SlideShare a Scribd company logo
7
Most read
10
Most read
15
Most read
Sabrina Paganoni, MD, PhD
Co-Director, Neurological Clinical Research Institute
Massachusetts General Hospital, Department of Neurology
Healey & AMG Center for ALS at Mass General
Associate Professor of PM&R
Spaulding Rehabilitation Hospital, Harvard Medical School
Getting Ahead of the ALS Curve Through Early Detection
and Intervention
Module 1: Enabling Earlier Diagnosis of ALS
Disclosures
Consultant: Amylyx, Arrowhead, Cytokinetics, Eikonizo
Grants/research support: Calico, Clene, Denali, Prilenia, Seelos,
UCB
i3 Health has mitigated all relevant financial relationships
Learning Objective
ALS = amyotrophic lateral sclerosis.
Evaluate factors that can inform an early and accurate diagnosis
of ALS
Amyotrophic Lateral Sclerosis (ALS)
“I might have been given a bad
break, but I've got an awful lot to
live for”
– July 4, 1939
Lou Gehrig’s Disease
Image courtesy of Columbiana Library, Columbia University (Wikimedia Commons).
What Is ALS?
ALS begins with motor neuron degeneration and death and results in
loss of function
Motor neuron cell death leads to muscle weakness, loss of motor
function, and progressive motor deficits
Death is usually from respiratory failure, typically within 3 to 5 years after
disease onset
Age of onset: 25 to 85 years (peak at 65 years)
Annual incidence is ~2 per 100,000, and worldwide prevalence is ~5 per
100,000
Hardiman et al, 2017; Brown & Al-Chalabi, 2017; Kiernan et al, 2011; Roggenbuck et al, 2017; Mehta et al, 2018.
Multiple Mechanisms Converge To Cause ALS
Upper
and
Lower
Motor
Neuron
Loss
Synaptic dysfunction
Excitotoxicity
Genetic abnormalities
Oxidative stress
Abnormal protein aggregation
Neuroinflammation
Aberrant mRNA processing & transport
Abnormal axonal transport
ER stress
Mitochondrial dysfunction
ALS: A Conspiracy of Genes,
Environment, and Time
“ALS is considered to be the
result of environmental risks
and time acting on a pre-
existing genetic load”
mRNA = messenger ribonucleic acid;
ER = endoplasmic reticulum.
Al-Chalabi & Hardiman, 2013; Hardiman et al, 2017.
ALS Patients Exhibit Genetic Heterogeneity
Sporadic ALS (sALS): 85%; ATXN2 may be risk factor
Familial ALS (fALS): 15%; >50 genes, especially SOD1
and C9orf72
ALS clinical symptoms (phenotypes) do not differ
between the sporadic and genetic groups
Sporadic (85%) Familial (15%)
ALS is pathophysiologically and clinically diverse
Lattante et al, 2015; Alsultan et al, 2016; Ingre et al, 2015.
Variability of Disease Progression
Swinnen & Robberecht, 2014; Lee & McCambridge, 2018; de Carvalho & Swash, 2023.
Revised ALSFRS (ALSFRS-R)
ALS is clinically and pathophysiologically diverse
• 70% of patients present with spinal-onset ALS
• 25% present with bulbar-onset ALS
• 5% present with initial trunk– or respiratory-onset ALS
ALSFRS (ALS Functional Rating Scale)
Spinal onset
Early Diagnosis Is the Key in ALS
 Early signs and symptoms that should elevate suspicion for ALS
Muscle weakness/stiffness, atrophy, twitches, slurred speech, difficulty
chewing/swallowing
 Importance of an early and accurate diagnosis
Essential for patients with ALS to receive specific clinical management that can be
more effective earlier in the disease course, such as disease-modifying
treatments, interprofessional care, and assistive devices. Early diagnosis also
facilitates inclusion in clinical trials
Benatar et al, 2019; Kiernan et al, 2021; Matharan et al, 2020; Miller et al, 2009; Paganoni et al, 2014; Swinnen et al, 2014.
Comprehensive Clinical Diagnosis of ALS
CNS = central nervous system; HIV = human immunodeficiency virus; CT = computed tomography.
Hardiman et al, 2017; Brown & Al-Chalabi, 2017; Kiernan et al, 2011.
Detailed personal history of symptom development and family
history of neuromuscular disease
Systemic neurologic examination to identify upper motor neuron
(UMN) and lower motor neuron
(LMN) dysfunction
Rule out other potential causes of symptoms,
eventually with:
Electromyography (EMG)
Nerve conduction study (NCS)
Magnetic resonance imaging (MRI)
Muscle biopsy
Genetic testing
Lumbar puncture
Lab tests for other diseases to rule out HIV, human T-
cell leukemia virus (HTLV), polio, West Nile virus, others
Hardiman et al, 2017; Brown et al, 2017; Kiernan et al, 2011.
