active patients, marathon, triathletes, football players (concussions). we have slight increase in prevalaence in this gorup. polio kills anterior horn cell (LMN only_). HI V also causes motor neuron disease- we test for htese. ALS as a group have sligh increased level of reverse transcriptase. this is info we know, hasnt come to us understanding the disease, bu tthings that will hopefully lead to that in the future. familiail only occurs in 5-10%. very likely to be sporadic. if you develop fasciculations, no weakness, reflexes are fine, you dont have ALS. in the 5-10% they can only pick up 23% of familial ALS. we do not have a test for it, it does not exclude that disease. our test does not pick up most of the problem we can test for SOD, but if they are SOD negative, we can’t test that. \n\nTHere is a lot of pleasure in life in spite of our hardships. she doesnt know anyone that would say they wouldnt want to be here because the pleasure outweighs that. \n
  • progression of disease is variable. a couple of patients, new one that move down here from NIH. had it in 1999. there are outliers. the progression is variable in the different groups. other motor neuron diseases. ALS is upper and motor neuron. PLS is just the upper. it is CST or CBT. not the lower ones. this patients present with incresaed reflexes, spastic gait, no fasciculations or atrophy and they do much better. \n
  • common clinical features. tell the difference between upper and lower is important. LMN- pt have lots of weakness, atrophy, fasciculations, cramps. fasciculations rarely present as isolated sign of ALS. a lot of people have benign ALS. these patients tend to have benign fasciculations. \n
  • LMN. anteiror horn cell here is healthy one. LMN part of this, anterior horn cell dies, resulting in loss of ionotropic input to the muscle muscle not receiveing innervation atrophies.\n
  • LMN atrophy. \n
  • bulbar is brainstem. brainstem area is affected in ALS. 20% have presentation in that area firs.t motor nucleia nd corticobulbar tracts. slurred speech, tongue atrphy and tongue fasciculations. hyperactive gag response. \n\nthey have a brisk jaw jerk. trigeminal upper motor neuron lesion. jaw jerk, hyperactive gag and pseudobulbar palsy. \n\npseudobulbar- if both sides- if those are involved, people develop pseudobulbar palsy. they laugh too much, cry too much in response to something a little sad but not that sad. this is not just ALS. pt with multiple strokes form both side does the same thing. important finding. ALS is a clinical diagnosis, you have to be good diagnostician to pickup upper and lower motor neuron. \n\nswallowing problem.\n
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  • 5-10% develop frontal temporal dementia. hard to pick up= memory is not as bad as you expect. personality and judgement are alittle off, they dont have normal inhibitions or saying things to family that are rude. sensory involvement is very rare. sensory exam is normal. sensory nerves are not involved. very rare is autonomic funciton. we see autonomic in japan. \n
  • learn this slide. be able to use it in scenarios. \n\nspinal muscular atrophy- LMN disorder. only have LMN involvement. werdig hoffman and coogeman?\nprimary lateral scleroris- corticospoinal and corticobulbar. no anterior horn invovlemtn. \npseudobulbar palsy- speech and swallowing problems. \nmonomelic amyopathy. benign condition, LMN usually affects the hand. frequent in japan. men 20-40 presen with weakness and loss of muscle in hand. \n\n*monomelic- LMN, benign. \n\nX linked spinobulbar muscular atrophy- kennedy’s disease predominantly LMN process. \n\nall these have LMN invovlement or just LMN except PLS\n
  • every patient is different. foot drop, can’t swallow. she has to figure them out. those are the different possibilities. also want to exclude others. neuropathy and others are LMN type problems. some metabolic conditions that look like MN disease becaues of weakness.\n
