Neurodegenerative diseases

Mechanisms of
neurodegeneration

DEGENERATION
=clinical and pathological term
Process of neuronal, myelin or tissue breakdown,
the degradative produts of which evoke a reaction
of phagocytosis and cellular astrogliosis
Pierderea progresiva a functiei si structurii
sistemelor neuronale din SNC si/ sau SNP

( alterare functionala , urmata de moartea neuronala ) care

anterior au atins un nivel normal de dezvoltare

(!)

Many of degenerative diseases are now known to have a

genetic
metabolic
toxic
nutritional basis
slow virus or nonviral
transmissible agent

Cele mai multe b. neurodegenerative: heterogene etiologic

( determinismul genetic nesuperpozabil expresiei fenotipice clinice )

Nu exista o clasificare ideala: manifestari clinice superpozabile

- spectru larg si continuu de manifestari clinice >> entitati bine delimitate

Characteristics of
neurodegenerative disease
They affect specific parts of functional system of
the nervous system
Insidious in onset
Progressive course
Selective death/dysfunction of neurons
Etiology unclear
Be classified according to their genetic and
molecular abnormalities

Examples of neurodegenerative
disease:

Alzheimers disease
Parkinsons disease
Frontotemporal dementia
Amyotrophic lateral sclerosis (Lou Gehrigs
disease)
Spinocerebellar ataxia
Huntingtons disease

Neurodegenerative disease is
common

Neurodegenerative disease
prevalence:
Alzheimers disease:
1-2% age 65-75; 50% over age 85

Parkinsons disease
13/100,00; 0.5-1% age 60-69; 1-3% over age 80

Frontotemporal dementia
1 per 10,000?

ALS
1-2 per 100,000 per year

Spinocerebellar ataxias
0.3-3 per 100,000

Huntingtons disease
1 in 10,000

Mecanisme generale ale neurodegenerarii

1.

GENETICE
- mutatii localizate pe o gena, fara o relatie evidenta patogenica cu
fenotipul clinic

mutatii genice insuficiente pentru a genera boala + factori de risc

( de obicei formele sporadice de boli neurodegenerative )

2.

ex. repetitii de triplete nucleotidice: CAG ( poliQ 9 boli diferite ), GAA, s.a.
mutatii ale unor proteine necesare functiei mitocondriale
mutatii ale unui singur codon ( alt aa. in structura polipeptidica )
mutatii ale unor proteine necesare functiei ARN ( ex. TDP-43, FUS )
mutatii ale unor enzime necesare in procesarea proteinelor normale
unele forme familiale de b. Alzheimer ( -secretaza, -secretaza )
enzime din sistemul proteazomilor
mutatii in introni dereglarea expresiei cantitative sau lungimii polipeptidice a unor
proteine ( ex. frataxine, SMA, s.a. )

mecanisme intracelulare intricate

MECANISME INTRACELULARE
- de regula consecinta anomaliilor induse de modificarile genetice

Mecanisme generale ale neurodegenerarii

2.

MECANISME INTRACELULARE

Modificari ale cailor de degradare a proteinelor

sistemul proteazomilor ( UPS = "ubiquitin proteasome system" )

agregare de proteine care perturba functiile celulare

Moartea celulara programata

APOPTOZA

NECROZA

indusa intrinsec sau extrinsec

AUTOFAGIA

situatie particulara: MITOFAGIA ( AUTOFAGIA MITOCONDRIALA )

MECANISMELE INTRACELULARE DE
TRAFIC AL PROTEINELOR

Macario AJL et al NEJM 2005; 353 (14):1489-1501

Misfolded proteins are normally detected and

cleared from cell (or stored in aggresomes)

Regulation of protein folding in the ER. Many newly synthesized proteins are translocated into the ER,
where they fold into their three-dimensional structures with the help of a series of molecular
chaperones and folding catalysts (not shown). Correctly folded proteins are then transported to the
Golgi complex and then delivered to the extracellular environment. However, incorrectly folded
proteins are detected by a quality-control mechanism and sent along another pathway (the unfolded
protein response) in which they are ubiquitinated and then degraded in the cytoplasm by
proteasomes.

CM Dobson, Protein folding and misfolding, Nature, 426, 884-890 (2003)

Mecanisme generale ale neurodegenerarii

2.

