MOTOR NEURON

DISEASE
Story of a helpless body but a
thoughtful mind…

Guide – Dr Prakash Kori

Student – Dr H B Nidish
 Overview of Upper Motor
Neurons
⚫ Upper motor neurons (UMN) are responsible for
conveying impulses for voluntary motor activity

⚫ UMN send fibers to the LMN, and that exert direct

or indirect supranuclear control over the LMN.

⚫ Lower motor neurons (LMN) directly innervate the

skeletal muscle
⚫ Axons from the cortical areas form the corticospinal and
corticobulbar tracts.

⚫ 1/3 from primary motor cortex (Betz’s cell axons -3- 5%,
and other 95% from small neurons)

⚫ 1/3 from Brodmann’s area 6

⚫ 1/3 from the somatic sensory cortex (areas 1, 2, and 3),

and adjacent temporal lobe region.
• The corticobulbar tract projects bilaterally to CNs V,
VII, IX, X and XII.

• The corticospinal tract decussates (75-90%) in the

lower medulla and forms the lateral corticospinal tract.
The remaining fibers form the ventral corticospinal
tract.

• These corticospinal axons provide direct and strong

glutamatergic excitatory input to alpha motor neurons.
• Basal ganglia and cerebellum-No direct input to the LMNs and thus
are NOT considered part of the UMNs.

• Basal Ganglia modulates

•Higher order functions,
•Cognitive aspect of motor control,
•Planning and execution of complex motor strategies.

• The cerebellum regulates mechanical execution of movements

because it receives input from the sensorimotor cortex and the spinal
cord.
 Signs & Symptoms of UMN
Disorders
• Loss of dexterity

• Stiffness, slowness, and clumsiness, in particular, rapid repetitive motions.

• Weakness is mild.

• Spasticity is hallmark of the UMN disease

• Pathological hyperreflexia.

• Pseudobulbar palsy is hallmark of the UMN

disorder, which is characterized by sudden unmotivated crying or laughing
 Overview of LMN
• The LMNs -Located in the brainstem and spinal cord

• The spinal LMNs are also known as anterior horn cell. The
neurons are clustered in nuclei, forming longitudinal columns.

• Dorsal anterior horn cells -Innervate distal muscles,

• Ventral located cells- Proximal muscles,

• Medially located neurons- Truncal and axial muscles.

• Markedly enlarged lateral parts of the cervical and lumbar

(lower thoracic) anterior horns innervate arm, hand, and
leg muscles.

• Large spinal cord LMNs are called alpha neurons.

LOWER MOTOR NEURON
Spinal cord ventral horn (Cervical spinal cord cross section)
 Signs & Symptoms of LMN Disorders

⚫ Weakness: Reduction in overall muscles strength.

⚫ Muscle atrophy and flaccidity

⚫ Muscle hypotonicity and hyporeflexia

⚫ Fasciculations

⚫ Muscle cramps
Overview Of Motor Neuron Disease

• Important to differentiate the terms MND and ALS from

the “Motor Neuron Disorders” which is used for a
heterogenous group of disease or disorders of neurons of
varied etiology having in common the involvement of
Upper AND/OR Lower motor neuron systems.
• The Motor Neuron Disorders include inflammmatory
immune disorders ,
sporadic /familial disorders and
disorders of undetermined cause.

• ALS or MND is ONE of the Motor neuron disorders

 Motor Neuron
Disorders

UMN & LMN

UMN
LMN Disorders
Disorders
Disorders

Neurodegenerative(Prog
Mus Atrophy;Benign focal
amyotrophy/brachial
Neurodegenerative monomelic amyotrophy)
Disorder(Primary Amyotrophic Lateral
lateral Sclerosis) Sclerosis Infections(Polio;Post
 Toxins(Neurolathyris • Sporadic ALS Polio;Subacute motor
m) • Familial ALS neuropathy of
Infections(HTLV-1/2 lymphoproliferative diseases)
asso. Myelopathy)
Inherited(SMA;Kennedy
disease;Hexaminidase
deficiency)

 Post radiation
 Spectrum of MND/ALS
⚫ Sporadic and Familial ALS
⚫ Primary lateral sclerosis
⚫ Progressive bulbar palsy
⚫ Progressive muscular atrophy
⚫ Juvenile ALS
⚫ Western Pacific ALS
⚫ Madras variant MND
 Amyotrophic Lateral Sclerosis
(ALS)
⚫ Named by Jean Martin Charcot in 19th century

⚫ Also known as Lou Gehrig’s disease after the

famous baseball player diagnosed of ALS in 1930.

