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
Motor cortex: the UMNs are located in the primary motor
cortex, Brodmann’s area 4, and the premotor areas, Brodmann’s area 6
(secondary motor complex and premotor complex).
Betz’s giant pyramidal neurons are the distinct group of neurons in layer 5
and other smaller neurons initiate the contraction of the small groups of the
skeletal muscles and control the force and contraction.
Axons from the cortical areas form the corticospinal and
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
•These corticospinal axons provide direct and strong
glutamatergic excitatory input to alpha
•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
•Loss of dexterity
•Stiffness, slowness, and clumsiness, in particular, rapid
•Weakness is mild.
•Spasticity is hallmark of the UMN disease
•Pseudobulbar palsy is hallmark of the UMN
disorder, which is characterized by sudden unmotivated
crying or laughing
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.
Weakness: Reduction in overall muscles strength.
Muscle atrophy and Hyporeflexia
Muscle hypotonicity and flaccidity
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
UMN & LMN
• Sporadic ALS
• Familial ALS
Mus Atrophy;Benign focal
Theses share a molecular and cellular pathology along
with intraneuronal inclusions.(ubiquitin-
immunoreactivity and TAR-DNAbinding protein-43)
Sporadic and Familial ALS
Primary lateral sclerosis
Progressive pulbar palsy
Progressive muscular atrophy
Western Pacific ALS
Madras variant MND
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.
Jean Martin Charcot
Epidemiology: Incidence - 1 to 2.7/lakh
Prevalence-2.7 to 7.4/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 like
Chamorro people of Guam and Kii penninsula of
• 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 &
10%-Live for 10 yrs
(Indian data suggests longer median
survival time may be due to earlier onset)
Complex genetic-environmental interaction for neuronal degenration.
90-95% are sporadic.
Proposed hypothesis of degeneration is viral infection,immune
activation & hormonal dysfunctions.
Sporadic ALS with predominantly autosomal dominant inheritance
Molecular pathway proposed are due to excitotoxicity,oxidative
stress,mitochondrial dysfunction,impaired axonal
Genetic susceptibility include APOE,SMN,peripherin,VEGF,paraoxonase
Western Pacific ALS(ALS parkinsonism dementia complex)-
Exposure to toxin β-N-methylamino-l-alanine, which is present in
seeds of theCycas circinalis in people of Chamorro natives of
Guam & Kii Peninsula of Japan.
Familial ALS(FALS)-(Type 1-10)(Type 2 & 5 have AR,rest have AD
i)Cu/Zn superoxide dismutase 1 (SOD1) in 20% of FALS
cases(autosomal recessive inheritance)
ii) 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 of European descent
iii)mutations in two RNA binding proteins, TAR DNA-binding
protein-43 (TDP-43) and fused in sarcoma (FUS)
2/3rd -Typical/Spinal form of ALS with focal motor weakness
of distal or proximal upper or lower limbs. Spread of weaknes to
contiguous muscles in the same region before another region is
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
1-2% -Weakness of respiratory group of muscles
10% - Bilateral upper limb weakness and wasting, flail arm of
flail person in barrel syndrome.
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.
Rarely involved: Bladder; bowels; Autonomic; Extraocular
More common in older females: 50% with bulbar
Bulbar onset in 20% to 30% of all ALS cases
Speech rate: Slow
Voice quality: Reduced
•Coticobulbar tracts involvement
•Emotional lability(forced crying or laughter)
•Brisk jaw jerk
•Hyperactive gag reflex
Clinical examination and electrophysiological
Differentiated from ALS mimickers-
Vit B12 Deficiency
HIV Infection(may present with flail arm syndrome)
Cervical spondylotic myelopathy(MRI helpful)
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'.
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.
Motor Unit Number Estimation-Quantitative
assesment of progressive motor axon loss.
Transcranial Magnetic stimulation –Measures the
central central motor conduction and so the upper
motor neuron involvement could be documented
#’SPLIT HAND’ Phenomenon-In cases of Severe changes
in the thenar eminence and the relative sparing of
hypothenar eminence ,observed on the EMG study
Clinical or electrophysiologic evidence of LMN *** and UMN signs in the bulbar region
At least two spinal regions or the presence of LMN and UMN signs in three spinal
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
Clinical or electrophysiologic signs of UMN and LMN dysfunction are in only one
UMN signs alone in two or more regions,
LMN signs rostral to UMN signs
(ALS mimics should be excluded by EMG, appropriate neuroimaging, and clinical
*** EMG evidence for denervation has equal value to clinical LMN signs; when there is
clinical suspicion for ALS, fasciculations have equivalent value to fibrillations and
positive waves in determining denervation
General: Hereditary vs Sporadic ALS
Males:Females 1:1 1.7:1
< 2 & > 5
3 to 4 years
Age distribution More younger More older
Mean age 46 years
56 to 63
Bulbar features 20% to 30% Unusual
Legs Common Occasional
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
The cornerstones of symptomatic treatment of ALS
include walking assists,management of respiratory
impairment, nutritional support, treatment of
sialorrhea,and palliative care.
Early institution of noninvasive positive pressure
ventilation probably improves survival and slows the
rate of decline of the FVC.
Cramps(Vit B complex,CCB,levitriacetam),
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
Stem cell transplantation
Transplantation of precursor neural cells
Antisense oligonucleotides and RNA interference
have been proposed
Presentation <25yrs of age
Both LMN and UMN symptoms and sign
Choreic movements,cerebellar ataxia and
mental retardation in the absence of
Patients don’t have bulbar involvement till
late in the disease
Mutation in the ALSIN gene has been
Madras variant of MND
Wasted Leg Syndrome
Reported from South India.