MECANISME INTRACELULARE

Modificari ale cailor de degradare a proteinelor

sistemul proteazomilor

agregare de proteine care perturba functiile celulare

Moartea celulara programata

APOPTOZA

NECROZA

indusa intrinsec sau extrinsec

( Apoptoza induce un fenomen de imunosupresie locala;
Necroza induce fenomen inflamator local )

AUTOFAGIA

situatie particulara: MITOFAGIA ( AUTOFAGIA MITOCONDRIALA )

Pathogenesis of neurodegenerative
diseases
Protein aggregation = major focus of
current research
= major histhopathologic
hallmark

? Protein aggregates contribute to neuronal

death or they are merely secondary
bystanders

Aggregation of Proteins in Neurodegenerative Diseases

Taylor JP, Hardy J, Fischbeck KH. (2002) Science

Aggregation of misfolded proteins in microscopically visible inclusions or plaques in various

neurodegenerative diseases. (A) Alzheimer's disease. Arrowhead, intracellular
neurofibrillary tangles; arrow, extracellular amyloid plaque. (B) Fibrillar tau inclusions in
Pick's disease. (C) PrPSc amyloid deposition in prion disease. (D) Multiple Lewy bodies in a
nigral neuron in Parkinson's disease. (E) Neuronal intranuclear inclusions of mutant ataxin-3
in Machado-Joseph's disease. (F) Higher power micrograph of nuclear inclusion of mutant
ataxin-3, demonstrating that it is distinct from the nucleolus. Magnification, 40.
Toxic Proteins in Neurodegenerative Disease, JP Taylor et al., Science, 296, 1991-1995, 2002

M Stefani and CM Dobson, Protein aggregation and aggregate toxicity: new insights into
protein folding, misfolding diseases and biological evolution, J. Mol. Med 81:678-699 (2003)

 Protein aggregates are usualy ubiquinated,

which targets them for degradation by the
26s component of the proteosome..
An inability to degrade protein aggregates
could lead to cellular dysfunction, impaired
axonal transport and cell death by apoptotic
mechanisms

MY Sherman and AL Goldberg, Cellular Defenses against Unfolded Proteins: A Cell Biologist
Thinks about Neurodegenerative Diseases, Neuron, Vol. 29, 1532, January, 2001,

M Stefani and CM Dobson, Protein aggregation and aggregate toxicity: new insights into
protein folding, misfolding diseases and biological evolution, J. Mol. Med 81:678-699 (2003)

APOPTOSIS
=programmed cell death
Plays an important role in both physiologic
and pathologic conditions
Characterized by- neuronal shrinkage
chromatin condensation
DNA fragmentation
Mitochondria are essential in controlling
specific apoptosis pathways.

 necrosis

cytoplasmic and mitochondrial swelling

followed by dissolution of the cell
membrane
Apoptotic and necroting cell death can coexist
or be sequential events, depending on the
severity of the initiating insult

MECANISMELE MORTII CELULARE

Hotchkiss RS et al NEJM 2009; 361(16):1570-1583

MAIN CLINICAL CATEGORIES

A. Syndrome of progressive dementia,other neurologic signs being absent

or inconspicuous Alzheimer disease
B. Syndrome of progressive dementia in combination with other neurologic
abnormalities Huntington disease
Lewy-body disease
C. Syndrome of disordered posture and movement Parkinson disease
D. Syndrome of progressive ataxia Spinocerebellar ataxia
E. Syndrome of slowly developing muscular weakness and atrophy ALS
F. Sensory and sensorimotor disorders Charcot Marie- Tooth
G. Syndrome of progressive blindness or ophtalmoplegia
H. Syndromes characterized by degenerative neurosensory deafness

Boli cu sd. demential progresiv,

.1
fara alte semne neurologice evidente
A. Cu atrofie cerebrala difuza
Boala Alzheimer

Atrofii cerebrale difuze non-Alzheimer

Boala difuza cu corpi Lewy

B. Atrofie cerebrala circumscrisa

Degenerescente fronto-temporale ( DFT )
Afaziile primare progresive
DFT comportamentala ( "b. Pick" )

2. Boli cu sd. demential progresiv asociat

anomalii neurologice

cu alte

Boala Huntington
Boala difuza cu corpi Lewy
Boala Parkinson in stadiii tardive ( unele cazuri )
Degenerescenta cortico-bazala
Degenerescenta cortico-strio-spinala
Complexul Guam ( Parkinson-SLA-dementa )
Degenerescenta cerebelo-cerebeloasa
Dementa familiala cu parapareza spastica, amiotrofie, sau mioclonus
Boala cu corpi de poliglucosan
Dementele fronto - temporale cu parkinsonism sau SLA
forme de degenerescenta cortico-bazala
forme de paralizie supranucleara progresiva

3. Boli cu tulburari de postura si de miscare

Boala Parkinson

Atrofia multi-sistem

Paralizia supranucleara progresiva ( PSP )

Boala Huntington

Achantocitoza cu miscari involuntare ( coree, distonie )

Degenerescenta cortico-bazala

Boala difuza cu corpi Lewy

Tremorul esential

Boala Gilles de la Tourette

4. Boli cu ataxie progresiva

Ataxiile spino-cerebeloase ( cu debut precoce )

B. Friedreich
Ataxia cu debut precoce non-Friedreich

Ataxiile cerebeloase corticale

Atrofia olivo-cerebeloasa pura familiala ( Holmes )
Ataxiile cerebeloase cu debut tardiv