  • to confirm ti, you have to do electrical studies. have to document loss of motor neuron anteiror horn cells. extensive enough that it couldnt be explaine by something enough. if the only thing on EMG is hand muscles nad roots innervated by the same, look closely to spinal cord. dnerevation all up here, have deneravation in leg and back, disorder hitting every anterior horn cell at every level. things dont do that and not invovle upper systems. combo of using EMG and otehr criteria. no otehr explanation for it. exclude myopathy and neuopathy. \n
  • what happens with myopathic potential. \n\nthis is the reverse. the problem isnt loss of muscle cell, loss of motor neurons. motor neuron remaining when one is lost innervates muscles cells that have lost their innervation. instead of 10 muscle cells, we have 20 or 30. that one motor neuron is controlling 20 or 30. you see very large potential. that is reinnervation.\n
  • imaging of brain and spinal cord. CK is elevated. CK occurs when muscle cells break down. if they lose innervation quickly and doesnt receive impulse, they break down. 80% have CK under 1000, but elevated. check for SOD 1 in familial ALS. someone else in family had this disease. tends to be autosomal dominant. she does muscle biopsy.\n
  • if you lose innervation to muscle cell, it shrinks. thats why you see atrophy. as more and more are lost, you get phenomenon of fascicular atrophy. entire muscle is atrophic. muscle fiber shrinks so much all you see are nuclei. special staining that we do. this shows target fibers- they mean acute deneravation. if you see this in someone’s muscle its bad prognostic sign if you see this much. Target sign-acute active denervation, typicaly of ALS.\n
  • pseudobulbar affect-she educates people. if you understand mom is not really crying bc shes sad and shes not being rude people are okay. the meds are expensive, so how upset is mom? is she worth $400 a month upset. cramps, thick mucous is a huge problem. they get a weak cough. they are constantly and driven crazy. they use mucinex. called a cough assist. we use that 4-5 repetitions in the morning, 4-5 in the evening.\n
  • sleeping problems- make sure due to sleeping problems, not due to sleeping. \n\nif patient start losing weight, they can’t get their strength back. nutrition is the best thing- there is a lot of denial, they dont wantt o mention that they have a problem because they dont want to hear about the feeding tube. treatmetn with . cough a lot form microrespiration. if shes not sure, she does a. electrically stimulate these muscles involved. she is hopeing th emuscle will not atrphy while reinnervation occurs. if you ahve a nerve injury and you are expecting reinnervation in the future, you want to prevent it while thats occurring. \n
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  • feeding tubes- most do end up with them. increases life span, personal choice. we need to place it before significant breathing problems. does not keep people from eating. goes directly from skin into the stomach. it bypasses the esophagus. there is a slight morbidity. if you wait too late, you can run into respiratory failure. peg tubes can be reversible. \n
  • it hangs out here, take syringe and put ensure in it. flush it with water, take care of it and thats it. tube feedings are what most people choose to eat. problem with happiness and enjoying to eat. most people continue to eat for pleasure\n\nthe amyotrophy in amyotrophy in teh disease ALS refers to:\nD. wasting of teh muscle. thats what is happening in the hands.\n
  • most serious component of ALS> they present with sleeping problems. when supine, diaphragm works the least well. headache early in the morning, orthopnea. dyspnea. giving short phases, have to get breath, sighing frequently to increase breath. FVC is decreasing. mechanical problem of getting enough air in and enough CO2 out. sometimes see them use accessory muscles. they use their scalene muscles, abdominal muscles. biPAP is a type of breathing assistive device that is not invasive. pt wears mask at night, when they take a breath it increses their breath. they take a breath, it makes it bigger. most patients do not elect mechanical ventillation. as disease progresses, produces locked in state. she cannot communicate with him at all. many pateitns elect not to continue. do everything up to that point but not continue. \n