Body Region Upper Motor Neuron Signs Lower Motor Neuron Signs
Cranial
• Spastic dysarthria
• Laryngospasm
• Palmomental reflex
• Jaw-jerk reflex
• Slurring of speech
• Tongue atrophy
• Tongue fasciculations
• Temporal wasting
• Decreased soft palate elevation
Cervical
• Limb spasticity
• Hyperreflexia
• Hoffman’s sign
• Muscle weakness/atrophy
• Muscle fasciculations
• Hyporeflexia
Thoracic • None
• Accessory muscle use with respiration
respiration
• Paradoxical breathing
Lumbosacral
• Limb spasticity
• Hyperreflexia
• Cross-adductor reflex
• Upgoing Babinski sign
• Muscle weakness/atrophy
• Muscle fasciculations
• Hyporeflexia
Upper and Lower Motor Neuron Signs by Body Region
Brooks et al, 2000.
El Escorial ALS Diagnostic Criteria Revised
Weakness/atrophy/hyperreflexia/spasticity
Progression over time
EMG/nerve conduction velocity/neuroimaging/biopsy
Neuropathology
LMN + UMN
1 region or UMN
≥1 regions
Clinically-
possible ALS
LMN + UMN 1 region
or UMN 1 region
With EMG acute denervation
≥2 limbs
Clinically-probable ALS
(laboratory-supported)
LMN + UMN
2 regions
Clinically-
probable ALS
LMN + UMN
3 regions
Clinically-
definite ALS
Documented
progressive
motor impairment
that
was preceded by
normal motor
function
Investigations
that
have excluded
other disease
processes
Upper + lower
motor neuron
dysfunction in ≥1
body region
or lower motor
neuron dysfunction
in ≥2 body
regions
Impairment must
be documented
by history or
repeated clinical
assessment
If only 1 body
region is affected,
upper + lower
motor dysfunction
must both be
present
Nerve conduction
studies, needle
EMG, imaging,
fluid studies (blood
or CSF), or other
modalities as
clinically
appropriate
+ +
CSF = cerebrospinal fluid.
Shefner et al, 2020.
Gold Coast Criteria for Diagnosing ALS
Evolving Genetic Testing Guidelines
Roggenbuck et al, 2023.
Genetic testing and counseling are becoming increasingly important
Required for emerging gene-specific therapies (eg, tofersen [SOD1])
Ethics regarding the genetic testing of family members of patients who
test positive for a familial form of ALS are shifting
Testing can be considered in patients who have gene mutations identified
in the family but are asymptomatic
Identifying patients at risk for familial ALS before the develop symptoms
will be key for early administration of targeted treatments
A Paradigm Shift in Management of ALS
Early Diagnosis Facilitates Initiation of Best Clinical Practice
Hogden et al, 2017.
Disease-modifying medications
Clinical research
Medications to treat symptoms
Physical and occupational therapy
Speech and assistive technology
Nutrition support
Breathing support
Palliative medicine and hospice
Interprofessional Approach
Key Takeaways
The diagnosis of ALS is based on clinical history and exam, with support
from a focused set of diagnostic tests
Diagnostic delays may be due to several factors, including clinical heterogeneity
Diagnostic tests are performed to rule out other diagnoses
Genetic testing is increasingly important
Early diagnosis is key in ALS
Leads to earlier initiation of interprofessional care (to improve function,
maximize quality of life, and extend survival)
Allows earlier inclusion in clinical research and clinical trials
Increased awareness, evolving clinical criteria, and emerging biomarkers
may enable earlier diagnosis in the near future
References
Al-Chalabi A & Hardiman O (2013). The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol, 9(11):617-28. DOI:10.1038/nrneurol.2013.203
Alsultan AA, Waller R, Heath PR, et al (2016). The genetics of amyotrophic lateral sclerosis: current insights. Degener Neurol Neuromuscul Dis. 6:49-64. DOI:10.2147/DNND.S84956
Benatar M, Turner MR & Wuu J (2019). Defining pre-symptomatic amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener, 20(5-6):303-309.