Boli ereditare complexe cu ataxie cerebeloasa sporadica ( ataxie cu debut

tardiv cu anomalii de trunchi cerebral si alte anomalii neurologice)

5. Boli cu deficit motor

si atrofii musculare progresive

Tulburari motorii cu amiotrofie

Scleroza laterala amiotrofica ( Boala neuronului motor, Boala Charcot,
Boala Lou-Gehring )
Boala neuronului motor si DFT
Atrofiile musculare spinale progresive
Paralizia bulbara progresiva
Sd. Kennedy & alte forme ereditare de atrofie musculara progresiva si
paraplegie spastica

Paraplegie spastica fara amiotrofie

Scleroza laterala primara
Paraplegia spastica familiala ( Strmpell-Lorrain )

6. Boli cu neuropatii senzitive si senzitivo-motorii

Neuropatiile senzitivo-motorii ereditare ( HSMN )

Neuropatii pur/ predominant senzitive sau motorii
Degenerescenta vegetativa Riley-Day

7. Boli cu cecitate progresiva sau oftalmoplegie, cu sau fara alte anomalii

neurologice

Degenerescenta retiniana pigmentara ( retinitis pigmentosa )

Boala Stargardt
Boli mitocondriale
Oftalmoplegia externa progresiva cu/ fara surditatesau alte atrofii de sisteme
( sd. Kearns-Sayre )
Neuropatia optica ereditara Leber
Encefalopatia necrozanta Leigh

8. Boli cu surditate neurosenzoriala degenerativa progresiva

Surditatea neurosenzitiva pura

Hipoacuzia ereditara asociata cu boli ale retinei
Hipoacuzia ereditara cu atrofii de sisteme ale sistemului nervos

Progressive ataxia syndromes

What lesion localization in the nervous
system can lead to ataxia?

Parietal lobe, thalamus (very rarely)

Cerebellum
Brain stem
Spinal cord
Peripheral nerves

Progressive ataxia syndromes

1.

2.

3.

Spinocerebellar ataxias (early onset)

Friedreich ataxia
Non-Friedreich ataxia
Cortical cerebellar ataxias
Familial Pure olivo-cerebellar atrophy (Holmes)
Cerebellar atrophy with late onset (Marie-Foix-Alajouanine)
Complicated cerebellar ataxias (late onset, brain stem affected as well)
Olivo-ponto-cerebellar degeneration
Pure
With extrapyramidal signs and autonomic failure (MSA)
With spino-cerebellar degeneration
Dentate-rubric degeneration (Ramsay-Hunt)
Others, associating other neurological signs

Friedreich ataxia (FA, FRDA, FRIEDREICH

ATAXIA 1, OMIM# *229300)
is an autosomal recessive ataxia resulting from a
mutation of a gene locus on chromosome 9. It was
first described in 1863 by Nikolaus Friedreich, a
professor of medicine in Heidelberg, Germany.
FA was the earliest of the inherited ataxias to be
distinguished from other locomotor ataxias and is
the most common of the autosomal recessive
ataxias.
It accounts for at least 50% of cases of hereditary
ataxias in most large series.

Cardinal features
include progressive -limb and gait ataxia,

dysarthria,

loss of joint position

and vibration senses,

absent tendon reflexes in

the legs,

and extensor plantar

responses.

Friedreich ataxia
Early onset, it typically presents in children aged 8-15 years and
almost always presents before age 20 years.

of cases of hereditary ataxia (aut rec transm )

progressive ataxia of limbs/gait
Spino-cerebellar, predominantly spinal
Mutation of a gene on chromosome 9
Trinucleotid expansion GAA
Deficit of frataxin (mitochondrial enzyme)
ROS agression, Fe deposits in mitoc.

Incidence rate: 1,5/100.000/year

PATHOPHISIOLOGY

Classic Friedreich ataxia is the result of a gene mutation at the

centromeric region of chromosome 9 (9q13-21.1) at the site of the
gene encoding for the 210-amino-acid protein frataxin.

This mutation is characterized by an excessive number of repeats of the GAA

(guanine adenine adenine) trinucleotide DNA sequence in the first intron of
the gene coding for frataxin. It is the only disease known to be the result of a
GAA trinucleotide repeat.
This expansion alters the expression of the gene, decreasing the synthesis of
frataxin protein.
The expanded GAA repeat is thought to result in frataxin deficiency by
interfering with transcription of the gene by adopting an unstable helical
structure. The larger the number of repeats, the more profound is the reduction
in frataxin expression.

Larger GAA expansions correlated with earlier age of onset and

shorter times to loss of ambulation.

Cells and tissues of the body are differentially sensitive to frataxin

deficiency. Cells normally requiring and producing greater amounts of
frataxin tend to be most affected by FA.

For example, sensory neurons in the dorsal

root ganglion responsible for position sense
highly express the frataxin gene and are
affected greatly in FA.
Myocardial muscle fiber also requires
comparably larger amounts of frataxin than
other tissues and is affected markedly in FA.

