AMYOTROPHIC

LATERAL
SCLEROSIS
 Outline: ALS
Anatomy
Physiology
Medical Background
Epidemiology
Etiology
Pathophysiology of the Disease
Clinical s/sx
Differential Diagnosis
WHAT IS ALS?

Degeneration and loss of motor neurons in the spinal

cord, brainstem, and brain, resulting in a variety of
UMN and LMN clinical s/sx
ANATOMY &
PHYSIOLOGY
NERVOUS SYSTEM

Central Nervous System

brain and spinal cord

Peripheral nervous system

anterior horn cell

spinal and cranial nerves
ANS
MOTOR NEURON
TYPES OF NERVE FIBERS
A fibers- large myelinated, fast conducting fibers
Alpha Beta Gamma Delta
efferent to motor afferent to efferent to intrafusal afferent monitoring
end plate Meissners fiber in mm spindle quick pain,
corpuscle temperature and
fast touch light touch
pressure, position
and movement
sense and 2
stretch to mm
spindle
B fibers
smaller and slower conducting, myelinated, afferent pre-ganglionic fibers of the ANS
C fibers
unmyelinated, post-ganglionic fibers of the SNS
small and conductive fibers
conducts pain
AXONAL INJURY

Axonal Degeneration
Wallerian Degeneration
begins 4-5 days postfocal or multifocal nn damage
completes in 7 days for motor nerves/ 11 days for sensory nn
SPINAL CORD
DESCENDING TRACT

General pathway:
N1: cerebral hemisphere (precentral gyrus BA 4)
N2: internuncial neuron (SC, anterior column)
N3: Final common pathway (VRG)
CORTICOSINAL TRACT

Anterior corticospinal tract

primary movement of axial
musculature
synapses contra at ventral white
commissure
Lateral corticospinal tract:
appendicular
synapses terminates contralateral
at motor end plate
MEDICAL
BACKGROUND
Loss of UMNL:
hyperreflexia and spasticity
cranial nn involvement
Loss of LMNL:
weakness
atrophy
fasciculations
EPIDEMIOLOGY
~30,000 in the United States have ALS, 15 cases dx
everyday
Average age at onset: mid-to-late 50s
M>F (1.7:1)
 EPIDEMIOLOGY

TYPES Description
SPORADIC majority of cases

FAMILIAL autosomal dominant trait

superoxide dismutase 1 (SOD1) genetic
mutations
JUVENILE very rare
LIMB ONSET 70-80% of cases
BULBAR ONSET 20-30%
common in middle-aged women
initial sx: difficulty speaking, chewing or
swallowing
ETIOLOGY
unknown
no one single mechanism but rather multiple or cumulative mechanisms:
oxidative stress
exogenous neurotoxicity
excitotoxicity
impaired axonal transportation
protein aggregation
apoptosis (programmed cell death)
lifestyle factors
ETIOLOGY
1. Superoxide Dismutase
2. Glutamate
3. Clumping of neurofilament proteins into
spheroids in the cell body and proximal axon
4. Autoimmune reaction in the etiology of ALS
5. Lack of neurotrophic factors & other
neurodegenerative disorders
ETIOLOGY:
SUPEROXIDE DISMUTASES
group of enzymes that eliminate oxygen free radicals
3 isoforms: CuZnSOD, MnSOD, ECSOD.
Chromosome 21
Mutation of SOD1 primary gene defect is unknown
SOD1 mutation free radicals death of motor neurons
ETIOLOGY:
GLUTAMATE
Excessive NT cell death
Increased: CSF, plasma
Theory: of excitotoxicity: Deficiency in excitatory amino acid transporters 2
(EEAT2) motor cortex and SC
ETIOLOGY:
CLUMPING OF NEUROFILAMENT
histopathological characteristic of ALS
ETIOLOGY:
AUTOIMMUNE REACTIONS
serum factors toxic to anterior horn motor neurons
antibodies calcium channel
RISK FACTORS:
disease-causing mutations
Gender
Age
Family history
Clusters
Occupation characteristics
Diet
Trauma
Lifestyle factors
Neurotoxicant exposure
Vigorous physical activity
P ATH O P H Y S I O L O G Y
AFFECTED SPARED
CN 5, 7, 9, 10, 12 CN 3, 4, 6
Anterior horn cell Onufs nucleus
Corticospinal Tract spinocerebellar
CLINICAL MANIFESTATIONS

clinical hallmark: UMNL and LMNL

CLINICAL FEATURES

loss of motor neurons results in the primary clinical s/sx:

limb, bulbar, axial and respiratory function
differences in site of onset, pattern and speed of spread, and degree of
UMN and LMN dysfunction produce a disorder that is remarkable variable
between ndividuals
INITIAL CLINICAL FEATURES

Asymmetric limb weakness (mc presentation, 80%)

bulbar sx: dysarthria, dysphagia (next common presentation, 20%)
less common patterns of ALS onset:
respiratory mm weakness (1-3%)
generalized weakness in the limbs and bulbar mm (1-9%)
axial mm weakness
weight loss c mm atrophy
CLINICAL FEATURES OF LIMB
WEAKNESS
UE onset:
cervical extensor weakness
hand weakness but may begin in sh girdle mm
LE onset: foot drop
CLINICAL FEATURES OF BULBAR
WEAKNESS
Dysarthria
Dysphagia
Pseudobulbar affect
CLINICAL FEATURES OF AXIAL MM
WEAKNESS
axial neck weakness: posterior neck pain
axial truncal weakness
OTHER CLINICAL MANIFESTATIONS

Respiratory impairments
Cognitive Impairments
DIAGNOSIS
 EMG-NCV
muscle and nn biopsies
neuroimaging studies
ALS: PROGRESSION AND PROGNOSIS

Progressive disorder with clinical course that is nearly always linear,

constant slope
unilateral limb onset the pattern of spread is to the contralateral limb then
ipsilateraleral then to bulbar mm
bulbar onset: mc pattern of spread is to one arm and then to contralateral
arm
life threatening aspects: neuromuscular respiratory failure and dysphagia
survival rate 3-5 years
10% of ALS pts can live 10 years or more
DIFFERENTIAL
DIAGNOSIS
DDX
SMA

predominantly LMN
chromosome 5 gene
neuropathologically: excessive loss of large motor neurons
muscle biopsy reveal evidence of denervation
Clinical feature
proximal mm weakness
absent of reflexes
PRIMARY LATERAL SCLEROSIS

predominant UMNL
rare disorder
onset sporadically in adult to mid life
pathology: corticospinal & corticobulbar tracts
clinical feature:
progressive spastic weakness of limb
peripheral and other nerve system are spared
course of dse: 3 year survival from onset to death