Cases are sporadic;Familial MMND appaers to be Aut.
Younger age of onset(1st and 2nd decade)
Wasting and weakness of predominately distal muscles of
Bulbar dysfunction(IX & XII cranial nerve nuclei) and
facial muscle involvement
Sensorineural hearing loss
Optic atrophy(if present,its named as Madras MND
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.
(*Prabhakar S, Chopra JS, Banerjee AK, Rana PV. Wasted leg syndrome: a clinical, electrophysiological
and histopathological study. Clin Neurol Neurosurg. 1981;83(1):19-28. PubMed PMID: 6273041.)
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
Primary Lateral sclerosis: a diagnosis of
Hereditary spastic paraplegia: AD disorder
HTLV-1 associated myelopathy: X-linked
recessive inheritance, increased serum of very-
long-chain fatty acids
Lathyrism: history of consumption of
Diagnosis of exclusion
Account for 2-4% of ALS
Absence of LMN Invovement
Presentation in early 50’s
Slowly evolving spastic paresis after involving upper
Median disease duration:19yrs
deficits & abnormal voluntary eye movement
Striking loss of Betz cells in layer 5 of frontal and
prefrontal cortex with laminar gliosis of layers 3 & 5 and
degeneration corticospinal tract
Also called familial spastic paraparesis or Strumpell-
The common feature of this syndrome is
progressive, often severe, spasticity in the lower
Inheritance may be X-linked, autosomal recessive, or
autosomal dominant (70-85%)
May occur at any age For patients with uncomplicated
HSP, the life expectancy is typically unchanged.
Caused by a human T-cell leukemia virus type I
(HTLV-I) after a long incubation period.
Characterized by a chronic progressive paraparesis
with sphincter disturbances, no/mild sensory
loss,the absence of spinal cord compression and
seropositivity for HTLV-I antibodies.
Endemic in Caribbean, southern Japan, equatorial
Africa, South Africa, and parts Central and South
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
Chronic neurogenic disease –long term ingestion of chickpeas
(Lathyrus sativus) containing β-N-oxalylamino-L-
alanine(BOA), which is an glutamate receptor agonist.
The onset is acute or chronic
Muscle spasm and leg weakness
Spastic paraparesis with or without some sensory and bladder
Leg motor neurons in the motor cortex and the corresponding
pyramidal tracts are predominately affected.
Found in Bangladesh, China, Ethiopia, India, Romania, Spain
Electromyography: loss of CMAP amplitude, diminished
conduction velocity, SNC studies are normal in pure LMN
Muscle biopsy: muscle fibers denervation could be seen early
than needle EMG examination
Acute poliomyelitis is prototypical disorder of acute
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
Further improvement may continue over the
ensuing 18-24 months.
Residual paralysis was generally absent or only
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 hypesthesia
No Definite cause has been determined
Slowly progressive, asymmetrical muscle weakness
Multifocal conduction block in motor nerve
Elevated titer GM1 antibodies
May be mistaken with ALS, SMA, benign focal
amyotrophy, progressive muscular
atrophy, CIDP, GBS.
Treatment: IVIG, and cyclophosphamide
Monomelic amyotrophy, and juvenile muscular atrophy are
used to describe this intriguing 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
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
Tremor (80%): On finger extension; Irregular &
Werdnig and Hoffmann in
SMN1 (Telomeric SMN
(SMNT)) gene mutated in
95% of SMA
According to the ISMAC system, the age of onset for
spinal muscular atrophies is as follows:
SMA type I (acute infantile or Werdnig Hoffman):
Onset is from birth to 6 months.
SMA type II (chronic infantile): Onset is between
6 and 18 months.
SMA type III (chronic juvenile): Onset is after 18
SMA type IV (adult onset): Onset is in adulthood
(mean onset, mid 30s).
Childhood or Juvenile
Cramps may be 1st symptom
Variable degrees of severity
Some never walk
Later onset: Better prognosis
Most have loss of function over time
? Change in strength over time
Difficult to measure
Tendon reflexes: Reduced
Serum CK: Normal
EMG: Fibrillations; Large amplitude
NCS: Small amplitude CMAPs; Mild
slowing; Sensory normal
Type I muscle fiber predominance
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
No effect on specific clinical features
Length inversely correlated with transcriptional activity
by the androgen receptor
Age: Mean 27 years; 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
Wasted; Weak; Moves rapidly
NO upper motor neuron signs
Androgen insensitivity related
Gynecomastia (50% to 70%)
Groin hernia: 33%
Diabetes mellitus in some patients
Pituitary microadenoma: Rare
Widespread Lower Motor Neuron Syndrome
Distal & Proximal: Either may be more prominent
Often involves paraspinous & respiratory muscles
Often spares bulbar musculature
Spontaneous motor activity
Cramps: Common in legs, at night
No upper motor neuron signs
Pain: Related to immobility
Similar to, more rapid, or slower than, typical ALS
Muscle pathology: Grouped atrophy >
Fiber type grouping
No serum antibodies
No conduction block
No evidence for response to treatment
Proximal lower motor neuron syndrome
Loss of motor neurons in anterior horn
of spinal cord
Shrinkage of remaining motor neurons
Primary muscular atrophy
Note wasting, including
The Disease can Kill Your Body But Not Your