A number of experiments have confirmed the mitochondrial

subcellular localization of frataxin in mammals.
Frataxin has been shown to be essential for normal
mitochondrial function, both for oxidative phosphorylation
and iron homeostasis.
frataxin deficiency results in iron accumulation within
mitochondria of affected cells in cell culture lines.
Apparently, the rate of mitochondrial export is reduced.
Hearts of patients with FA have revealed mitochondrial
ironlike deposits that are not present in healthy hearts.
Frataxin-deficient cells not only generate more free radicals,
but also show a reduced capacity to mobilize antioxidant
defenses. Iron excess inactivates mitochondrial enzymes
essential for the production of adenosine triphosphate
(ATP).

Cell death, particularly of neurons of the spinal

cord and peripheral nervous system, ensues

The major pathophysiologic finding in Friedreich ataxia is a "dying back

phenomena" of axons, beginning in the periphery with ultimate loss of
neurons and a secondary gliosis.

The primary sites of these changes are the spinal cord and
spinal roots.

This results in loss of large myelinated axons in

peripheral nerves, which increases with age and disease
duration. Unmyelinated fibers in sensory roots and peripheral
sensory nerves are spared.
The posterior columns and corticospinal, ventral, and lateral
spinocerebellar tracts all show demyelination and depletion of
large myelinated nerve fibers to differing extents. This is
accompanied by a fibrous gliosis that does not replace the bulk
of the lost fibers.
Overall, the spinal cord becomes thin and the anteroposterior
(AP) and transverse diameters of the thoracic cord are reduced.

The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons
associated with proliferation of capsular cells.

The posterior column degeneration accounts for the loss of

position and vibration senses and the sensory ataxia.

The loss of large neurons in the sensory ganglia causes
extinction of tendon reflexes.
The dentate nuclei exhibit mild to moderate neuronal loss and the
middle and superior cerebellar peduncles are reduced in size. The
cerebellar ataxia is explained by loss of the lateral and ventral
spinocerebellar tracts and involvement of the Clarke column, dentate
nucleus, superior vermis, and dentatorubral pathways.
The corticospinal tracts are relatively spared down to the level of the
cervicomedullary junction. Beyond this point, the corticospinal tracts
are severely degenerated, which becomes progressively more severe
moving down the spinal cord. This explains the common finding of
bilateral extensor plantar responses and weakness late in the disease.

 Myocardial muscle fibers also show degeneration and are

replaced by macrophages and fibroblasts. Essentially,
chronic interstitial myocarditis occurs with hypertrophy of
cardiac muscle fibers; fibers become hypertrophied and
lose their striations. This is followed by swelling and
vacuolation and finally interstitial fibrosis. The nuclei
appear hyperchromatic and occasionally vacuolated. The
cytoplasm appears granular with frequent lipofuscin
depositions.
Kyphoscoliosis is likely; it is secondary to spinal muscular
imbalance.

Friedreich Ataxia - neuropathology

Spinal cord - thin
Posterior columns and spinocerebellar tracts few
fibers/gliosis
Reduced neuronal number in sensory ganglions
Degeneration of dentate nuclei + and reduced
Purkinje cells number
Degeneration of myocardiocites
Minor degeneration of cortico-spinal tract

Friedreich ataxia clinical signs

I
First simptom: gait ataxia mixed sensory and
cerebellar type (tabetocerebellar)
Sometimes assimetrical onset, sometimes after a
febrile illness
Superior limb later, after months/years
Later - dysarthria
Tendon reflexes always affected = abolished
(sensorial areflexia), ! Babinski sign
Profound anesthesia (vibratory, mioartrokinetic) in
late phases also superficial (touch, pain,
temperature)

Friedreich ataxia clinical signs

II
Romberg +
Intentional tremor

pts pes cavus, hammer toes, kifoscoliosis

Cognition-intact/ emotional instability
Rarely deafness/vertigo/blindness
More than pts cardiomiopathy(arrhythmias, heart
failure death)
pts optic nerve atrophy
D.M. 10% pts

PES CAVUS

DEGETE "IN
CIOCAN"

Ataxia Friedreich ancillary investigations

EMG - Sensory conduction velocities and amplitudes - normal
ECG left ventricle hypertrophy, cardiomiopathy, arrhythmias
Rx spine (kifoscoliosis)
CT/MRI MRI of the brain and spinal cord in patients with FA
consistently shows atrophy of the cervical spinal cord with
minimal evidence of cerebellar atrophy .
CSF normal
Genetic counseling is available for prenatal diagnosis of
Friedreich ataxia for parents with one affected child.