  • where is the caregiver social burden? it takes teh whole family- take healthy person who cant make money and disease costs a fortune. they need caregiver, equipment, all these resources. very hard. \n
  • we dont know what causes this. everything is theory. there is unidentified trigger superimposed on genetic predisposition. some people have same trigger that dont get the same disease. leads to cascade of motor cell death. cells right next to the affected cells are the ones that die. something is put out that goes in predictable pattern of spread. we put our fingers in the dyke. buil up of neurotoxins, what we do with meds and treatment, we suppress the secondary response, not the initial response. we need to suppress teh initial response for a cure. cytoskeleton is affected, mitochondria are not working. microglia are very activated. metabolism is revved up, they produce free radicals and glutamate.\n
  • what do they have that other pateitns dont have? chang ein RNA processing. is that a result of cell loss or is it causing cell loss? in familial ALS, there are 2 other mutations. 5% have TDP 43, 4% have FUS. other information we use to get further in our understanding of htis disease. she stops here. \n\nshe asks that we read this over. the only drug we have available is rivuzole. \n\ndifferent trials how these things that didnt work, didnt work didntwork. stem cells are still being worked on, we cant use it yet. we try to pace the diaphragm electrically. can we stimulate the diaphragm? helped a little, but not as much. \n\nSMA differes form ALS in that:\nA. pateitns with SMA do not have spasticity\nB. patients with SMA do not have fasciculations \nC. Patients with SMA have pseudobulbar affect\nD. They are the same escept SMA pt progress more slowly\n\nSMA is a LMN process. pt with spinal muscular atrophy will not have spasticity. it is an upper motor neuorn process. its hyperreflexia, its spasticiyt. SMA, fasciculations are LMN process. Pt with SMA have pseudobulbar affect- no, thats upper motor neuron process. SMA is pure LMN process. fasciculations, weakness, atrophy. what are the UMN things? spasticity, pseudobulbar affect. \n\nUMN- spasticity, stiffness. you would expect reflexes to be brisk. with ALS, sometimes you see mixture. reflex is too brisk for as weak and atrophied thta she is. jaw jerk- upper motor neuron in corticobulbar tract. \nLMN- foot drop. it doesnt have tone. cramps, fasciculations, foot drop, lots of weakness. \n\nstiff, robotic. \n
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  • 101111 als

    1. 1. Amyotrophic Lateral Sclerosis Gwen C. Claussen, MD University of Alabama - Birmingham Birmingham, Alabama
    2. 2. Amyotrophic Lateral Sclerosis  Neurodegenerative disorder of motor neurons  Progressive weakness  Variability in region of onset, time course, relative degree of upper and lower motor neuron signs (many subtypes)
    3. 3. Anatomy of ALS yassermetwally.files.wordpress.com
    4. 4. ALS Epidemiology and Etiology More prevalent; 3-5/100,000, mid-late life onset, slight male predominance, 3-5 y LE Unknown etiology  Only known association- smoking  Enviromental-Gulf War/ military; Toxic waste site study; Soccer and football players  Infection- viruses (polio, HIV) increased levels of reverse transcriptase (retroviral enzyme) in ALS pts.  Familial 5-10% (SOD1 20%of these)/ genetic predisposition
    5. 5. Variability of Disease Progression  ALS compared to PLS (primary lateral sclerosis) patientslikeme.com/ wp
    6. 6. Common Clinical Features  Lower motor neuron- weakness, atrophy, fasciculations, cramps  Fasciculations rarely present as an isolated sign of ALS  Benign fasciculations  Other LMN disorders- radiculopathy, neuropathy, occasionally myopathy
    7. 7. ALS- Anterior Horn Cell
    8. 8. Hand Muscle Atrophy
    9. 9. Bulbar Involvement in ALS  20% ALS patients present with bulbar palsy  Brainstem motor nuclei and corticobulbar tracts  Slurred speech, tongue atrophy, fasciculations  Hyperactive gag response, brisk jaw jerk  Pseudobulbar palsy (bilateral corticobulbar tracks)- emotional lability  Swallowing problems, increased saliva, and laryngospasm