⚫ Degeneration of the motor neuron(UMN &

LMN) in motor cortex,brainstem & spinal cord.
⚫ Amyotrophy-Atrophy of muscle fibres
consequent of denervation due to anterior horn
cell degeneration

⚫ Lateral sclerosis-Sclerosis of the anterior and lateral

corticospinal tracts which are replaced by progressive
gliosis.
 Epidemiology
 Incidence - 1 to 2.7/lakh

 Prevalence-2.7 to 6.4/lakh

 Sex predisposition-M>F(2:1 to 7:1) (F>M in bulbar onset

ALS)

 Age-Risk increases with age up to 74 years

 Geographical distribution-In regions of Japan.

• Cases from India with distinct features- Madras variant
MND

• Peak onset-sixth to seventh decade(one to two decades

earlier in India)

• 20% live for 5 years and 10% live for 10 years

(Indian data suggests longer median survival time may be
due to earlier onset)
 Aetiopathogenesis
⚫ Undetermined aetiology.

⚫ Complex genetic-environmental interaction for neuronal

degeneration.

⚫ 90-95% are sporadic.

⚫ Proposed hypothesis of degeneration is viral

infection,immune activation & hormonal dysfunctions.
⚫ Sporadic ALS - autosomal dominant inheritance

⚫ Molecular pathway- excitotoxicity,oxidative

stress,mitochondrial dysfunction,impaired axonal
transport,neurafilament aggregation.

⚫ Genetic susceptibility - APOE,SMN,peripherin,VEGF,paraoxonase

gene alteration

⚫ Western Pacific ALS(ALS parkinsonism dementia complex)-

Exposure to toxin β-N-methylamino-l-alanine.
⚫ Familial ALS(FALS)-(Type 1-10)(Type 2 & 5 have AR, rest have
AD
inheritance)

1. Cu/Zn superoxide dismutase 1 (SOD1) in 20% of

FALS cases(autosomal recessive inheritance)

2. Expansions of a GGGGCC hexanucleotide repeat in a

noncoding region of chromosome 9 is present in 37%
to 46% of FALS and 6% to 20% of sporadic ALS

3. Mutations in two RNA binding proteins, TAR DNA-

binding protein-43 (TDP-43) and fused in sarcoma
(FUS)
 Clinical Presentation

⚫ 2/3rd -Typical/Spinal form

focal motor weakness of upper or lower limbs.
Spread of weakness to contiguous muscles in the same region
before another region is involved.

⚫ Pseudoneuritic pattern-
Involvement of muscles in the apparent distribution
of a peripheral nerve

⚫ Monomelic-Involvement of one limb

⚫ Pseudopolyneuritic-
Weakness in the both distal lower limbs

⚫ Mill’s Hemiplegic variant-

Weakness restricted to one half of the body

⚫ Bulbar/pseudobulbar palsy
⚫ 1-2% -Weakness of respiratory group of muscles

⚫ 10% - Bilateral upper limb weakness and wasting- flail arm or

flail person in barrel syndrome.

⚫ Head drop
⚫ Fasiculations-(Not the initial presenting symptom but almost seen
in all patients at presentation)

⚫ Cramps-thighs,abdomen,back or even tongue

⚫ Non motor symptoms-Sleep disturbance, Subtle cognitive

Dysfunction and mood changes.

⚫ Extremely Rare involvement: Bladder; bowels; Autonomic;

Extraocular movements; Sensory
 Bulbar dysfunction
• More common in older females: 50% with bulbar presentation
• Bulbar onset in 20% to 30% of all ALS cases

Features
– Dysarthria
o Speech rate: Slow
o Voice quality: Reduced
– Dysphagia
 Pseudo-Bulbar dysfunction
•Coticobulbar tracts involvement

•Spastic dysarthria,dysphonia,dysphagia

•Emotional lability(forced crying or laughter)

•Brisk jaw jerk

•Hyperactive gag reflex

 UMN LMN
⚫ Weakness ⚫ Weakness
⚫ Slowed rapid alternating ⚫ Muscle atrophy
movements ⚫ Fasciculations
⚫ Spasticity, clasp knife ⚫ Cramps
phenomenon ⚫ Attenuated or absent
⚫ Hyperreflexia reflexes
⚫ Pathologic reflexes, including ⚫ Bulbar palsy
Babinski and Hoffmann
⚫ Presence of reflexes in
atrophic limbs
⚫ Pseudobulbar palsy (labile
affect, spastic
speech, dysarthria,brisk jaw
jerk, and gag reflex)
 ’SPLIT HAND’ Phenomenon-In cases of Severe changes in the thenar
eminence and the relative sparing of hypothenar eminence ,observed on the
EMG study

 Motor Unit Number Estimation-Quantitative assesment of progressive

motor axon loss.