Friedreich Ataxia differential dg

Familial cerebellar cortical atrophy

Familial spastic paraparesis with ataxia
Peronier amyotrophy (Charcot-Marie-Tooth)
Avitaminosis E in children (no dysarthria, no
cardiomiopathy) treatable!
CIDP
Multiple sclerosis
Cervical spondylosis

Friedreich Ataxia - treatment

There is little effective therapy
5-hidroxi-triptofan (serotoninergic)
alleviates cerebellar signs
Idebenone alleviates heart hypertrophy
Antioxidants basic research studies (vit E)
Treatment of arrhythmias, DM, skeletal
deformities

The prognosis of FA is poor.

Cardiac dysfunction is the most frequent cause of death in almost two

thirds of the patients, most commonly from congestive heart failure or
arrhythmia. More research is needed to establish the clinical
significance of hypertrophy in FA.[16]
No distinct interrelations between FA cardiomyopathy and
neurological status could be determined; therefore, regular follow-up
of potential cardiac involvement in FA patients is essential in clinical
practice.[17]
The disorder is progressive, with a mean duration of 15-20 years.
More than 95% of patients are wheelchair bound by age 45 years.
Commonly, patients survive to 25-30 years of age, although some
patients have survived into the sixth and seventh decades, especially if
they are free of heart disease and diabetes.

MOTOR SYSTEM DISEASE

=group of progressive degenerative disorders of
motor neurons in the spinal cord, brainstem and
motor cortex
Clinical muscular weakness
atrophy
corticospinal tract signs
Disease of middle life
Progress to death in a matter of 2-5 years

BOALA NEURONULUI MOTOR

(SCLEROZA LATERALA AMIOTROFICA SLA;
Boala Charcot; Boala Lou Gehring)
Grup de boli neurodegenerative
leziuni ale neuronilor motori centrali ( cortexul motor )
+
leziuni ale neuronilor motori periferici ( spinali, bulbo-pontini )

Subtypes
* ALS= amyotrophic lateral sclerosis
amyotrophy + weakness + hyperreflexia
* Progressive spinal muscular atrophy
weakness + atrophy
without corticospinal tract dysfunction
* Progressive bulbar palsy
* Primary lateral sclerosis
spastic weakness + hyperreflexia + Babinski
later lower motor neuron aspects

 ALS = the most common neurodegenerative disease of the

motor neuron system.
In its classic form, it affects motor neurons at 2 or more
levels supplying multiple regions of the body.

affects - lower motor neurons that reside in the

anterior horn of the spinal cord and in the brain stem leads
to progressive muscle weakness and wasting (atrophy).

-corticospinal upper motor neurons that

reside in the precentral gyrus stiffness (spasticity),
abnormally active reflexes, and pathological reflexes

- prefrontal motor neurons that are

involved in planning or orchestrating the work of the upper
and lower motor neurons special forms of cognitive
impairment

(oculomotricity)
(spinal cord, anterior horn, micturition, defecatory continence)

Bunina bodies

www.niigata-nh.go.jp/nanbyo/als/alspath.htm

ALS: Epidemiology
ALS is the most common form of motor
neuron disease.
Sporadic forms (unknown cause) account
for about 90-95 percent of ALS cases.
Familial forms (AD inherited disease) make
up approximately 5-10 percent.
Slight male predominance for sporadic
ALS.

SLA

PATOGENIE
cca. 10%- forme familiale
~ 20% mutatii gena SOD1-chr.21q
("misfolding" SOD1 )
cel putin alte 14 defecte genetice cunoscute ( autosomal dominante sau
recesive ) mutatii f. numeroase in fiecare gena
gena pt. TDP43 ( chr. 9q ) in formele asociate cu FTD
gena pt. FUS ( chr. 16 )

90% - forme sporadice

cel putin 10 locusuri genice semnificativ asociate cu SLA
cel putin alte 41 locusuri genice posibil asociate cu SLA
Zinman L, Cudkowicz M - Lancet Neurology 2011; 10 (5): 481 490
Ticozzi N et al - Archives Italiennes de Biologie, 149: 65-82, 2011
Dunckley T et al NEJM 2007; 357 (8):775-788
Kwiatkowski Jr TJ et al Science 2009; 1205 1208

ALS: Epidemiology
The incidence of ALS increases with each decade,
especially after age 40 years.
Peak age of onset is 50-70s.
The only established risk factors for ALS are age and
family history.
? Smoking
Increased risk for developing ALS has been suggested for
laborers engaged in agricultural work, factory work, heavy
manual labor, exposure to welding or soldering, and work
in the plastics industry.

Mutant SOD1 exerts its effect through gain

of function (ie, toxicity that is not related
to loss of its natural activity). Oxidative
damage, mitochondrial dysfunction,
caspase-mediated cell death (apoptosis),
defects in axonal transport, growth factor
expression, glial cell pathology, and
glutamate excitotoxicity may all mediate
the pathways, causing cell death in AL

(oculomotricity)
(spinal cord, anterior horn, micturition, defecatory continence)

ALS: Clinical Features

The clinical hallmark of ALS is the
combination of upper motor neuron and
lower motor neuron signs.
UMN signs include hyperreflexia,
spasticity, extensor plantar response (up
going toes), and positive jaw jerk.
LMN signs include weakness, muscle
atrophy, cramps and fasciculations.

