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					ALS from Bench to Bedside

 2008 ALS Symposium at Cedars-Sinai
  Catherine Lomen-Hoerth, MD, PhD
 University of California, San Francisco
Lou Gehrig
   Poor 1938 season                         Insidious onset
       Leg > arm weakness
   Winter 38-39, many falls
    when skating, dropped things
   Played 2,130 games
       14 years straight
       Played 8 games in 1939                                 6937
       Stopped May 2, 1939

   Diagnosed June 19,1939
       His 36th birthday                   Weeks in the baseball season

   Vit E trial at Mayo (daily      „But even from the midst of it, he saw
                                      himself “not a mere victim of a form
                                      of paralysis but a symbol of hope for
   1940, Hoarse speech               thousand of suffers of the same
   Died peacefully June              disorder.”
    2, 1941, aged 38 years         Kasarskis, EJ, Neurology1989;39:1243-1245
Clinical Features
             •   Upper motor neuron findings
                  • Slow speech
                  • Brisk gag and jaw jerk, brisk
                    limb reflexes
                  • Spasticity
                  • Hoffman‟s or Babinski signs
             •   Lower motor neuron findings
                  • Atrophy
                  • Fasciculations
                  • weakness
El Escorial Criteria to diagnose ALS

 UMN degeneration by clinical exam
 LMN degeneration by clinical exam or EMG
 Progressive spread of signs within a region or
  into other spinal or brainstem regions
 Absence of evidence of other diseases by
  EMG or imaging to explain the findings
ALS-Mimic Syndromes
  Post-poliomyelitis syndrome
  Multifocal motor neuropathy
  Endocrinopathies
      hyperparathyroidism and hyperthyroidism
  Lead intoxication
  Infections
      Lyme disease and HIV/AIDS
  Paraneoplastic syndromes - lymphoma,
   Post-poliomyelitis syndrome
   MRI of affected region
   EMG/nerve conduction studies
   Other laboratory tests may include
       CSF: cells, glu, pro, VDRL, cytology, IgG
       Blood: anti-GM1 Ab, SPEP, serum IF, calcium,
        TSH, Lyme Ab, HIV, lead, B12
Motor Neuron Diseases
 Only lower motor neuron signs
   Kennedy‟s disease
   Spinal muscular atrophy
   Progressive muscular variant of ALS
   Segmental motor neuron disease
   Progressive bulbar palsy
 Only upper motor neuron signs
   Primary lateral sclerosis
   Progressive bulbar palsy
 Genetics of ALS
phenotype        inheritance       chromosome      gene

ALS 1            AD                21q22.1         SOD1

ALS 2            AR                2q33            Alsin

ALS 3            AD                18q31           unknown

ALS 4            AD                9q34            SETX

ALS 5            AR                15q15.1-q21.1   unknown

ALS 6            AD                16q12           unknown

ALS 7            AD                20p13           unknown

ALS 8            AD                20q13.3         VAPB

ALS-FTD          AD                9q21-22         unknown

ALS-FTD-PD       AD                17q24-25        unknown

ALS-FTD          AD                9p21            unknown

ALS or ALS-FTD   AD and sporadic   2p13            DCTN1

ALS              AD and sporadic   14q11.2         ANG

ALS-FTD-PD       AD                17q21           MAPT
TAR-DNA binding protein and ALS
 TDP-43 abnormalities have been found in
  ALS and FTLD
 Abnormalities in both familial and sporadic
  ALS cases
 Causes apoptosis
 Exciting possibilities for a new mouse model
  and new therapy target
Collaborative Gene Discovery
 Large collaboration underway sponsored by with
  ALSA and the NIH already collected samples from
  2332 MND patients and 4692 controls^
 Academia joined with industry to perform a whole
  genome analysis of sporadic ALS patients and
  controls and identified 10 genetic regions associated
  with sporadic ALS*

^Gwinn, K et al, PLosONE 2(12):e1254
*Dunkley, T et al, NEJM 2007; 357:775-88
Mechanisms of Motor Neuron
 The precise mechanisms are still unknown
 There may be convergence of multiple pathways
 There are many potential targets for drug intervention and
  innovative delivery methods
 Current experimental trials are targeting these pathways
 Riluzole, a glutamate antagonist, is the only FDA approved drug
  to treat ALS

