Esclerosis Lateral Amiotorfica

(ALS)

Jose R. Carlo, M.D.,FAAN

Director, Clinica MDA
Catedratico de Neurología
Escuela de Medicina, UPR
Esclerosis Lateral Amiotrófica (ALS)
 Motor Neuron Diseases
• Combined upper & lower motor neuron
– Amyotrophic Lateral Sclerosis
• Sporadic
• Familial Adult Onset
• Familial Juvenile onset
– Madras-Type MND
• Pure Lower Motor Neuron
– Proximal Spinal Muscular Atrophies
• Acute infantile form (Werdnig Hoffman, SMA I)
• Chronic Childhood Form (Kugelberg-Welander, SMA II)
• Adult Onset Form (SMA III)
– With Bulbar involvement
• X-linked bulbospinal neuronopathy (Kennedy’s Disease)
• With deafness (Brown-Violetta-Van Laere)
• Without Deafness (Fazio-Londe)
– Hexosaminidase deficiency
– Post-polio syndrome
– Post-irradiaton
– Monomelic, focal or segmental spinal muscular atrophy
• Pure Upper Motor Neuron
– Primary Lateral Sclerosis
– Neurolathyrism
– Konzo
 Amyotrophic Lateral Sclerosis
(ALS, Lou Gehrig’s Disease)
• Progressive Neurodegenerative Disorder
• 2 principal forms: sporadic and Familial (FALS)
• Incidence of ± 2 per 100,000
• Upper and Lower Motor Neuron
• Risk increases with age up to 74 years
• Onset 56 to 63, rare before 20 years
• Male to female ratio of 1.5 :1
 Amyotrophic Lateral Sclerosis
• Sporadic ALS
– Amyotrophic Lateral Sclerosis- 90%
– Progressive Muscular Atrophy - <10%
– Primary Lateral Sclerosis – 2- 4%
– Progressive Bulbar Palsy - < 1%
• Hereditary
– Familial ALS (5-10 % of all ALS)
 Familial ALS (FALS)
• 5-10 % of all cases of ALS
• Majority are AD
• Several genes identified:
– ALS 1- Superoxide Dismutase 1 (SOD1) mutations in
± 20% of all familial ALS
– ALS2- ALSIN gene (AR)
• Rare Juvenile forms and PLS ( Pure Upper Motor Neuron)
– ALS-Fronto Temporal Dementia
– ALS 4 -Senataxin (DNA/RNA Helicase)
– Peripherin (Intermediate filament Type III)
 Amyotrophic Lateral Sclerosis +
Frontotemporal Dementia

• Subgroup of patients with personality change,

executive dysfunction and motor weakness
• Estimates of prevalence in ALS – 5-15%
• Often more rapid than MND alone-death within 3
years
• Bulbar presentation more common
• Mutations in MAPT, CHMP2B, PGRN (pro-
granulin) gene
• Abnormal deposition of TDP-43
 Se estima que existen 4.8
personas con ALS por cada
100,000 habitantes de PR

BARCELONETA Dorado
AGUADILLA ISABELA Vega Toa CATA ÑO LOIZA
QUEBRADILLA VEGA
HATILLO

MANATI BAJA Alta Baja SAN

CAMUY JUAN
ARECIBO Toa CAROLINA RIO
BAYAM ÓN LUQUILLO
Alta CANOVANAS GRANDE
FLORIDA TRUJILLO
MOCA
MOROVIS COROZAL GUAYNABO ALTO
AGUADA SAN FAJARDO
SEBASTIAN NARANJITO
RINC ÓN
CIALES
GURABO CEIBA
AÑASCO LARES UTUADO AGUAS
BUENAS JUNCOS NAGUABO
COMERIO
OROCOVIS CAGUAS
LAS MARIAS BARRANQUITAS LAS
MAYAGUEZ A
JAYUYA PIEDRAS
CIDRA HUMACAO
SAN
ADJUNTAS
LORENZO
MARICAO AIBONITO
VILLALBA
HORMIGUEROS CAYEY
SAN COAMO
GERM ÁN SABANA YYABUCOA
GRANDE YAUCO
PATILLAS
PEÑUELAS
CABO PONCE
ROJO JUANA MAUNABO
DIAZ
GUAYANILLA SANTA ARROYO
SALINAS
ISABEL GUAYAMA
LAJAS
GUANICA

Censo población estimada (3,927,776) para 2006 en

Puerto Rico del Centro de Datos Censales UPR
ALS: Clinical Features

• Weakness (Asymmetric)
• Atrophy
• Spasticity
• Fasciculations
• Cramps
• Difficulty swallowing-dysphagia
• Slurred Speech- dysarthria
• Shortness of breath
Upper Motor Neuron Lower Motor Neuron
Spastic Paralysis Flaccid Paralysis
Atrophy not prominent Prominent Atrophy
No Fasciculations or Fasciculations and
fibrillations fibrillations
Hypereflexia Normo or Hyporeflexia
ALS: Bulbar Symptoms/Signs
• Dysarthria: spastic (slow), flaccid or
mixed
• Dysphagia
– “Food stuck or coughing with food
• Drooling
• Pseudobulbar affect
 Absent in ALS