DOI:10.1080/21678421.2019.1587634
Brooks BR, Miller RG, Swash M, et al (2000). World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic
lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord, 1(5):293-9. DOI:10.1080/146608200300079536
Brown RH & Al-Chalabi A (2017). Amyotrophic lateral sclerosis. N Engl J Med, 377(2):162-172. DOI:10.1056/NEJMra1603471
de Carvalho M & Swash M (2023). Diagnosis and differential diagnosis of MND/ALS: IFCN handbook chapter. Clin Neurophysiol Pract, 9:27-38. DOI:10.1016/j.cnp.2023.12.003
Hardiman O, Al-Chalabi A, Chio A, et al (2017). Amyotrophic lateral sclerosis. Nat Rev Dis Primers, 3:17071. DOI:10.1038/nrdp.2017.71
Hogden A, Foley G, Henderson RD, et al (2017). Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach. J Multidiscip Healthc, 10:205-215. DOI:10.2147/JMDH.S134992
Ingre C, Roos PM, Piehl F, et al (2015). Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol, 2015(7):181-93. DOI:10.2147/CLEP.S37505
Kiernan MC, Vucic S, Cheah BC, et al (2011). Amyotrophic lateral sclerosis. Lancet, 377(9769):942-55. DOI:10.1016/S0140-6736(10)61156-7
Kiernan MC, Vucic S, Talbot K, et al (2021). Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol, 17(2):104-118. DOI:10.1038/s41582-020-00434-z
Lattante S, Ciura S, Rouleau GA & Kabashi E (2015). Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet, 31(5):263-
73. DOI:10.1016/j.tig.2015.03.005
Lee M & McCambridge A (2018). Clinimetrics: Amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R). J Physiother, 64(4):269-270. DOI:10.1016/j.jphys.2018.07.005
Matharan M, Mathis S, Bonabaud S, et al (2020). Minimizing the diagnostic delay in amyotrophic lateral sclerosis: the role of nonneurologist practitioners. Neurol Res Int, 2020:1473981.
DOI:10.1155/2020/1473981
Mehta P, Kaye W, Raymond J, et al (2018). Prevalence of amyotrophic lateral sclerosis - United States, 2014. MMWR Morb Mortal Wkly Rep, 67(7):216-218. DOI:10.15585/mmwr.mm6707a3
Miller RG, Brooks BR, Swain-Eng RJ, et al (2013). Quality improvement in neurology: amyotrophic lateral sclerosis quality measures: report of the quality measurement and reporting
subcommittee of the American Academy of Neurology. Neurology, 81(24):2136-40. DOI:10.1212/01.wnl.0000437305.37850.f9
References (cont.)
Miller RG, Jackson CE, Kasarskis EJ, et al (2009). Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and
cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 73(15):1227-33.
DOI:10.1212/WNL.0b013e3181bc01a4
Paganoni S, Macklin EA, Lee A, et al (2014). Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Frontotemporal Degener. 15(5-6):453-6.
DOI:10.3109/21678421.2014.903974
Roggenbuck J, Eubank BHF, Wright J, et al (2023): ALS genetic testing and counseling guidelines expert panel. evidence-based consensus guidelines for ALS genetic testing and counseling.
Ann Clin Transl Neurol, 10(11):2074-2091. DOI:10.1002/acn3.51895
Roggenbuck J, Quick A & Kolb SJ (2017). Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med, 19(3):267-274.
DOI:10.1038/gim.2016.107
Shefner JM, Al-Chalabi A, Baker MR, et al (2020). A proposal for new diagnostic criteria for ALS. Clin Neurophysiol, 131(8):1975-1978. DOI:10.1016/j.clinph.2020.04.005
Swinnen B & Robberecht W (2014). The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol, 10(11):661-70. DOI:10.1038/nrneurol.2014.184
Wikipedia (2024). Lou Gehrig. Available at: https://en.wikipedia.org/w/index.php?title=Lou_Gehrig&oldid=1223111575

More Related Content

PPTX
Case Study - Aplastic Anemia
PPTX
Shock in children
PPTX
Hypopituitarism
PPTX
HYPERTHYROIDISM GRAVE'S DISEASE
PPTX
Autoimmune epilepsy
PPTX
Approach to case of arthritis
PPTX
Dic Dr Umashankar
PPTX
Organophosphate poisoning national guideline
Case Study - Aplastic Anemia
Shock in children
Hypopituitarism
HYPERTHYROIDISM GRAVE'S DISEASE
Autoimmune epilepsy
Approach to case of arthritis
Dic Dr Umashankar
Organophosphate poisoning national guideline

What's hot (20)

PPTX
Cushing syndrome
PPTX
Cerebral Venous Sinus Thrombosis (CVST): Causes, Risks, Complications, Diag...
PPTX
Atherosclerosis and myocardial infarction
PPT
Vasculitis
PDF
APS in daily practice 2022.pdf
PPTX
Autoimmune encephalitis ppt
PDF
Thyrotoxicosis
PDF
Approach to muscle weakness
PPTX
Approch to paraplegia.pptx
PPTX
Lewy Body Dementia
PPTX
Inflammatory myositis
PPT
CNS myasthenia gravis davidson 10 MCQs.
