Amyotrophic lateral sclerosis is one of motor neuron diseases https://youtube.com/playlist?list=PL2XcrMWxPBLRIFeiviK7iovbwAJrw6kXt&si=0wqCjc9WphiPYH0a

1. Amyotrophic Lateral Sclerosis
By
Dr Mohammud Ibraheem

2. OUR POINTS
1) The motor neuron system
2) Discovery of ALS
3) Definition of ALS
4) Epidemiology
5) Etiology
6) Pathophysiology
7) DIAGNOSTIC EVALUATION

3. THE MOTOR NEURON SYSTEM
The motor neuron system is composed of:
A. Upper motor neurons reside in the primary motor
cortex of the brain, and their axons comprise the
corticobulbar tract and the corticospinal tract
(connecting to the spinal cord).
B. Lower motor neurons (alpha motor neurons or
anterior horn cells), are located in motor nuclei
in the brainstem or the anterior gray matter of
the spinal cord. Their axons connect to muscles
of the bulbar region or limbs.

5. DISCOVERY
The first detailed description was by
Jean Martin Charcot in 1869, in
which he discussed the clinical and
pathological characteristics of
“Amyotrophic Lateral Sclerosis ,” a
disorder of muscle wasting
(amyotrophy) and gliotic hardening
(sclerosis) of the anterior and lateral
corticospinal tracts

6. DEFINATION
ALS is a neurodegenerative disorder of
undetermined etiology that primarily
affects the motor neuron cell populations
in the motor cortex, brainstem, and spinal
cord.
It is progressive, and most patients
eventually succumb to respiratory failure.

7. EPIDEMIOLOGY
90-95% of cases are sporadic ALS.
5%-10% of cases are familial ALS.
For sporadic ALS, male-to-female ratio is 1 to 2.
Within the US, the prevalence is 5.2/100,000.
Worldwide prevalence is between 4.1 and 8.4 per
100000.
The incidence is between 0.6 and 3.8 per 100000
person-years

8. EPIDEMIOLOGY
The incidence increase with increases in age,
particularly after 40 years of age.
Risk of ALS increases with age until the eighth
decade.
The average age of onset is between 51 and 66
years.
Patients with fALS tend to have an earlier age of
onset compared with patients with sALS

9. EPIDEMIOLOGY
The risk factors for ALS are
1. High levels of physical fitness/athleticism and
slimness
2. Age
3. Family history
4. Ethnicity; a higher incidence is associated with White
ethnicity.
5. Cigarette smoking, exposure to certain organic
solvents and pesticides
6. US military persons; other occupations with risks
associated with ALS include veterinarian, hairdresser,
and power-production plant operator.

10. ETIOLOGY
A precise, single etiology of sALS is yet unproven.
Studies suggest that sALS may likely involve
complex interactions between a combination of
1. multiple genetic
2. environmental factors.
In sporadic cases, the disease risk attributable to
genetics approaches 60% and 40% related to
environmental factors

11. Common causes of adult-onset AD
ALS
1. C9ORF72::Hexanucleotide repeat as an
intronic expansion in chromosome 9 open
reading frame 72 9p
2. SOD1::Missense mutations in Cu/Zn
superoxide dismutase 1 21q
3. TDP43::Missense mutations in TAR DNA
binding protein-43 1p
4. FUS::Missense mutations in fused in sarcoma
16q

12. ETIOLOGY
Superoxide dismutase type 1 mutations leading to
free radical toxicity, cascading inflammatory
responses, and excessive concentrations of
glutamate, among others.
C9ORF72 gene is a hexanucleotide repeat
expansion (GGGGCC). Typically, 5–10 copies of
this hexanucleotide repeat expansion are present
in the gene, but ALS patients with the expansion
may have hundreds to thousands of repeats. This
hexanucleotide repeat expansion occurs in
approximately 34% of fALS and 5% of sALS

13. ETIOLOGY
TDP-43 is a DNA/RNA binding protein
composed of 414 AAs, encoded by the TARDBP
gene; TDP-43 homeostasis is critical for normal
cellular function. Excess TDP-43 in the cytoplasm
may result in the formation of inclusion bodies
leading to cellular dysfunction whilst nuclear
depletion may induce widespread
FUS encodes a ubiquitously expressed 526 AA
protein belonging to the FET family of RNA
binding proteins

14. PATHOPHYSIOLOGY
The pathology of ALS is characterized by the
degeneration and gliosis of axons within the
anterior and lateral columns of the spinal cord.
Motor neurons within the spinal cord anterior
horns and Betz cells within the motor cortex are
also lost.
a. Bunina bodies
b. Intracellular TDP-43 inclusions

15. Bunina bodies
Classic pathologic features of
ALS include Bunina bodies,
small eosinophilic cytoplasmic
inclusions found in the
cytoplasm of surviving motor
neurons in nearly all types of
ALS; however, their significance
has not yet been explained.