 Transcranial Magnetic stimulation –Measures the central motor

conduction and so the upper motor neuron involvement could be
documented
 Diagnosis
⚫ Clinical examination and electrophysiological assessment.

⚫ Differentiated from ALS mimickers-

 Paraneoplastic
 Hyperthyroidism
 Parathormone dysfunction
 Vit B12 Deficiency
 HIV Infection(may present with flail arm syndrome)
 Cervical spondylotic myelopathy(MRI helpful)
 Myeloradiculopathy
 Multiple Sclerosis
 Craniovertebral Anomalies
⚫ NEUROIMAGING-

⚫ MRI helps in excluding mimickers.

⚫ Coronal T2WI shows bilateral symmetrical hyperintensity

along corticospinal tract (thin white arrows) forming a
'WINE GLASS APPEARANCE‘ or ‘GARLAND SIGN’
Coronal T2WI showing bilateral symmetrical hyperintensity along corticospinal tract
(thin white arrows) forming a 'wine glass appearance'.
 Awaji Criteria
 Definite ALS

⚫ Clinical or electrophysiologic evidence of LMN and UMN signs in

bulbar region and at least two spinal regions
or
The presence of LMN and UMN signs in three spinal regions

 Probable ALS

⚫ Clinical or electrophysiologic evidence by LMN and UMN signs in at

least two regions with some UMN signs necessarily rostral to (above)
the LMN signs
•Possible ALS

⚫ Clinical or electrophysiologic signs of UMN and LMN

dysfunction are in only one region,

OR

⚫ UMN signs alone in two or more regions,

OR

⚫ LMN signs rostral to UMN signs

(ALS mimics should be excluded by EMG, appropriate
neuroimaging, and clinical laboratory studies)
General: Hereditary vs Sporadic
ALS
Sporadic
Feature Hereditary ALS ALS

Males:Females 1:1 1.7:1

Bimodal Unimodal
Disease Duration <2&>5 3 to 4 years
years

Onset
Age distribution More younger More older
Bulbar features 20% to 30% Unusual
Legs Common Occasional
 Electrophysiology

⚫ Nerve Conduction Study -Normal in ALS except for low

amplitude of compound muscle action potential(CMAP) which is
due to wasting of muscles being recorded . Sensory nerve
conduction is normal

⚫ Electromyogram- signs of denervation include

fibrillations, positive sharp waves,fasciculations,
neurogenic units, and a neurogenic pattern of
recruitment.
 Management
⚫ NO CURE is presently available for ALS, so the goal of
therapy is improving the quality of life.

⚫ Riluzole (blocks TTX-sensitive sodium channels) is the only

medication that has been shown to be effective in ALS

⚫ 50 mg twice a day, improves 1-year survival by about 15% and

prolongs overall survival by 2 to 3 months
 symptomatic treatment of ALS - walking assists, management of
respiratory impairment, nutritional support, treatment of sialorrhea,
and palliative care.

 Early institution of non-invasive positive pressure ventilation

probably improves survival and slows the rate of decline of the
FVC.

 Supportive treatment

⚫ Spasticity(Baclofen/tizanidine),
⚫ Cramps(Vit B complex, CCB, levetiracetam),
⚫ Sialorrhea(TCA, anticholinergics),
⚫ Depression(SSRIs/TCA)
• Diaphragm pacing has been used in selected patients with
ALS with moderately impaired respiratory function and viable
phrenic nerves and diaphragm

• Percutaneous endoscopic gastrostomy(before FVC drops

<50%)

• Stem cell transplantation

• Transplantation of precursor neural cells

• Antisense oligonucleotides and RNA interference have been

proposed
 Juvenile ALS
• Presentation <25yrs of age

• Both LMN and UMN symptoms and sign

• Choreic movements,cerebellar ataxia and mental retardation in

the absence of deafness

• Patients don’t have bulbar involvement till late in the disease

• Mutation in the ALSIN gene has been recognized

 Focal Variants Of MND
• Madras variant of MND

• Wasted Leg Syndrome

• Monomelic Amyotophy

• Hirayama Disease
 Madras Variant Of MND

• Reported from South India.

• Cases are sporadic

• Familial MMND appears to be Autosomal Recessive

• Younger age of onset(1st and 2nd decade)

• Wasting and weakness of predominately distal muscles of

limbs
• Bulbar dysfunction(IX & XII cranial nerve nuclei) and facial
muscle involvement

• Pyramidal dysfunction

• Sensorineural hearing loss

• Optic atrophy(if present,its named as Madras MND variant)

 Wasted Leg Syndrome
• Majority of patients were adults engaged in heavy manual
work.