ALS: Clinical Features

The loss of motor neurons results in the primary
clinical symptoms and signs ALS. These may
produce impairment affecting limb, bulbar, axial
and respiratory function.
Differences in site of onset, pattern and speed of
spread, and the degree of upper motor neuron
(UMN) and/or lower motor neuron (LMN)
dysfunction produce a disorder that is remarkably
variable between individuals.

ALS: Initial Clinical Features

Asymmetric limb weakness is the most common presentation of
ALS (80 percent).
In the most typical forms of disease weakness in a distal
part of one limb
Bulbar symptoms, usually manifested as dysarthria or dysphagia,
is the next most common presentation (20 percent).
Less common patterns of ALS onset include:
respiratory muscle weakness (1 to 3 percent)
generalized weakness in the limbs and bulbar muscles (1 to 9
percent)
axial muscle weakness
hemiplegic variant
weight loss with muscle atrophy.

ALS: Clinical Features of Limb

Weakness
Lower extremity onset of ALS most often
begins with foot drop.
Patients with proximal leg weakness often
complain of difficulty climbing stairs and
difficulty arising from chairs.
Either proximal or distal leg weakness can
cause falls.

ALS: Clinical Features of Limb

Weakness
Upper extremity onset is most often
heralded by hand weakness but may begin
in the shoulder girdle muscles.
Patients with hand weakness may complain
that they drop things and have difficulty
with tasks such as pinching, writing, typing,
managing buttons or zippers, and picking up
small objects.

ALS: Clinical Features of Limb

Weakness
Patients with shoulder girdle weakness may
report difficulty using their arms in
activities such as washing, drying, or
combing their hair as well as lifting things
above their head.

Typical form
The triad : atrophic weakness of the hands, arms
or legs and generalized hyperreflexia. Coarse
fasciculation are evident in weakened muscles.
in the absence of sensory change
sphincteric control is maintained
The muscle of the upper limb and shoulder girdles
are typically involved later
Later the atrophic weakness spreads to the neck,
tongue, pharyngeal and laryngeal muscles.

ALS: Clinical Features of Bulbar

Weakness
Patients with dysarthria complain of slurring of
speech that is often worse at the end of the day or
with more vigorous use of their voice.
Patients with dysphagia initially complain of
difficulty swallowing thin liquids, and may report
the need to swallow multiple times in order to
manage a single liquid bolus.

ALS: Clinical Features of Bulbar

Weakness
With progression, patients may choke or
cough when drinking thin liquids and
eventually develop difficulty managing
thicker liquids, their own secretions, and
solids.

ALS: Clinical Features of

Respiratory Muscle Weakness
Initially complain of fatigue/shortness of
breath triggered by decreasing levels of
activity or by lying flat.
Often develop disturbed nocturnal sleep
with frequent awakenings and excessive
daytime sleepiness.

ALS: Clinical Features of Axial

Muscle Weakness
Patients with axial neck weakness complain of
posterior neck pain or strain with a gradually
worsening tendency for head drop.
Patients with axial truncal weakness complain of
difficulty maintaining an erect posture when
standing and of stooping when walking. Some will
support their trunk by placing their hands in their
front pants pockets or on their upper thighs.

FORME CLINICE PARTICULARE

ATROFIA MUSCULARA PROGRESIVA
forma limitata: doar afectarea NM periferic
barbati: x4 mai frecvent decat femei
progresie mai lenta, supravietuire mai lunga ( > 15 ani )
cu neuropatii motorii cronice autoimune +/- bloc de conducere
PARALIZIA BULBARA PROGRESIVA
dizartrie, disfonie vorbire neinteligibila
disfagie, tulburari de masticatie ( nmc + nmp )
atrofii ms. & fasciculatii + spasticitate la nivelul fetei, limbii, mm. masticatori,
faringelui, laringelui
semne de spasticitate in teritoriul bulbar ( r. maseterin +++ )
SCLEROZA LATERALA PRIMARA ( PRIMITIVA )
debut in a 5-a 6-a decada de varsta
debut de obicei cu parapareza spastica progresiva, asimetrica
t afectarea mb. superioare & mm. orofaciali
semne clinice de sd. nmc ( uneori semne subclinice de nmp in < 1 an )

ALS: Other Clinical Features

* ALS + Fronto-temporal dementia
Frontotemporal executive dysfunction may precede or
follow the onset of UMN and LMN dysfunction.
Symptoms include changes in personality, impairment
of judgment, and development of obsessional behaviors.