16. TDP-43 intracytoplasmic inclusions
Ubiquitinated cytoplasmic inclusions
that contain transactive response
DNA-binding protein 43 (TDP-43)
are present in nearly all patients with
ALS.
TDP-43 intracytoplasmic inclusions
represent the pathologic link
between the phenotypes of ALS and
FTD.

17. DIAGNOSTIC EVALUATION
A. CLINICAL PRESENTATION
B. PHENOTYPES OF ALS
C. INVESTIGATIONS
D. DIFFERENTIAL DIAGNOSIS
E. DIAGNOSTIC CRITERIA

18. CLINICAL FEATURES
A. Motor features
B. Pseudobulber features
C. Cognitive features

19. Motor Features
70% of patients with ALS present with weakness of
the limbs, which is typically asymmetric and distal
at onset.
25%of patients present with bulbar symptoms,
which manifest as difficulty speaking, chewing, or
swallowing.
A small minority of patients have respiratory onset,
and less than 1% present with diffuse fasciculations
and a wasting syndrome.
Extraocular movements are spared until late-stage
disease.

20. Motor Features
The progressive nature of symptoms is a critical
component to diagnosis.
Symptoms begin insidiously in an affected region
and progress in that region as spread to other
regions also occurs.
Some patients with ALS will describe “sudden”
onset or stepwise symptoms, but careful review of
their history will typically reveal progressive
symptoms before the loss of a particular functional
ability

21. Motor Features
UMN weakness is caused by loss of downgoing
inhibition in the corticobulbar and corticospinal
tracts and leads to
1) increased tone
2) spasticity,
3) slowness of movement,
4) increased tendon reflexes,
5) presence of pathologic reflexes.

22. Motor Features
LMN weakness is caused by damage to the
anterior horn cell or its axon and results in:
1) pure motor weakness,
2) reduced reflexes,
3) muscle atrophy,
4) fasciculations,
5) cramps.

23. Motor Features
In the bulbar segment, these symptoms and signs
can manifest as dysarthria and dysphagia, along
with facial weakness.
I. UMN, spastic dysarthria is characterized by
slow and strained speech, often with spastic
dysphonia.
II. LMN, flaccid dysarthria is characterized by
weakness of lingual, facial, and palatal muscles
causing imprecise, breathy, and hypernasal
speech.

24. Motor Features
Laryngospasm and involuntary cheek or tongue
biting.
Facial weakness and dysphagia often lead to
sialorrhea.
Brisk and pathologic reflexes include the jaw
jerk, palmomental signs, and facial reflexes

25. Motor Features
Cramps may frequently occur in
1) the limbs,
2) thoracic region,
3) neck
Cramps are often brought about by activity that
causes contraction and shortening of the involved
muscle.

26. Motor Features
Respiratory insufficiency is typically thought to be
caused preferentially by LMN dysfunction of the
diaphragm and accessory muscles of respiration
resulting in:
1. shortness of breath,
2. orthopnea,
3. sleep-disordered breathing,
4. paradoxical breathing.

27. Pseudobulbar Affect
Pseudobulbar affect is a disorder of emotional
expression that is caused by disruption of
corticopontocerebellar pathways.
Patients describe laughing or crying that is not
under voluntary control and is out of proportion
to their internal emotional state.
excessive yawning in some cases.

28. Cognitive Features
Up to 50% of patients with ALS have
neuropsychological abnormalities, most
commonly manifesting as
Executive dysfunction.
A smaller population of patients with ALS (5%
to 15%) have frank frontotemporal dementia
(ALS-FTD).

29. Cognitive Features
Most patients with ALS-FTD present with the
behavioral variant of FTD, demonstrating ::
1) Disinhibition,
2) Lack of empathy,
3) Poor initiation,
4) Impaired executive functioning
5) Disorders of language production manifesting
as the nonfluent/agrammatic variant of primary
progressive aphasia

30. Cognitive Features
Common tools for evaluation of cognitive
functions include:
I. the Edinburgh Cognitive and Behavioral ALS
Screen (ECAS)
II. the ALS Cognitive Behavioral Screen (ALS-
CBS)

31. PHENOTYPES OF ALS
A. Limb onset
B. Bulbar onset
C. Progressive muscular atrophy
D. Primary lateral sclerosis
E. ALS- plus syndrome

32. Limb onset ALS (LO)
LO present in 70% of patients. LO ALS is classified as
A. flail arm syndrome or brachial amyotrophic diplegia,
which is characterized by LMN weakness and
wasting. It usually starts proximally and often
symmetrically, then progresses distally to a point
where upper extremity function is severely impaired.
B. flail leg syndrome or pseudopolyneuritic variant,
which is characterized by LMN weakness and
wasting, but of the lower extremities and with distal
onset. Patients have a slower rate of progression to
the involvement of other body segments and
respiratory muscle weakness