• Strictly unilateral wasting of the whole lower limb

• The nerve conduction studies and the electromyographic

pattern suggested anterior horn cell disorder.

• Neurogenic atrophy is seen in muscle biopsies

• Suggested that possibly these cases represent an entity,

clinically different from other anterior horn cell disorders.
 Hirayama Disease

• Hirayama disease is also known as juvenile muscular

atrophy of the distal upper extremity

• Affects predominantly males in either their 2nd or their

early 3rd decade of life

• Typical clinical features-Muscular weakness and atrophy

in the hand and forearm
• Unilateral involvement in the majority of patients, but
asymmetric and symmetric bilateral involvement are also
observed .

• Since the brachioradialis muscle is spared, the pattern of forearm

involvement is also referred to as an oblique amyotrophy.
 UMN Disorders
• Primary Lateral sclerosis: a diagnosis of exclusion

• Hereditary spastic paraplegia: AD disorder

• HTLV-1 associated myelopathy: X-linked recessive inheritance,

increased serum of very- long-chain fatty acids

• Adrenomyeloneuropathy

• Lathyrism: history of consumption of chickpeas

 Primary Lateral Sclerosis

• Diagnosis of exclusion

• Account for 2-4% of ALS

• Absence of LMN Involvement

• Presentation in early 50’s

• Slowly evolving spastic paresis after involving upper limbs.

• Median disease duration:19yrs
• Fasciculation, cramps, bladder dysfunction, cognitive deficits &
abnormal voluntary eye movement
• Striking loss of Betz cells and degeneration corticospinal tract
 Hereditary Spastic Paraplegia
• Also called familial spastic paraparesis or Strumpell- Lorrain
syndrome

• The common feature of this syndrome is progressive, often severe,

spasticity in the lower extremities.

• Inheritance may be X-linked, autosomal recessive, or autosomal

dominant (70-85%)
 HTLV-1 Associated Myelopathy

• Caused by a human T-cell lymphotropic virus type I (HTLV-I) after

a long incubation period.

• Characterized by a chronic progressive paraparesis with sphincter

disturbances,
no/mild sensory loss,
absence of spinal cord compression and
seropositivity for HTLV-I antibodies.
 Adrenomyeloneuropathy
• Variant of adrenoleukodystrophy, an X-linked recessive disorder (X-
ALD).

• The genetic defect is located in the Xq28 region, which encodes a

peroxisomal membrane protein.

• X-ALD causes progressive demyelination in brain, the adrenal gland

and testicular atrophy.

• Mean age of onset is 27 years, slow progressive spastic paraparesis

and sphincter dysfunctions.

• 88% presents with Addison’s disease

 Lathyrism
• Chronic neurogenic disease –long term ingestion of chickpeas
(Lathyrus sativus) containing β-N-oxalylamino-L-alanine(BOAA),
which is an glutamate receptor agonist.

• The onset is acute or chronic

• Muscle spasm and leg weakness

• Spastic paraparesis without or with some sensory and bladder

dysfunction.
 Leg motor neurons in the motor cortex and the corresponding
pyramidal tracts are predominately affected.

 Found in Bangladesh, China, Ethiopia, India, Romania, Spain

 LMN Disorders
• Poliomyelitis
• Multifocal Motor Neuropathy
• Benign Focal Amyotrophy
• Spinal Muscular Atrophy
• Bulbo-Spinal Muscular Atrophy (BSMA; Kennedy's
Syndrome; X-linked)
• Primary Muscular Atrophy (PMA)
 Diagnostic Modalities
• Electromyography: loss of CMAP amplitude, diminished
conduction velocity, NCS studies are normal in pure LMN
disorder.

• Muscle biopsy: muscle fibers denervation could be seen early

than needle EMG examination
 Acute Poliomyelitis
• Acute poliomyelitis is prototypical disorder of acute LMN
dysfunction.

• Caused by RNA poliovirus, genus Enterovirus, family

Picornavirus.

• Small proportion -Either minor illness (gastroenteritis) or the major

illness several days after the infection.

• Major illness resembles aseptic meningitis. Approximately 50% of

patient progress to paralytic disease within 2-5 days.
• Paralytic phase: localized fasciculations, severe myalgia,
hyperesthesia, and usually fulminant focal and asymmetrical
paralysis.

• Leg muscle involvement is more frequent, than arm, respiratory, and

bulbar muscles.