    10. 10. Tongue Atrophy and Fasciculations neuromuscular.wustl.edu/.../alstonguerest.jpg
    11. 11. Uncommon Clinical Features  Dementia- 5-10%, memory loss, personality change, loss of normal inhibitions, loss of judgment  Sensory involvement, 25% minor sensory complaints  Autonomic dysfunction, only occasional bladder involvement
    12. 12. Other Motor Neuron Diseases  Spinal muscular atrophy- LMN disorder  Primary lateral sclerosis- UMN disorder  Progressive bulbar palsy- brainstem motor nuclei and corticobulbar tracks  Monomelic amyotrophy  X- linked spinobulbar muscular atrophy (Kennedy’s disease)
    13. 13. ALS Differential Diagnosis  Unique to each presentation  Neuropathy (MMN, CIDP), myasthenia gravis, myopathy (IBM, acid maltase deficiency), polyradiculopathy  myelopathy, multisystem atrophy, adrenomyeloneuropathy, brainstem lesion  Metabolic - hyperparathyroid , hyperthyroid, vit. B12 deficiency
    14. 14. Diagnostic Studies  NCS/EMG is critical to document loss of motor neuron and to evaluate for another etiology  Denervation findings are not specific to ALS  Electrodiagnostic criteria
    15. 15. EMG-Denervation andReinnervation in ALS www.ncbi.nlm.nih.gov/ bookshelf/picrender.fcgi
    16. 16. Other Diagnostic Studies  Imaging of brain and spinal cord  Laboratory studies- decide on individual basis CBC, Chem profile (Ca, phos), CPK, ESR, RPR, Vit B12, TFT’s, serum immunofixation electropheresis, GM1 antibody, hexosaminidase A, urine heavy metals  Lumbar puncture  Familial ALS- SOD1 mutation  Muscle biopsy
    17. 17. Symptomatic Treatment of ALS  Spasticity - lioresal, tizanidine  Increased saliva- Amitriptyline, Sal- tropine (atropine), scopalamine patch, suction machine, Botulinum toxin  Pseudobulbar Affect- antidepressants, dextromethorphan 30mg/ quinidine 30 mg bid
    18. 18. Symptomatic Treatment of ALS  Pain- Cramps, muscle fatigue  Thick mucous/ saliva- hydration, guaifenesin, Cough Assist  Depression- SSRI’s-serotonin reuptake inhibitors  Insomnia- watch hypoventilation
    19. 19. Swallowing Problems  Malnutrition and aspiration pneumonia  Treatment decreases mortality (Desport et, al., Neurology, 1999)  Signs- Drooling, wet voice, coughing, excessive time to eat  Modified barium swallow, swallowing tx, electrical stimulation
    20. 20. PEG Tube in ALS  PEG tube needed before significant breathing problems (percutaneous endoscopically- placed gastric tube)  Needed when wt loss >10%, aspiratrion, impaired quality of life  PEG morbidity 2-19%, mortality 0-10% (Chio et. al., Neurology, 1999; Strong et.al., J Neurol Sci, 1999); no randomized trials  Mortality- respiratory failure  Reversible
    21. 21. PEG Tube
    22. 22. Respiratory Weakness  Symptoms- insomnia, headache, orthopnea, dyspnea on exertion  Signs- frequent sighing, shallow breathing, short phrase speech, weak cough, use of accessory muscles  Treatment- BiPAP, trachiostomy, mechanical ventilation- or oxygen for palliative care
    23. 23. Caregiver/ Social Burden  Financial crisis- expedited disability, drug assistance programs, MDA clinic, ALS Association, family medical leave  Over-extended caregiver-extended family and care teams, home health services, long term care policies, Hospice services  Other resources- ALS Foundation, MDA, ALS Ironhorse Foundation, NORD
    24. 24. Neurobiology of ALS  Unidentified trigger, superimposed upon a genetic predisposition of aging motor neurons, leads to a final molecular cascade of motor neuron death  Multifactorial process  Cellular cytoskeleton derangements, mitochondrial dysfunction, microglial activation, changes in metabolism of reactive oxygenating species and glutamate
    25. 25. Biomarkers- Proteinopathy?  RNA Protein Processing Disorder  TAR DNA binding protein located in the nucleus acts as a RNA protein processor  Abnormal inclusions of this protein found in the cytoplasm of 90% sporadic ALS  Familial ALS-  5% have TDP 43 gene mutation  4% have FUS/TLS gene mutation (another RNA processing protein)