33. Bulbar onset ALS
Bulbar onset ALS accounts for 25% of patients and
is characterized by UMN and LMN involvement of
the cranial nerves, usually manifesting as
a) speech difficulties
b) dysphagia
This is followed by limb involvement in later stages

34. lower motor neuron-onset ALS
The disease is initially exclusively involving the
LMN.
Most Patients go on to develop clinical signs and
symptoms of UMN disease.
Those patients who never show clinical evidence
of UMN involvement, corticospinal tract
involvement is detected at autopsy in up to 50%
to 66% of patients with an antemortem diagnosis
of PMA

35. Upper motor neuron-dominant ALS
These patients have slower progression, lacking
weight loss, and LMN symptoms/signs in the first 4
years of the disease.
Most of them will develop LMN manifestations,
however, and at this point is known as upper motor
neuron-dominant ALS. These patients have a better
prognosis than typical ALS but worse than patients
with PLS

36. ALS-plus syndrome
There are any additional symptoms/signs besides
LMN and UMN disease, such as
A. dementia (mostly frontotemporal),
B. extrapyramidal,
C. autonomic dysfunction,
D. ocular motility disturbance,
E. sensory loss,

37. ALS-plus syndrome
15% of patients with ALS demonstrating criteria for
FTD.
30% to 50% diagnosed with ALS will develop
varying degrees of cognitive impairment.
While not overt dementia, patients can experience
changes related to executive function and fluency,
as well as behavioral changes as apathy and
disinhibition.

38. INVESTIGATIONS
a) Electrophysiologic tests
b) Imaging
c) Markers

39. ELECTROPHYSIOLOGY
NCS demonstrate preservation of sensory responses
with normal or reduced motor amplitudes. As
comorbid sensory polyneuropathy may occur.
Sensory involvement that maps to the regions of
weakness should suggest an acquired or inherited
polyneuropathy
distal latencies >30% prolonged, conduction velocity
<70% normal, or conduction block, which, if
present, suggest demyelinating neuropathy as CIDP

40. ELECTROPHYSIOLOGY
Motor responses are often preserved in early or
slowly progressive ALS because of collateral
sprouting of the remaining motor neurons.
Needle EMG should demonstrate signs of active
denervation (fibrillation potentials and positive
sharp waves) along with chronic denervation in
multiple myotomes.

41. IMAGAING
The role of radiology is the exclusion of other
possible etiologies, a few subtle imaging findings
have been associated with the upper motor disease
found in ALS.
Studies have shown patients with ALS to
demonstrate iron accumulation within the
precentral gyrus, which is known as the “motor
band sign.”

42. MRI GRE sequence demonstrating iron deposition in the precentral gyrus (motor
band sign)

44. IMAGAING
Advanced MRI methods detect an early
degeneration of upper motor neurons as well as
other systems involvement such as the sensory
system or basal ganglia, demonstrating that ALS
is a multisystem disorder

45. MARKERS OF ALS
Specific biomarkers have been developed for
certain forms of familial ALS, including CSF
1) superoxide dismutase 1 (SOD1)
2) neurofilaments (NF),
3) TDP-43
4) the tau protein

46. DIFFERENTIAL DIAGNOSIS
In patients with isolated findings of diffuse
weakness, a broad differential should be considered,
including
A. Myopathy,
B. A defect in neuromuscular junction transmission,
C. Polyradiculopathy,
D. Motor predominant polyneuropathy.

47. DIFFERENTIAL DIAGNOSIS
A myopathy is typically excluded by
1) the presence of fasciculations,
2) the pattern of weakness (distal and
asymmetric),
3) the degree of creatine kinase elevation
(typically <1000 U/L in ALS),
4) the lack of myopathic findings on needle EMG.

48. DIFFERENTIAL DIAGNOSIS
Myopathic processes as fascioscapulohumeral
muscular dystrophy and inclusion body myositis,
may be asymmetric, but in these instances the
overall pattern of weakness typically suggests the
underlying diagnosis.
Some myopathies have modest creatine kinase
elevations or have a “neurogenic appearance” on
needle EMG (both are common with inclusion body
myositis). Rarely, it may be necessary to resort to
muscle biopsy to confirm a neurogenic process.

51. Diagnostic criteria

52. diagnostic criteria
The revised El Escorial and Awaji criteria are
common diagnostic criteria used for the clinical
diagnosis of ALS.
It is important to note that these are classification
criteria and not a measure of disease severity.

53. Revised El Escorial and Awaji
diagnostic criteria

54. Staging of ALS
Staging systems that aim to inform disease progression
and prognosis have also been proposed and are starting to
gain ground and acceptance. The King’s staging system
classifies ALS into
1) stage 1, symptom onset (involvement of first region);
2) stage 2A, diagnosis;
3) stage 2B,involvement of second region;
4) stage 3, involvement of third region;
5) stage 4A, need for gastrostomy;
6) stage 4B, need for noninvasive ventilation.

55. Thank you