PPTX
Approach to Anemia
PPT
Introduction to neurology Walid Reda Ashour
PPT
Rheumatology
PDF
Spinal cord disease and Lower motor neurone disorders in Paediatrics
PPTX
1st seizure ppt
PDF
RGUHS Medicine PG question bank
PPTX
WHIPPLES DISEASE power point summary slides
PDF
Stroke in Young
Cushing syndrome
Cerebral Venous Sinus Thrombosis (CVST): Causes, Risks, Complications, Diag...
Atherosclerosis and myocardial infarction
Vasculitis
APS in daily practice 2022.pdf
Autoimmune encephalitis ppt
Thyrotoxicosis
Approach to muscle weakness
Approch to paraplegia.pptx
Lewy Body Dementia
Inflammatory myositis
CNS myasthenia gravis davidson 10 MCQs.
Approach to Anemia
Introduction to neurology Walid Reda Ashour
Rheumatology
Spinal cord disease and Lower motor neurone disorders in Paediatrics
1st seizure ppt
RGUHS Medicine PG question bank
WHIPPLES DISEASE power point summary slides
Stroke in Young
Ad

Similar to Getting Ahead of the ALS Curve Through Early Detection and Intervention: Module 1 – Enabling Earlier Detection of ALS (20)

PPTX
Review of Amyotrophic Lateral Sclerosis.pptx
PPTX
Amyotrophic Lateral Sclerosis
PDF
Slowing Disease Progression and Optimizing Quality of Life for Patients With ALS
PDF
Amyotrophic lateral sclerosis- A review
PPTX
Amyotrophic Lateral Sclerosis - Overview.pptx
PPTX
MOTOR NEURON DISEASE presentation- publish
PPT
ALS - amyotrophic lateral sclerosis
PPTX
Amylotrophic lateral sclerosis.pptx.....
PPTX
Motor Neuron Disease
PPTX
mnd-151204195837-lva1-app6892.pptx
PPTX
Amyotrophic lateral sclerosis (als)
PPTX
ALS_Detailed_Academic_Presentation .pptx
PPTX
Amyotrophic Lateral Sclerosis
PPTX
Amyotrophic Lateral Sclerosis
PDF
Amyotrophic Lateral Sclerosis ( Important Points ).pdf
PPTX
OT 537 ALS
PDF
The Main Molecular Bases of Amyotrophic Lateral Sclerosis: An Integrating Review
PPTX
ALS - KV.pptx
PPTX
Motor ND seminar.pptx
PPTX
Motor neuron disease
Review of Amyotrophic Lateral Sclerosis.pptx
Amyotrophic Lateral Sclerosis
Slowing Disease Progression and Optimizing Quality of Life for Patients With ALS
Amyotrophic lateral sclerosis- A review
Amyotrophic Lateral Sclerosis - Overview.pptx
MOTOR NEURON DISEASE presentation- publish
ALS - amyotrophic lateral sclerosis
Amylotrophic lateral sclerosis.pptx.....
Motor Neuron Disease
mnd-151204195837-lva1-app6892.pptx
Amyotrophic lateral sclerosis (als)
ALS_Detailed_Academic_Presentation .pptx
Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis ( Important Points ).pdf
OT 537 ALS
The Main Molecular Bases of Amyotrophic Lateral Sclerosis: An Integrating Review
ALS - KV.pptx
Motor ND seminar.pptx
Motor neuron disease
Ad

More from i3 Health (20)

PDF
Increasing Detection and Improving Outcomes in Hereditary Transthyretin Amylo...
PPTX
Optimizing Neuroendocrine Tumor Outcomes: Closing the Gaps in Diagnosis and Care
PPTX
Optimizing Cancer Screening With MCED Technologies: From Science to Practical...
PPTX
Optimizing Cancer Screening With MCED Technologies: From Science to Practical...
PPTX
Optimizing Cancer Screening With MCED Technologies: From Science to Practical...
PPTX
What’s New With HER2: Charting New Paths in NSCLC Care — Module 2
PPTX
What’s New With HER2: Charting New Paths in NSCLC Care Module 1: HER2 in NSC...
PPTX
Patient Point of View: PDE4 Inhibitors for the Treatment of Adult Plaque Psor...
PPTX
Pathways to Precision: Integrating Genetic Counseling and Testing Into Cancer...
PPTX
Cracking the Code to Successful Stem Cell Mobilization in Multiple Myeloma
PPTX
Toxicity Management and Symptom Control in Advanced RCC: Playbook Update
PPTX
Comprehensive Management of Von Hippel-Lindau Disease: Genetic and Oncologica...
PPTX
Getting Ahead of the ALS Curve Through Early Detection and Intervention: Modu...
PPTX
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...
PPTX
Exploring Novel Treatments for Rett Syndrome
PPTX
Exploring New Treatment Advances for Acid sphingomyelinase Deficiency
PPTX
Current Standards and New Directions in the Treatment of Acquired Thrombotic ...