* ALS + Parkinson syndrome

DIAGNOSTIC
Tabloul clinic

SINDROM SLA
DIAGNOSTIC DIFERENTIAL
compresie cronica de maduva cervicala
* hernie de disc cervicala
* stenoza de canal cervical ( probabil prin ischemie cronica )
* pahimeningita cervicala
* alte cauze ( mai rare )
sd. SLA paraneoplazic ( in limfoame, carcinoame )
sd. SLA post-poliomielitic ( debut tardiv; benign ! )
scleroza multipla ( rar ! )
neuropatia Charcot-Marie-Tooth (istoric familial )
cu amiotrofia spinala progresiva
miopatie inflamatorie
distrofie musculara a centurilor
pt. SLA cu debut proximal
miastenia gravis
atrofia bulbo-spinala ereditara
pt. paralizia bulbara progresiva
sd. pseudobulbar
polineuropatia motorie cronica cu bloc de conducere
intoxicatia cronica cu plumb
miozita cu incluzii ( debut distal asimetric )

Ancillary investigations
Blood analysis (ESR, autoab, tyroidian hormons, protein
electrophoresis, B12 vit and folic acid, VDRL, etc)
EMG, conduction velocities- denervation and reinervertion
(reduction in number of motor action potentials, with
increase in amplitude and duration, fibrilations,
fascicullations), normal conduction velocities both sensory
and motor)
Brain and spine MRI slight atrophy of the motor cortices
and wallerian degeneration of the motor tracts (hypersignal
on T2 and FLAIR sequences)
Motor evoked potentials - prolonged
Genetic tests for SOD mutations

EMG
1. widespread fibrillations and fasciculations
(active denervation)
2. Enlarged motor units (reinnervation)
3. Motor nerve conduction slight slowing
Denervation in at least three limbs

ALS: Diagnosis
The clinical standard for diagnosis is the Revised El
Escorial World Federation of Neurology criteria
which requires:
Evidence of LMN degeneration by clinical,
electrophysiological, or neuropathological examination
Evidence of UMN degeneration by clinical examination
Progressive spread of symptoms or signs within a region
or to other regions (The body is divided into four regions:
cranial, cervical, thoracic and lumbosacral)
Absence of electrophysiological, pathological or
neuroimaging evidence of other disease processes.

ALS: Diagnosis
ALS is primarily a clinical diagnosis
sensory and motor nerve conduction
studies and electromyography (EMG) are a
standard part of the evaluation of motor neuron
disease.
EMG findings in ALS combine features of acute
and chronic denervation.

Criteriile WFN - El ESCORIAL revizuite pentru

diagnosticul sclerozei laterale amiotrofice

Diagnosticul SLA necesita:

A. PREZENTA:
(A:1) dovezilor de degenerescenta a neuronului motor periferic (NMP) prin
examinare clinica, electrofiziologica sau neuropatologica
(A:2) dovezilor de degenerescenta a neuronului motor central (NMC) prin
examinare clinica, si
(A:3) evolutiei progresive a semnelor si simptomelor intr-una sau mai multe
regiuni, determinata prin istoricul bolii sau examinare medicala
impreuna cu

B. ABSENTA:
(B:1) dovezilor electrofiziologice si patologice pentru alte procese patologice
care pot explica semnele de degenerescenta ale NMP si/ sau NMC,
si
(B:2) dovezilor neuroimagistice in favoarea altor procese patologice care pot
explica semnele clinice si electrofiziologice observate.

Criteriile WFN - El ESCORIAL revizuite pentru

diagnosticul sclerozei laterale amiotrofice
SLA clinic definita:
doar dovezi clinice pentru semne de NMC si NMP in cel putin 3 regiuni diferite
SLA clinic probabila:
doar dovezi clinice pentru semne de NMC si NMP in cel putin 2 regiuni diferite,
cu necesitatea ca unele semne de NMC sa fie localizate rostral de semnele de
NMP
SLA clinic probabila sustinuta de probe de laborator:
semne clinice de NMC si NMP doar intr-o singura regiune, sau doar semne de
NMC prezente intr-o singura regiune iar semnele de NMP definite prin
criterii EMG sunt prezente la cel putin 2 membre, plus utilizarea adecvata a
neuroimagisticii si protocoalelor de laborator clinic pentru a exclude alte cauze.
SLA clinic posibila:
semne clinice de NMC si NMP impreuna intr-o singura regiune / sau doar
semne de NMC in 2 sau mai multe regiuni;
sau,
semnele de NMP se gasesc rostral de semnele de NMC si diagnosticul de
" SLA clinic probabila sustinuta de probe de laborator " nu poate fi sustinut pe
baze clinice asociate cu semne electrodiagnostice, neurofiziologice,
neuroimagistice sau studii de laborator clinic. Trebuie excluse alte diagnostice
pentru a accepta dg. de SLA clinic posibila.
SLA suspectata clinic:
sd. de NMP pur, in cadrul caruia dg. de SLA nu poate fi considerat suficient de
sigur, pentru a include pacientul intr-un studiu de cercetare ( dg. exclus din
Criteriile revizuite El Escorial pt. SLA)

