Motor neuron disease

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DR.Rudrashis Samal
JUNIOR RESIDENT
P. G. Department of Medicine

DEFINITION

 Motor neuron disease (MND) refers to a heterogeneous
group of conditions characterized by degenerati...

SPECTRUM OF MOTOR NEURON DISEASE

Amyotrophic lateral sclerosis (ALS) is one of multiple
degenerative motor neuron disease...

 Primary Lateral sclerosis

 Hereditary spastic paraplegia

 HTLV-1 associated myelopathy

 Adrenomyeloneuropath...

 Poliomyelitis
 MultifocalMotor Neuropathy
 Benign Focal Amyotrophy
 Hopkins’ syndrome: Acute post-asthmatic
amyotro...

ALS PLUS syndrome

ALS is considered a degenerative disorder of the upper and lower
motor neurons.

However, some patients...

Also known as LOU GEHRIG’S DISEASE

Degeneration of UMN and LMN

1869 - First described in publication by Dr. Jean-Martin Charcot, in Paris

1881 - Lectures translated into English

A-myo-trophic Lateral Sclerosis

Amyotrophic: no muscle
nourishment

...

INCIDENCE AND PREVALENCE
•Incidence rates for ALS in Europe and North America range
between 1.5 and 2.7 per 100,000/year.[...

GEOGRAPHIC CLUSTERS
High prevalence clusters of ALS are found in three regions of
the western Pacific including Guam, West...

RISK FACTORS
•The only established risk factors for ALS are age and family
history.

•Increased risk for developing ...

GENERAL: HEREDITARY VS SPORADIC ALS

Sporadic
Hereditary ALS
...

INDIAN SCENARIO
The classical motor neuron disease seen in India is similar to
that in the west in the clinical picture an...

The second type, the Madras pattern of motor neuron
disease was first described by Meenakshisundaram et al
from South Indi...

PATHOLOGY
•ALS is characterized by motor neuron degeneration and death
with gliosis replacing lost neurons.

•Cortical mot...

•Intracellular inclusions — Intracellular inclusions in
Degenerating neurons and glia are frequent neuropathological
findi...

PATHOGENESIS

GENETICS OF ALS

TOXIC MECHANISMS IN ALS

SOD1-MEDIATED TOXICITY
• Superoxide dismutase type 1 (SOD1) is a metalloenzyme that
catalyzes the conversion of toxic supe...

THE MITOCHONDRION AS A TARGET OF MUTANT SOD1

Mitochondrial
Permeability
Transition
...

Protein misfolding — Another hypothesis is that mutant
SOD1 induces protein aggregates that are potentially toxic to
motor...

Excitotoxicity — The excitotoxicity hypothesis postulates
that excessive levels of the excitatory neurotransmitter
gluta...

Cytoskeletal and axonal transport defect

•Deranged neurofilaments could disrupt axonal transport and
Cause axonal strangu...

Mitochondrial dysfunction
The cause of the mitochondrial dysfunction is accumulation of
aggregated proteins (such as mSOD1...

Apoptosis

Apoptosis or programmed cell death cascades have been
implicated in several studies .
These reports have shown ...

CLINICAL FEATURES:
LOWER MOTOR SYMPTOMS

 Loss of muscle strength
 Atrophy
 Fasciculations
 Muscle cramps
 Difficulty...

CLINICAL FEATURES:
UPPER MOTOR SYMPTOMS
 Loss of dexterity
 Slowed movements
 Loss of muscle strength
 Stiffness
 Emo...

DIAGNOSIS OF ALS
• No biological marker has been identified yet.

• Series of clinical and neurological exams.

• MRI

• M...

EL ESCORIAL DIAGNOSTIC CRITERIA

 Other Motor Neuron Diseases  Neurodegenerative Diseases
 Primary lateral sclerosis (UMN on...

Riluzole
Riluzole — Three separate mechanisms of riluzole are thought
to reduce glutamate-induced excitotoxicity:

• inhib...

Recommendations
The American Academy of Neurology has issued a practice
advisory on the treatment of ALS with Riluzole.

P...

SIDE EFFECTS
Very Common
Asthenia.
Nausea.

Common

Alterations in liver function tests.
Headache.
Abdominal pain.
Pain.
V...

CONTRAINDICATIONS
•Hepatic disease or baseline transaminases greater than 3 times the
upper limit of normal or raised bili...

Ceftriaxone

•A cephalosporin antibiotic.

•It increases expression of EAAT2/GLT1 and prolongs
survival in MND patie...

•IV ceftriaxone, 4 gm/day, four sequential days weekly in early 2004.

•Patient improvement was rapidly evident.

•Object...

Edavarone

Has multiple ALS-relevant mechanisms of action,
including
• free ...

• 20 subjects with ALS received either 30 mg (5 ) or 60 mg (15) of
edaravone via intravenous drip once per day.

•Two we...

Tamoxifen

• Used to treat breast cancer.

• Acts as an anti-inflammatory through inhibition of PKC. In a
Phase II study o...

•Two-year study of 60 people with (ALS)who took varying dosages of
tamoxifen.

•Participants who took more than 20 mill...

Arimoclomol
•Heat shock proteins are involved in protein repair, and
thus are cytoprotective.

•Motor neurons appear...

Lithium
•An antiapoptotic agent that promotes autophagy , and
may therefore have neuroprotective effects.

• An open-label...

Stem cells
There are a number of ways in which stem cells could be
beneficial in ALS. These include
•Replacement of dying ...

ANTISENSE OLIGONUCLEOTIDE
•Another approach to gene therapy employs antisense
oligonucleotides

•To downregulate or silenc...

COMPOUNDS ALS Research Stage MECHANISM

Co-enzyme q10 Phase II Antioxidant.
...

 Spasticity
 Baclofen 5 to 10 mg twice daily to three
times daily.
 Tizanidine 2 to 4 mg by mouth twice
daily u...

 Non-pharmacologic management
 Suction machine (not usually helpful for thick
mucus, but helpful with sialor...

 Also known as: pseudobulbar palsy,
emotional incontinence, pathologic
crying/laughing
 The emotional lability is N...

 Amitriptyline 100-150mg QHS
 Fluvoxamine 100-200mg QD
 Alternatively may try Lithium or L-Dopa

 Speech therapy often helpful early
 Computer technology offer many options to
assist with patient communication

 Urinary frequency/urgency
 In the absence of UTI, often due to spasticity that
responds well to Oxybutinin
 ...

 Steven Hawking
 Proved Einstein's Theory
of Relativity
 He currently uses an
electric wheelchair to
get around
...

1. ROWLAND LP , SCHNEIDER N : Amyotrophic lateral sclerosis . New. Engl J. Med. ( 2002) 344 ( 22 ) : 1691 – 1700

2. Worms...

12. SMITH RA , MILLER TM ,YAMANAKA K et al. : Antisense oligonucleotide therapy for
neurodegenerative disease. J. Clin.Inv...

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