PDF
Optimizing Personalized Care Plans for Patients With Advanced Non-Small Cell ...
PPTX
New Thinking, New Strategies in Advanced Urothelial Carcinoma
PPTX
Enhancing Treatment Experiences in Castration-Resistant Prostate Cancer: The ...
Increasing Detection and Improving Outcomes in Hereditary Transthyretin Amylo...
Optimizing Neuroendocrine Tumor Outcomes: Closing the Gaps in Diagnosis and Care
Optimizing Cancer Screening With MCED Technologies: From Science to Practical...
Optimizing Cancer Screening With MCED Technologies: From Science to Practical...
Optimizing Cancer Screening With MCED Technologies: From Science to Practical...
What’s New With HER2: Charting New Paths in NSCLC Care — Module 2
What’s New With HER2: Charting New Paths in NSCLC Care Module 1: HER2 in NSC...
Patient Point of View: PDE4 Inhibitors for the Treatment of Adult Plaque Psor...
Pathways to Precision: Integrating Genetic Counseling and Testing Into Cancer...
Cracking the Code to Successful Stem Cell Mobilization in Multiple Myeloma
Toxicity Management and Symptom Control in Advanced RCC: Playbook Update
Comprehensive Management of Von Hippel-Lindau Disease: Genetic and Oncologica...
Getting Ahead of the ALS Curve Through Early Detection and Intervention: Modu...
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...
Exploring Novel Treatments for Rett Syndrome
Exploring New Treatment Advances for Acid sphingomyelinase Deficiency
Current Standards and New Directions in the Treatment of Acquired Thrombotic ...
Optimizing Personalized Care Plans for Patients With Advanced Non-Small Cell ...
New Thinking, New Strategies in Advanced Urothelial Carcinoma
Enhancing Treatment Experiences in Castration-Resistant Prostate Cancer: The ...

Recently uploaded (20)

PDF
Yogi Goddess Pres Conference Studio Updates
PPTX
Orientation - ARALprogram of Deped to the Parents.pptx
PDF
O5-L3 Freight Transport Ops (International) V1.pdf
PDF
A systematic review of self-coping strategies used by university students to ...
PDF
Complications of Minimal Access Surgery at WLH
PPTX
Pharmacology of Heart Failure /Pharmacotherapy of CHF
PPTX
202450812 BayCHI UCSC-SV 20250812 v17.pptx
PPTX
1st Inaugural Professorial Lecture held on 19th February 2020 (Governance and...
PPTX
Pharma ospi slides which help in ospi learning
PDF
Classroom Observation Tools for Teachers
PDF
2.FourierTransform-ShortQuestionswithAnswers.pdf
PPTX
Final Presentation General Medicine 03-08-2024.pptx
PPTX
Lesson notes of climatology university.
PDF
STATICS OF THE RIGID BODIES Hibbelers.pdf
PDF
Weekly quiz Compilation Jan -July 25.pdf
PDF
The Lost Whites of Pakistan by Jahanzaib Mughal.pdf
PDF
RTP_AR_KS1_Tutor's Guide_English [FOR REPRODUCTION].pdf
PDF
Abdominal Access Techniques with Prof. Dr. R K Mishra
PDF
Chapter 2 Heredity, Prenatal Development, and Birth.pdf
PPTX
Microbial diseases, their pathogenesis and prophylaxis
Yogi Goddess Pres Conference Studio Updates
Orientation - ARALprogram of Deped to the Parents.pptx
O5-L3 Freight Transport Ops (International) V1.pdf
A systematic review of self-coping strategies used by university students to ...
Complications of Minimal Access Surgery at WLH
Pharmacology of Heart Failure /Pharmacotherapy of CHF
202450812 BayCHI UCSC-SV 20250812 v17.pptx
1st Inaugural Professorial Lecture held on 19th February 2020 (Governance and...
Pharma ospi slides which help in ospi learning
Classroom Observation Tools for Teachers
2.FourierTransform-ShortQuestionswithAnswers.pdf
Final Presentation General Medicine 03-08-2024.pptx
Lesson notes of climatology university.