ALS: Differential Diagnosis

Other Motor Neuron Diseases

Primary lateral sclerosis (UMN
only)
Progressive muscular atrophy
(LMN only)
Progressive bulbar palsy

Parkinsons, Progressive
Supranuclear Palsy, MS

Neuropathies
Myopathies
PM, inclusion body myositis

NM Junction
Myasthenia gravis

Malignancy
Primary/mets CNS
Motor neuron syndromes with
MM, Lymphoma, lung, breast

GB, CIDP

Neurodegenerative Diseases

Toxic Exposure
EtOH, heavy metals

Endocrine
TSH, adrenal, pituitary

Infectious
HIV, CMV

ALS: Progression and Prognosis

ALS is a relentlessly progressive disorder with a
clinical course that is nearly always linear, with a
relatively constant slope. (ie no remissions or
exacerbations)
Rate of progression varies between individuals.
Symptoms initially spread within the segment of
onset and then to other regions in a relatively
predictable pattern.

ALS: Progression and Prognosis

Patients with unilateral limb onset the
pattern of spread is to the contralateral limb,
then to the ipsilateral U/LE, then to the
contralateral remaining U/LE, and then to
the bulbar muscles.
In patients with bulbar onset the most
common pattern of spread is to one arm and
then to the contralateral arm.

ALS: Progression and Prognosis

The life-threatening aspects of ALS are
neuromuscular respiratory failure and
dysphagia.
The median survival from the time of
diagnosis is three to five years.
10% of ALS patients can live 10 years or
more.

Complications

Progressive inability to perform activities of daily living (ADLs),

including handling utensils for self-feeding
Deterioration of ambulation
Aspiration pneumonia
Respiratory insufficiency
Complications from being wheelchair-bound or bedridden, including
decubitus ulcers and skin infections (While rare in patients with ALS,
these complications can emerge if appropriate padding is not used.)
Deep vein thromboses and pulmonary emboli (These complications
are rare in patients with ALS, but have been encountered with greater
frequency in the active treatment arm of some clinical trials.)

ALS: Supportive Treatment

Progressive neuromuscular respiratory failure is
the most common cause of death in ALS.
! Periodic monitoring of respiratory function
Intiation of noninvasive positive pressure
ventilation (in patients with FVC < 50%) can
prolong survival up to 20 months. BiPAP = bilevel
positive airway pressure
5 to 10 percent of patients choose tracheostomy
and permanent ventilation when respiratory
compromise becomes severe.

ALS: Supportive Treatment

Dysphagia poses a risk for aspiration of
food, liquids, or secretions with resultant
pneumonia and may also lead to
malnutrition and dehydration.
Symptoms can be minimized in patients
who choose gastrostomy tube insertion with
aggressive management of secretions.

Symptomatic treatments
Antispasticity agents may be used to treat limb stiffness.
Antisiallorea treatments include anticholinergics, sympathomimetics, botulinum
toxin type B, and salivary gland irradiation.
Mucolytics, such as guaifenesin may be used to make thickened secretions thinner
(patient experience). Adequate hydration and humidification of room air may prove
helpful and are recommended.
Mechanical suction devices may be needed to remove secretions.
When using antidepressants, SSRIs work best (eg, citalopram 10-40 mg/d; patient
experience). If the desired benefit is not achieved with one agent, another may be
tried.
A common anxiolytic used is lorazepam (0.5-1.0 mg as needed; patient
experience). There is potential for respiratory depression with benzodiazepines and
careful titration is needed.
If analgesics are needed, tramadol Hcl (Ultram), ketorolac tromethamine (Toradol),
morphine (IR, ER), or fentanyl patch may be considered. Respiratory depression
with opiates may occur. Careful titration, starting with low doses, is needed.

ALS: Pharmacologic Treatment

Riluzole (Rilutek) is the only currently
available medications for the treatment of
ALS.
Glutamate Inhibitor although precise
mechanism of action in ALS is unclear.
Clinical trials have shown prolonged
survival of approximately 2-3 months.

ALS: Pharmacologic Treatment

Patients most likely to benefit from
treatment include those who have:
Definite or probable ALS by El-Escorial
criteria in whom other causes of progressive
muscle atrophy have been ruled out
Symptoms present for less than five years
Vital capacity (VC) greater than 60 percent of
predicted
No tracheostomy

ALS: Board Review Questions

A 50yoM is evaluated for 4month h/o progressive
R foot drop and slurred speech. PE reveals tongue
weakness associated with tongue fasciculations,
atrophy and +jaw jerk. R leg is atrophic
w/faciculations. He has R ankle clonus and
extensor plantar response. Sensory exam is
normal. Most likely diagnosis is?

ALS
Spinal Muscle Atrophy
Myasthenia Gravis
Cervical spondylosis