• Prominent Sensory Symptoms

• Sphincter involvement
– Urinary incontinence or retention
• Eye movement abnormalities
• Prominent Pain
 Diagnosis of ALS*
• Requires presence of:
– Evidence of LMN involvement in at least 2 limbs
– Evidence of UMN involvement in 1 region
– Progressive spread of symptoms and signs

• Requires absence of:

– Sensory signs
– Neurogenic sphincter abnormalities
– Clinically evident CNS disease apart from ALS
– Clinically evidenct PNS disease
– Neuroimaging evidence of other disease processes

* Revised El Escorial Criteria for ALS

ALS-Differential Dx
• Structural Spinal Cord lesion
• Multifocal Motor Neuropathy
• Hyperthyroidism
• Hyperparathyroidism
• Radiation to Brain or Spinal Cord
• Lead Poisoning
• Hexosaminidase A deficiency
• HTLV-I, HTLV-II
• ? HIV
ALS: Awaji-Shima Revised
Diagnostic Criteria

Clinical Neurophysiology: 2007

 ALS: Electrodiagnosis
• Confirm LMN dysfunction in clinically affected
regions
• Detect LMN dysfunction in clinically unaffected
regions
• Exclude other pathophysiologic processes
• Signs of active and chronic denervation in 2 of 4
regions (bulbar, cervical, thoracic, lumbosacral)
• Cervical and lumbosacral = 2 or more muscles
with different peripheral innervation
 ALS: Electrodiagnosis
• Active Denervation
– Fibrillaton potentials
– Positive sharp waves
• Chronic denervation
– Large motor unit potentials
– Reduced interference pattern (FF > 10Hz)
– Unstable motor unit potentials
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 Primary Lateral Sclerosis (PLS)
• Discrete syndrome v ALS variant
• Clinical
– Spasticity in legs > arms
– Increased DTRs
– Pseudobulbar signs ( with onset > 45 yrs)
• Laboratory
– TMS: absent of prolonged MEPs
– MRI: focal atrophy of precentral gyrus
• Differential
– Hereditary Spinal Disorders
ALS: Pseudobulbar Palsy
• Upper motor neuron dysfunction
– corticobulbar tracts
• “Emotional incontinence”
• Inappropriate laughter or crying
• Disinhibition of limbic motor control
• May occur in up to 50%
• Tx: Amytriptiline, Fluvoxamine
ALS: BUNINA BODY
ALS: Pathogenetic Theories
• Aberrant protein processing and
degradation
• Neurofilament disorganization
• Glutamate excitoxicity (loss of EAAT2)
• Oxidative damage
• Activation of microglial& astroglial cells
• Mitochondrial Damage
• Aggregation of mutant proteins
• Defects in axonal transport
Cu++/Zn++ SUPEROXIDE DISMUTASE
Western Pacific-Guamanian ALS

Science, 2002
ALS: Principles of Management

• Multidisciplinary approach
• Patient and caretaker support groups
• Nutrition
• Respiratory care
• Palliative care
• Drug therapy
 Pharmacologic Treatment
• Riluzole – FDA approved (1995) glutamate
antagonist
• Experimental compounds
– Creatine (excitotoxicity/ apoptosis)
– Celebrex (neuroinflammation)
– Minocycline (apoptosis/ neuroinflammation)
– Coenzyme Q10 (mitochondrial function/
antioxidant)
– Vitamins E, C (antioxidants)
ALS: Lower Motor Neuron
• Flaccid Weakness
– Ex. Head Drop
• Muscle Atrophy
• Normoreflexia or hypo in advanced
• Hypotonia
• Fasciculations
• Cramps
 Spinal Muscular Atrophies

• Phenotypically Heterogeneous disorders

• 2nd most common childhood lethal genetic
• One gene: different diseases
• Survival Motor Neuron (SMN1) gene in 5q11
– 2 copies: telomeric (SMN1) and centromeric (SMN2)
– Mutations in 98% of SMA children (SMN1)
– Severity of disease: # of copies of SMN2
• Neuronal Apoptotic Inhibitory Protein (NAIP)
• Proximal SMA I (Werdnig-Hoffman)
– Onset birth to 6 mo
– Never able to sit without support
– Death before age 2
• Proximal SMA II (Intermediate)
– Onset after 18 months
– Unable to stand or walk w/o aid
– Death after 2 years
• Proximal SMA III (Kugelberg-Welander)
– Onset after age 18 months
– Reach ability to stand and walk
– Death as adult
• Adult SMA IV
Ogino, S. et.al., Eur J Hum Genet, 2004
Spinobulbar Muscular Atrophy
(Kennedy’s Disease)
 Spinobulbar Muscular Atrophy
(Kennedy’s Disease)
• X-linked recessive
• Mean onset 30 years (range 15 to 60 years)
• Most common adult onset SMA
• 1 in 50,000
• Unstable trinucleotide repeat (CAG) in androgen
receptor gene
 Spinobulbar Muscular Atrophy
(Kennedy’s Disease)

• Slowly progressive proximal > distal weakness

• Perioral and facial fasciculation
• Gynecomastia and infertility
• Dysphagia (may be late)
• Motor and sensory neurons
 Post-Polio Syndrome
• New onset symptoms 20-40 years after polio
– New or progressive weakness
– Fatigue
– Muscle and joint pain
– Neuropathic EMG findings
• Pathogenesis:
– Attrition and premature exhaustion of neurons
– Normal age-related attrition of neurons
– Overuse of muscles
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