STATICS OF THE RIGID BODIES Hibbelers.pdf
Weekly quiz Compilation Jan -July 25.pdf
The Lost Whites of Pakistan by Jahanzaib Mughal.pdf
RTP_AR_KS1_Tutor's Guide_English [FOR REPRODUCTION].pdf
Abdominal Access Techniques with Prof. Dr. R K Mishra
Chapter 2 Heredity, Prenatal Development, and Birth.pdf
Microbial diseases, their pathogenesis and prophylaxis

Getting Ahead of the ALS Curve Through Early Detection and Intervention: Module 1 – Enabling Earlier Detection of ALS

  • 1. Sabrina Paganoni, MD, PhD Co-Director, Neurological Clinical Research Institute Massachusetts General Hospital, Department of Neurology Healey & AMG Center for ALS at Mass General Associate Professor of PM&R Spaulding Rehabilitation Hospital, Harvard Medical School Getting Ahead of the ALS Curve Through Early Detection and Intervention Module 1: Enabling Earlier Diagnosis of ALS
  • 2. Disclosures Consultant: Amylyx, Arrowhead, Cytokinetics, Eikonizo Grants/research support: Calico, Clene, Denali, Prilenia, Seelos, UCB i3 Health has mitigated all relevant financial relationships
  • 3. Learning Objective ALS = amyotrophic lateral sclerosis. Evaluate factors that can inform an early and accurate diagnosis of ALS
  • 4. Amyotrophic Lateral Sclerosis (ALS) “I might have been given a bad break, but I've got an awful lot to live for” – July 4, 1939 Lou Gehrig’s Disease Image courtesy of Columbiana Library, Columbia University (Wikimedia Commons).
  • 5. What Is ALS? ALS begins with motor neuron degeneration and death and results in loss of function Motor neuron cell death leads to muscle weakness, loss of motor function, and progressive motor deficits Death is usually from respiratory failure, typically within 3 to 5 years after disease onset Age of onset: 25 to 85 years (peak at 65 years) Annual incidence is ~2 per 100,000, and worldwide prevalence is ~5 per 100,000 Hardiman et al, 2017; Brown & Al-Chalabi, 2017; Kiernan et al, 2011; Roggenbuck et al, 2017; Mehta et al, 2018.
  • 6. Multiple Mechanisms Converge To Cause ALS Upper and Lower Motor Neuron Loss Synaptic dysfunction Excitotoxicity Genetic abnormalities Oxidative stress Abnormal protein aggregation Neuroinflammation Aberrant mRNA processing & transport Abnormal axonal transport ER stress Mitochondrial dysfunction ALS: A Conspiracy of Genes, Environment, and Time “ALS is considered to be the result of environmental risks and time acting on a pre- existing genetic load” mRNA = messenger ribonucleic acid; ER = endoplasmic reticulum. Al-Chalabi & Hardiman, 2013; Hardiman et al, 2017.
  • 7. ALS Patients Exhibit Genetic Heterogeneity Sporadic ALS (sALS): 85%; ATXN2 may be risk factor Familial ALS (fALS): 15%; >50 genes, especially SOD1 and C9orf72 ALS clinical symptoms (phenotypes) do not differ between the sporadic and genetic groups Sporadic (85%) Familial (15%) ALS is pathophysiologically and clinically diverse Lattante et al, 2015; Alsultan et al, 2016; Ingre et al, 2015.
  • 8. Variability of Disease Progression Swinnen & Robberecht, 2014; Lee & McCambridge, 2018; de Carvalho & Swash, 2023. Revised ALSFRS (ALSFRS-R) ALS is clinically and pathophysiologically diverse • 70% of patients present with spinal-onset ALS • 25% present with bulbar-onset ALS • 5% present with initial trunk– or respiratory-onset ALS ALSFRS (ALS Functional Rating Scale) Spinal onset
  • 9. Early Diagnosis Is the Key in ALS  Early signs and symptoms that should elevate suspicion for ALS Muscle weakness/stiffness, atrophy, twitches, slurred speech, difficulty chewing/swallowing  Importance of an early and accurate diagnosis Essential for patients with ALS to receive specific clinical management that can be more effective earlier in the disease course, such as disease-modifying treatments, interprofessional care, and assistive devices. Early diagnosis also facilitates inclusion in clinical trials Benatar et al, 2019; Kiernan et al, 2021; Matharan et al, 2020; Miller et al, 2009; Paganoni et al, 2014; Swinnen et al, 2014.