Bruijn, LI, Miller TM, Cleveland DW Ann Rev Neurosci 2004 27: 723-49
Experimental Treatments Target
Pathogenic Mechanisms in ALS
Excitotoxicity              Tamoxifen
Growth factor modulation    IGF-1/Buspiron
Protein aggregation         Arimoclomol
Damage to mitochondria      Coenzyme Q10
Activation of caspases      Minocycline
Decreased glutamate         Ceftriaxtone
Neuroprotection             AVP-923, KNS-760704,
Slow Disease Progression
 To date Riluzole is the only FDA drug approved to
    treat ALS
   Riluzole prolongs survival by 10% and delays
    disease progression modestly
   The drug costs approximately $1000 for those
    without prescription drug coverage
   All other drugs tested to date either had no efficacy or
    caused more rapid progression compared with the
    placebo group
   Despite the need to expedite therapies in ALS, there
    is a need to test the safety of drugs before larger
    clinical trials are initiated
Stem cells and ALS
 Healthy supporting cells can extend survival
  of mutant motor neurons
 Neural stem cells transpanted into mice
  extends survival
 Stem cells have been safely injected into the
  spinal cord of ALS patients
 More work is needed to keep cells alive and
  make sure they stay in the right place
Breaking the News

 Discuss the diagnosis and its implications
    Face-to-face in quiet, comfortable place with sufficient time
    Find out how much the patient knows and wants to know
    Give warning that you are about to give bad news
    Discuss no cure, symptoms progress, prognosis variable
    Ask and allow patient to express emotional reaction
    Summarize discussion verbally, in writing or on tape
 Reassure
    Many symptoms and complications are treatable
    You are interested in continuing your care for them
    Their decisions will be respected; second opinion?
    If interested, they may be able to participate in research
Steps in the Management

   Making the diagnosis and breaking the news
   Starting treatments that slow or arrest disease process
   Managing respiratory insufficiency
   Managing dysphagia / preventing malnutrition
   Treating symptoms that reduce quality of life
     Sialorrhea, pseudobulbar affect, spasticity, cramps
     Maintaining mobility
     Palliative care
    AAN Practice Guidelines Neurology 1999;52:1311
Changes in management of ALS
 Attitudes toward care of people with ALS
 Diagnostic process
 Research opportunities
 Recognition of symptomatic issues
 Examples of definitive changes in practice
    Nutrition
    Respiratory Care
    Cognitive and behavioral changes
    Mobility
    Multidisciplinary care
Poor Nutrition
 Causes
   swallowing trouble
   arm weakness
   shortness of breath
   Increased energy expenditure
 Solutions
   Breathing support
   Eating aids
   High Calorie High Protein Diet
   Food consistency modifications
   Feeding tube
  Feeding Tube
 No consensus on PEG timing
 A Quality of life and Quantity of life issue
 AAN Practice Parameter Guidelines for ALS 1999
      “PEG is indicated when patients with ALS have
       symptomatic dysphagia with accelerated weight
       loss due to insufficient caloric intake, dehydration,
       or ending meals prematurely because of
       dysphagia or choking on food…before FVC falls
       below 50%”
        Miller RG, et al. Neurology, 1999; 52:1311-1323
Poor Breathing

 Causes
     Diaphragm weakness
     Chest muscle weakness
     Increased energy expenditure
 Solutions
     Breathstacking
     Non-invasive positive pressure ventilation
     Diaphragm stimulation
     Invasive ventilation
 Respiratory Care
 Role of FVC, MIF, breathstacking, and
  nocturnal oximetry
 AAN Practice Parameter guidelines 1999
     Consider NPPV when FVC approaches 50%
     Increases longevity
     Increases quality of life

      Miller RG, et al. Neurology, 1999; 52:1311-1323
              Frequency of Symptoms in ALS Patients

        DRY MOUTH

                      0   20       40       60   80
                          Percent With Symptom

                 Forshew and Bromberg, 2003
Optimization of home and work

                  Work assessments with
                   AT Network
                  Home assessment with
                   home safety
                  Specialty contractors for
                   home remodeling
                  Hospice
 Equipment Advances
 Flexible Ankle Foot Orthodics
 Lighter, sturdier walkers, canes, and crutches
 Manual wheelchairs with tilt and recline features
 Electric wheelchairs weighing just 14 pounds
 Stair lifts and climbers
 Portable ramps and rail systems
 Specialized beds that turn patients
 Driving and ALS

 Provide a handicapped placard early
 Assess cognitive and physical function
 Report to the DMV as needed
 Driving assessments every 6 months
 Car modifications as appropriate
 Wheelchair van for powerchairs

            Prolongs survival
            Improves quality of life
            Reduces spasticity
            Strengthens stronger
            Elevates mood
  Resistance exercise is
  beneficial in ALS
 Randomized controlled trial of daily stretching and
  resistance exercise 3X a week in 27 ALS patients
 After 6 months
      Quality of life was better
      ALS functional rating score was improved
      Muscle strength declined more slowly