• Recovery may begin during first week, but it estimated that 80% of
recovery occurs in 6 months.

• Further improvement may continue over the ensuing 18-24 months.

Progressive Postpoliomyelitis
Muscular Atrophy (PPMA)
• Antecedent poliomyelitis
• Residual paralysis was generally absent or only minimal.
• Both polio-affected and unaffected site of the limb are equally
involved by PPMA
• Asymmetrical proximal muscular atrophy and flaccid motor paresis in
one or two limbs with decreased tendon reflexes.
• Fasciculation;myalgia, and hypoesthesia
• No Definite cause has been determined
 Multifocal Motor Neuropathy
• Slowly progressive, asymmetrical muscle weakness

• Multifocal conduction block in motor nerve conduction studies

• Elevated titer GM1 antibodies

• May be mistaken with ALS, SMA, benign focal amyotrophy,

progressive muscular atrophy, CIDP, GBS.

• Treatment: IVIG, and cyclophosphamide

 Benign Focal Amyotrophy
• Monomelic amyotrophy, and juvenile muscular atrophy are
used to describe this entity.

• Etiology is unknown.

• Hirayama's disease: Progressive weakness over 1 to 4 years,

then plateau

• O'Sullivan-McLeod syndrome: Slow progression

• 15 to 25 years; Male > Female: Up to 10:1

• Weakness:
 Often confined to a single arm
 Distal involvement (97%): C7, C8 & T1 innervated
muscles; Hand & Forearm
 Proximal > Distal: 10%
 Side: Right = Left

• Atrophy: "Oblique amyotrophy"; Sparing brachioradialis

• Tremor (80%): On finger extension; Irregular & Coarse

(Minipolymyoclonus)
 Spinal Muscular Atrophy
• Werdnig and Hoffmann in 1891 independently described
• SMN1 (Telomeric SMN (SMNT)) gene mutated in 95% of
SMA
 Classification
• According to the ISMAC system, the age of onset for spinal
muscular atrophies is as follows:

o SMA type I (acute infantile or Werdnig Hoffman): Onset is

from birth to 6 months.
o SMA type II (chronic infantile): Onset is between 6 and 18
months.
o SMA type III (chronic juvenile): Onset is after 18 months.
o SMA type IV (adult onset): Onset is in adulthood (mean onset,
mid 30s).
 Clinical features
• Childhood or Juvenile
• Cramps may be 1st symptom
• Weakness
• Proximal; Symmetric
• Variable degrees of severity
 Some never walk
 Poor prognosis
 Scoliosis early
 Later onset: Better prognosis
• Progression
 Most have loss of function over time
 Change in strength over time
 Difficult to measure

• Tremor

• Tendon reflexes: Reduced

• Laboratory
 Serum CK: Normal
 Electrophysiology
 Muscle biopsy
Bulbo-Spinal Muscular Atrophy (BSMA)
• Most common adult onset SMA

• BSMA: Long, 40-65 CAG repeats

• CAG repeat length effects

• Longer the repeats

 Earlier disease onset
 More severe SBMA disease
 Impaired spermatogenesis
• Age: Range 15 to 60 years
• Early symptoms & signs:Adolescence but symptoms usually at 30
years
• Muscle discomfort: Cramps or Pain
• Fatigue: General; Chewing
• Gynecomastia: May be asymmetric
• Weakness: Not common early; May be distal
• Lower > Upper limb weakness
• Tremor: Hands; Postural & Action
• Tongue - Wasted; Weak; Moves rapidly
• NO upper motor neuron signs
• Androgen insensitivity related
Gynecomastia (50% to 70%)
Reduced fertility
Testicular atrophy
• Diabetes mellitus in some patients
 Progressive Muscular Atrophy
• Widespread Lower Motor Neuron Syndrome

• Weakness: Distribution
 Distal & Proximal: Either may be more prominent
 Asymmetric
 Often involves paraspinous & respiratory muscles
 Often spares bulbar musculature
• Spontaneous motor activity
 Cramps: Common in legs, at night
 Fasciculations

• No upper motor neuron signs

• Pain: Related to immobility

• Time course
 Progressive
 Similar to, more rapid, or slower than, typical ALS
 Laboratory
• Muscle pathology: Grouped atrophy > Fiber
type grouping
• No serum antibodies
• No conduction block
• No evidence for response to treatment
 THANK YOU

The Disease can Kill Your Body But Not Your

Imaginations……..
 References
• Harrisons Principal of internal medicine edition – 21st
• Bradley’S Neurology In Clinical Practice , 7Th Edition
• Adams and Victor's Principles of Neurology 10th Edition