  • 10. Comprehensive Clinical Diagnosis of ALS CNS = central nervous system; HIV = human immunodeficiency virus; CT = computed tomography. Hardiman et al, 2017; Brown & Al-Chalabi, 2017; Kiernan et al, 2011. Detailed personal history of symptom development and family history of neuromuscular disease Systemic neurologic examination to identify upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction Rule out other potential causes of symptoms, eventually with: Electromyography (EMG) Nerve conduction study (NCS) Magnetic resonance imaging (MRI) Muscle biopsy Genetic testing Lumbar puncture Lab tests for other diseases to rule out HIV, human T- cell leukemia virus (HTLV), polio, West Nile virus, others
  • 11. Hardiman et al, 2017; Brown et al, 2017; Kiernan et al, 2011. Body Region Upper Motor Neuron Signs Lower Motor Neuron Signs Cranial • Spastic dysarthria • Laryngospasm • Palmomental reflex • Jaw-jerk reflex • Slurring of speech • Tongue atrophy • Tongue fasciculations • Temporal wasting • Decreased soft palate elevation Cervical • Limb spasticity • Hyperreflexia • Hoffman’s sign • Muscle weakness/atrophy • Muscle fasciculations • Hyporeflexia Thoracic • None • Accessory muscle use with respiration respiration • Paradoxical breathing Lumbosacral • Limb spasticity • Hyperreflexia • Cross-adductor reflex • Upgoing Babinski sign • Muscle weakness/atrophy • Muscle fasciculations • Hyporeflexia Upper and Lower Motor Neuron Signs by Body Region
  • 12. Brooks et al, 2000. El Escorial ALS Diagnostic Criteria Revised Weakness/atrophy/hyperreflexia/spasticity Progression over time EMG/nerve conduction velocity/neuroimaging/biopsy Neuropathology LMN + UMN 1 region or UMN ≥1 regions Clinically- possible ALS LMN + UMN 1 region or UMN 1 region With EMG acute denervation ≥2 limbs Clinically-probable ALS (laboratory-supported) LMN + UMN 2 regions Clinically- probable ALS LMN + UMN 3 regions Clinically- definite ALS
  • 13. Documented progressive motor impairment that was preceded by normal motor function Investigations that have excluded other disease processes Upper + lower motor neuron dysfunction in ≥1 body region or lower motor neuron dysfunction in ≥2 body regions Impairment must be documented by history or repeated clinical assessment If only 1 body region is affected, upper + lower motor dysfunction must both be present Nerve conduction studies, needle EMG, imaging, fluid studies (blood or CSF), or other modalities as clinically appropriate + + CSF = cerebrospinal fluid. Shefner et al, 2020. Gold Coast Criteria for Diagnosing ALS
  • 14. Evolving Genetic Testing Guidelines Roggenbuck et al, 2023. Genetic testing and counseling are becoming increasingly important Required for emerging gene-specific therapies (eg, tofersen [SOD1]) Ethics regarding the genetic testing of family members of patients who test positive for a familial form of ALS are shifting Testing can be considered in patients who have gene mutations identified in the family but are asymptomatic Identifying patients at risk for familial ALS before the develop symptoms will be key for early administration of targeted treatments A Paradigm Shift in Management of ALS
  • 15. Early Diagnosis Facilitates Initiation of Best Clinical Practice Hogden et al, 2017. Disease-modifying medications Clinical research Medications to treat symptoms Physical and occupational therapy Speech and assistive technology Nutrition support Breathing support Palliative medicine and hospice Interprofessional Approach
  • 16. Key Takeaways The diagnosis of ALS is based on clinical history and exam, with support from a focused set of diagnostic tests Diagnostic delays may be due to several factors, including clinical heterogeneity Diagnostic tests are performed to rule out other diagnoses Genetic testing is increasingly important Early diagnosis is key in ALS Leads to earlier initiation of interprofessional care (to improve function, maximize quality of life, and extend survival) Allows earlier inclusion in clinical research and clinical trials Increased awareness, evolving clinical criteria, and emerging biomarkers may enable earlier diagnosis in the near future
  • 17. References Al-Chalabi A & Hardiman O (2013). The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol, 9(11):617-28. DOI:10.1038/nrneurol.2013.203 Alsultan AA, Waller R, Heath PR, et al (2016). The genetics of amyotrophic lateral sclerosis: current insights. Degener Neurol Neuromuscul Dis. 6:49-64. DOI:10.2147/DNND.S84956 Benatar M, Turner MR & Wuu J (2019). Defining pre-symptomatic amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener, 20(5-6):303-309. DOI:10.1080/21678421.2019.1587634 Brooks BR, Miller RG, Swash M, et al (2000). World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord, 1(5):293-9. DOI:10.1080/146608200300079536 Brown RH & Al-Chalabi A (2017). Amyotrophic lateral sclerosis. N Engl J Med, 377(2):162-172. DOI:10.1056/NEJMra1603471 de Carvalho M & Swash M (2023). Diagnosis and differential diagnosis of MND/ALS: IFCN handbook chapter. Clin Neurophysiol Pract, 9:27-38. DOI:10.1016/j.cnp.2023.12.003 Hardiman O, Al-Chalabi A, Chio A, et al (2017). Amyotrophic lateral sclerosis. Nat Rev Dis Primers, 3:17071. DOI:10.1038/nrdp.2017.71 Hogden A, Foley G, Henderson RD, et al (2017). Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach. J Multidiscip Healthc, 10:205-215. DOI:10.2147/JMDH.S134992 Ingre C, Roos PM, Piehl F, et al (2015). Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol, 2015(7):181-93. DOI:10.2147/CLEP.S37505 Kiernan MC, Vucic S, Cheah BC, et al (2011). Amyotrophic lateral sclerosis. Lancet, 377(9769):942-55. DOI:10.1016/S0140-6736(10)61156-7 Kiernan MC, Vucic S, Talbot K, et al (2021). Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol, 17(2):104-118. DOI:10.1038/s41582-020-00434-z Lattante S, Ciura S, Rouleau GA & Kabashi E (2015). Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet, 31(5):263- 73. DOI:10.1016/j.tig.2015.03.005 Lee M & McCambridge A (2018). Clinimetrics: Amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R). J Physiother, 64(4):269-270. DOI:10.1016/j.jphys.2018.07.005 Matharan M, Mathis S, Bonabaud S, et al (2020). Minimizing the diagnostic delay in amyotrophic lateral sclerosis: the role of nonneurologist practitioners. Neurol Res Int, 2020:1473981. DOI:10.1155/2020/1473981 Mehta P, Kaye W, Raymond J, et al (2018). Prevalence of amyotrophic lateral sclerosis - United States, 2014. MMWR Morb Mortal Wkly Rep, 67(7):216-218. DOI:10.15585/mmwr.mm6707a3 Miller RG, Brooks BR, Swain-Eng RJ, et al (2013). Quality improvement in neurology: amyotrophic lateral sclerosis quality measures: report of the quality measurement and reporting subcommittee of the American Academy of Neurology. Neurology, 81(24):2136-40. DOI:10.1212/01.wnl.0000437305.37850.f9
  • 18. References (cont.) Miller RG, Jackson CE, Kasarskis EJ, et al (2009). Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 73(15):1227-33. DOI:10.1212/WNL.0b013e3181bc01a4 Paganoni S, Macklin EA, Lee A, et al (2014). Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Frontotemporal Degener. 15(5-6):453-6. DOI:10.3109/21678421.2014.903974 Roggenbuck J, Eubank BHF, Wright J, et al (2023): ALS genetic testing and counseling guidelines expert panel. evidence-based consensus guidelines for ALS genetic testing and counseling. Ann Clin Transl Neurol, 10(11):2074-2091. DOI:10.1002/acn3.51895 Roggenbuck J, Quick A & Kolb SJ (2017). Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med, 19(3):267-274. DOI:10.1038/gim.2016.107 Shefner JM, Al-Chalabi A, Baker MR, et al (2020). A proposal for new diagnostic criteria for ALS. Clin Neurophysiol, 131(8):1975-1978. DOI:10.1016/j.clinph.2020.04.005 Swinnen B & Robberecht W (2014). The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol, 10(11):661-70. DOI:10.1038/nrneurol.2014.184 Wikipedia (2024). Lou Gehrig. Available at: https://en.wikipedia.org/w/index.php?title=Lou_Gehrig&oldid=1223111575

Editor's Notes

  • #5: This talk focuses on Amyotrophic Lateralis Sclerosis, also called Lou Gehrig’s Disease, named after the first baseman for the Yankees who received the nick named “The Iron Horse.” He removed himself from the lineup May 2, 1939, when his performance was affected by weakness due to ALS. The Luckiest Man on the Face of the Earth speech at Yankee stadium became iconic and moved masses of people. Lou Gehrig died in 1941 at the age of 37.
  • #8: Because the same phenotypes arise from multiple genetic causes, there may be multiple molecular mechanisms causing ALS, implying that it is a syndrome Conversely, multiple phenotypes can be caused by a single-gene mutation, implying clinical heterogeneity for a single-molecular mechanism
  • #11: Conduct a detailed personal history of symptom development and family history of neuromuscular disease Perform a systemic neurologic examination to identify UMN and LMN dysfunction and rule out other potential causes of symptoms, which may include: Electromyography (EMG) Nerve conduction study (NCS) Magnetic resonance imaging (MRI) Muscle biopsy Genetic testing Lumbar puncture Lab tests for other diseases to rule out HIV, human T-cell leukemia virus (HTLV), polio, West Nile virus, others
  • #14: Shape formats are a bit different, but I was not able to maintain the same size.
  • #15: As knowledge about the genetics of ALS continues to grow, genetic testing and counseling will become increasingly important Genetic testing required for emerging gene-specific therapies (eg, tofersen [SOD1]), so it needs to be incorporated into routine ALS management Recommend all patients diagnosed with ALS be tested to determine whether they have a targetable mutation Current US management guidelines for ALS do not address the issue of genetic testing European Federation of Neurological Societies recommends genetic testing only in symptomatic patients with a family history of ALS and not in those with sporadic ALS Ethics regarding the genetic testing of family members of patients who test positive for a familial form of ALS are shifting Testing can be considered in patients who have gene mutations identified in the family but are asymptomatic Identifying patients at risk for familial ALS before they develop symptoms will be key for early administration of targeted treatments