 V. Dal Bello-Hass et al Neurology 2007 88:2003-2007
Multidisciplinary ALS Team
        Core Members               Consultants
   Neurologist               Rehabilitation
   Nurse                      physician
   Speech pathologist        Pulmonologist
   Dietitian                 Gastroenterologist
   Respiratory therapist
   Physical therapist             Associates
   Occupational therapist
                              Research scientists
   Social worker
   Rehabilitation
   Psychologist
End of Life Issues
 Talk about end of life
  issues throughout the
  disease process
 Enroll in hospice as soon
  as eligible
 Utilize home care if not
  hospice eligible
 Continue to follow the
  patient while in hospice
 Medications are available to treat many of the
  symptoms of ALS
 Equipment advances enable patients to be
  more independent than ever
 Multidisciplinary clinics improve the quality of
  life for ALS patients and prolong survival
ALS is not just a disease of the motor system


                                 LMN degeneration
  UMN degeneration
    Sensory abnormalities
                             Autonomic dysfunction
                 Major FTLD variants
           Three prototypical presentations

   Frontotemporal              Semantic    Progressive non-fluent
   dementia (FTD)            Dementia (SD)     aphasia (PA)
       ‘Frontal’              ‘Temporal’      Left perisylvian
   L             R          L               R      L               R

  Apathy, disinhibition Loss of semantic knowledge,     Non-fluent,
Decreased speech output, Poor word comprehension,    effortful speech,
    Disorganization,      Word finding problems,    agrammatism, good
      Poor insight               Good insight        comprehension,

 36 patients with sporadic FTLD and no known
  motor neuron disease
     14% definite ALS
     36% possible ALS
     14% fasciculations (1 pt = definite ALS after 1 yr)
     17% swallowing trouble
     5% other abnormalities
  C. Lomen-Hoerth, T. Anderson, B. Miller, Neurology, 2002

 31 abnormal on word generation tests
     17 underwent further evaluation
          15 confirmed FTLD
          2 low normal on language testing
 69 normal on word generation tests
     27 underwent further evaluation
          8 confirmed FTLD
          19 normal
  Lomen-Hoerth et al, Neurology, 2003

                      SD   PPA
      Normal               Normal
                           Low NL
Does this milder form of FTLD
have clinical significance?
 Two hypothesis:
 Survival is shorter in patients with ALS-FTLD than
  ALS alone
 Compliance with treatment recommendations is
  significantly less in patients with ALS-FTLD than ALS
   Olney R, Murphy J, Forshew D, Garwood E, Miller B,
     Langmore S, Kohn M, Lomen-Hoerth C, “The effects of
     executive and behavioral dysfunction on the course of ALS”
     Neurology 2005; 65: 1774-1777.
Affect of FTLD on survival

                             Chi sq =5.14
                             P <0.02
Criteria for Compliance
 Noninvasive Positive Pressure Ventilation
     Obtained equipment within 1 month
     Used at least 4 hours per 24 hours within 1
 Percutaneous Endoscopic Gastrostomy (PEG)
     Obtained within 2 months
     Use consistent with dietitian‟s recommendation
NPPV and PEG Compliance
               NPPV      PEG
ALS-FTLD        25%      28%
ALS only        62%      69%
z               2.22     2.01
p (one-tail)   < 0.02   < 0.03
Impact of FTLD on ALS
 Lack of judgment when walking or
  maneuvering a power wheelchair
 Poor insight into the disease process
 Refusal of equipment recommendations
 Difficulty using the equipment
 Lack of acceptance of outside help in the
 Denial of symptoms and refusal to take
    Summary: Treatment for ALS
   Make an accurate diagnosis
   Break the news carefully
   Slow disease progression
   Treat symptoms
   Provide multidisciplinary care
   Manage end of life issues
   Recognize the complications of dementia on
    treatment recommendations
Thanks to the UCSF ALS Center
 Clinical Team
      Jennifer Coggiola-Speech Pathologist
      Miriam Crennan-Occupational Therapist
      Mira Kletyman-Respiratory Therapist
      Andrew Lui-Physical Therapist
      Amy Mahoney-Nurse Coordinator
      Colleen Meier-Respiratory Therapist
      Jennifer Murphy-Neuropsychologist
      Carolyn Rodriguez-Clinic Coordinator
      Virginia Santos-New Patient Coordinator
      Madelon Thomson-Social Worker
      Linda White-Dietitian
 Research Team
      Fizaa Ahmed-Research Assistant
      Claudia Villierme-Senior Research Assistant
Richard K. Olney, MD
Founding Director ALS Treatment and Research
Center at UCSF