    26. 26. Neurobiology of ALS Mutations of Cu/Zn superoxide dismutase  3% ALS, gene promotes apoptosis  Toxic gain of function  Mutant enzyme accumulates at mitochondria, interacts with antiapoptotic protein Bcl-2  Oxidative stress  Mitochondrial dysfunction (treatment- co- enzyme Q10, creatine)  Neurofilaments accumulation(secondary to oxidative stress)
    27. 27. Oxidative Stress Hypothesis www.als.ca/.../images/damaged-cells
    28. 28. Neurobiology of ALS  Excitotoxicity  ALS decreased excess glutamate transport Rothstein 1992  Numerous studies demonstrating glutamate transport/receptor abnormalities  SMN selectively vulnarable to AMPA receptor mediated excitotoxicity (massive calcium influx) Kawahara 2005
    29. 29. Neurobiology of ALS  Inflammation  Increase in activated microglia and astrocytes  Upregulation of proinfammatory cytokines (tumor necrosis factor)  Marked elevation of serum activated moncytes/ macrophages in sALS, degree of activation correlated with rate of progression (systemic immunological role?) Zhang 2005
    30. 30. Neurobiology  Inflammation- activation of microglia  Upregulation of proinflammatory cytokines www.als-mda.org/
    31. 31. Therapy of ALS  Riluzole-antiglutamate agent  Prolonged survival in SOD1 mouse model  Prolonged survival in ALS patients compared to placebo (1100 pts)  Expensive ($10,000 a year)  Monitor LFT and CBC  Only drug FDA approved for ALS
    32. 32. Therapy of ALS  Difficulty in development has been lack of clear understanding of cause  Once disease begins, we haven’t been able to stop or reverse progression  All current and future trials of proposed therapy has only shown slowing of progression in animal models  Importance of basic science research
    33. 33. Recent Trials  Lithium-Fornai et al. PNAS, 2/08  Neuroprotective in mice (suppression of reactive astrogliosis, increased mitochondria in motor neurons, decreased MN necrosis)  Study Design- 44 pts. , riluzole alone vs. riluzole plus lithium, followed for 15 months  Results- Slower progression in lithium group measuring functional rating scale (14.3 % loss vs 39.8%) and FVC; reduced deaths in lithium group  Small trial- needs follow up
    34. 34. Recent Trials  Thalidomide- anti-inflammatory properties- modulates cytokines TNF, extends life in ALS mice  Dose 400 mg  Pilot, phase II  Co Q10- mitochondrial co-factor, antioxidant, prolonged survival mice  Vit C, Vit E- Antioxidant trials in ALS patients have had mixed (predominantly negative) results  Minocycline- inhibitor of nitric oxide synthase and caspase enzymes  5/1/07- ineffective in large US trial  Detrimental
    35. 35. Current and Planned Trials  Arimoclomol- up-regulator of molecular chaperones involved in cellular response to stress/ protein misfolding  Ceftriaxone- stimulates glutamate transporter GLT1 through increased GLT1 gene transcription, inactivates glutamate.  Initial study- CNS penetration of IV ceftriaxone  Follow-up- efficacy trial
    36. 36. Current and Future Trials  Talampanel – antiglutamate activity, completed safety study and demonstrated preliminary efficacy  Tamoxifen-completed safety study and demonstrated preliminary efficacy  Sodium phenylbutyrate- early phase II- tolerable/safe in 40 pts. , now needs efficacy trial
    37. 37. Current and Planned Trials  Fetal cell implants- Beijing, China  Dr. H Huang, >150 ALS pts., human fetal olfactory ensheathing glial cells injected in subcortical white matter, some reports of “improvement”  Stem cells- embryonic stem cells and animal studies of SOD1 mutation
    38. 38. Recent and Current Trials  Diaphragm pacing- implanted pacing device of the phrenic nerves and diaphragm  Attempt to maintain muscle bulk/ decrease atrophy  Promote axonal sprouting of the phrenic nerve- must have intact motor neurons  May delay need for the ventilator
    39. 39. Recent and Planned Trials  Mild to moderate resistance exercise and stretching increased function and quality of life (V Dal Bello-Has, Neurology 2007)  Early BiPAP prolongs survival (Lechtzin et al., ALS, 2007)
    40. 40. Available Treatment of ALS  Riluzole 50 mg bid  Co-enzyme Q10 300mg- 1200mg /day  Antioxidant vitamins-  Vit C  Vit E  Beta carotene  Excellent nutrition, hopeful attitude, large support group  Early BiPAP and PEG