Motor Neuron Diseases/Disorders-A Simple Understanding.

2.  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

3. 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.

5.  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.

6. •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
motorneurons.

7. •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.

8. •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

9.  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.

10. LOWER MOTOR NEURON
Spinal cord ventral horn (Cervical spinal cord cross section)

11.  Weakness: Reduction in overall muscles strength.
 Muscle atrophy and Hyporeflexia
 Muscle hypotonicity and flaccidity
 Fasciculations
 Muscle cramps

12.  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

13. Motor Neuron
Disorders
UMN
Disorders
UMN & LMN
Disorders
LMN
Disorders
Neurodegenerative
Disorder(Primary lateral
Sclerosis)
Toxins(Neurolathyrism)
Infections(HIV-1/2 asso.
Myelopathy)
Amyotrophic Lateral
Sclerosis
• Sporadic ALS
• Familial ALS
Neurodegenerative(Prog
Mus Atrophy;Benign focal
amyotrophy/brachial
monomelic amyotrophy)
Infections(Polio;Post
Polio;Subacute motor
neuropathy of
lymphoproliferative diseases)
Inherited(SMA;Kennedy
disease;Hexaminidase
deficiency)
Post radiation

14. 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
 Juvenile ALS
 Western Pacific ALS
 Madras variant MND

16.  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

18.  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
Japan.

19. • 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)

20.  Undetermined aetiology.
 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
transport,neurafilament aggregation.
 Genetic susceptibility include APOE,SMN,peripherin,VEGF,paraoxonase
gene alteration

21.  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
inheritance)
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)

22.  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
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

23.  1-2% -Weakness of respiratory group of muscles
 10% - Bilateral upper limb weakness and wasting, flail arm of
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.
 Rarely involved: Bladder; bowels; Autonomic; Extraocular
movements; Sensory

24.  More common in older females: 50% with bulbar
presentation
 Bulbar onset in 20% to 30% of all ALS cases
 Features
 Dysarthria
 Speech rate: Slow
 Voice quality: Reduced
 Dysphagia
•Coticobulbar tracts involvement
•Spastic dysarthria,dysphonia,dysphagia
•Emotional lability(forced crying or laughter)
•Brisk jaw jerk
•Hyperactive gag reflex

25. UMN
 Weakness
 Slowed rapid alternating
movements
 Spasticity, clasp knife
phenomenon
 Hyperreflexia
 Pathologic reflexes, including
Babinski and Hoffmann
 Presence of reflexes in
atrophic limbs
 Pseudobulbar palsy (labile
affect, spastic
speech, dysarthria,brisk jaw
jerk, and gag reflex)
LMN
 Weakness
 Muscle atrophy
 Fasciculations
 Cramps
 Attenuated or absent
reflexes
 Bulbar palsy)

26.  Clinical examination and electrophysiological
assesement.
 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

27.  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’

28. Coronal T2WI showing bilateral symmetrical hyperintensity along corticospinal tract
(thin white arrows) forming a 'wine glass appearance'.

29.  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.

30.  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

31. Definite ALS
 Clinical or electrophysiologic evidence of LMN *** and UMN signs in the 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)
*** 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

32. General: Hereditary vs Sporadic ALS
Feature
Hereditary ALS
Sporadic
ALS
Males:Females 1:1 1.7:1
Disease Duration
Bimodal
< 2 & > 5
years
Unimodal
3 to 4 years
Onset
Age distribution More younger More older
Mean age 46 years
56 to 63
years
Bulbar features 20% to 30% Unusual
Legs Common Occasional

33.  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.

34.  Early institution of noninvasive positive pressure
ventilation probably improves survival and slows the
rate of decline of the FVC.
 Spportive treatment
 Spasticity(Baclofen/tizanidine),
 Cramps(Vit B complex,CCB,levitriacetam),
 Sialorrhoea(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

35.  Percutaneous endoscopic gastrostomy(before FVC
drops <50%)
 Stem cell transplantation
 Transplantation of precursor neural cells
 Antisense oligonucleotides and RNA interference
have been proposed

36.  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
recognised

37.  Madras variant of MND
 Wasted Leg Syndrome
 Monomelic Amyotophy
 Hirayama Disease

38.  Reported from South India.
 Cases are sporadic;Familial MMND appaers to be Aut.
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)

39.  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.)

40.  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.

42.  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

43.  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
limbs.
 Median disease duration:19yrs
 Fasiculation,cramps,bladder dysfunction,cognitive
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

44.  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%)
 May occur at any age For patients with uncomplicated
HSP, the life expectancy is typically unchanged.

45.  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
America

46.  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

47.  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
dysfunction.
 Leg motor neurons in the motor cortex and the corresponding
pyramidal tracts are predominately affected.
 Found in Bangladesh, China, Ethiopia, India, Romania, Spain

50.  Poliomyelitis
 Multifocal Motor Neuropathy
 Benign Focal Amyotrophy
 Hopkins’ syndrome: Acute post-asthmatic
amyotrophy
 Spinal Muscular Atrophy
 Bulbo-Spinal Muscular Atrophy (BSMA; Kennedy's
Syndrome; X-linked)
 Primary Muscular Atrophy (PMA)

51.  Electromyography: loss of CMAP amplitude, diminished
conduction velocity, SNC studies are normal in pure LMN
disorder.
 Muscle biopsy: muscle fibers denervation could be seen early
than needle EMG examination

52.  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.

53.  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.

54.  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 hypesthesia
 No Definite cause has been determined

55.  Slowly progressive, asymmetrical muscle weakness
and atrophy
 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

56.  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

57.  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

58.  Werdnig and Hoffmann in
1891 independently
described
 SMN1 (Telomeric SMN
(SMNT)) gene mutated in
95% of SMA

59. 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
months.
 SMA type IV (adult onset): Onset is in adulthood
(mean onset, mid 30s).

60.  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

61.  Laboratory
 Serum CK: Normal
 Electrophysiology
EMG: Fibrillations; Large amplitude
action potentials
NCS: Small amplitude CMAPs; Mild
slowing; Sensory normal
 Muscle biopsy
Grouped atrophy
Type I muscle fiber predominance

62.  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
 No effect on specific clinical features
 Length inversely correlated with transcriptional activity
by the androgen receptor

63.  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

64.  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
 Groin hernia: 33%
Other endocrine
 Diabetes mellitus in some patients
 Pituitary microadenoma: Rare

65. Bulbo-Spinal Muscular Atrophy
Gynecomastia

66.  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

67. Laboratory
 Muscle pathology: Grouped atrophy >
Fiber type grouping
 No serum antibodies
 No conduction block
 No evidence for response to treatment
 Differential diagnosis
 Proximal lower motor neuron syndrome
Pathology
 Loss of motor neurons in anterior horn
of spinal cord
 Shrinkage of remaining motor neurons
 Inclusion bodies:
Intracytoplasmic, Hyaline
Primary muscular atrophy
Note wasting, including
paraspinal muscles

68. The Disease can Kill Your Body But Not Your
Imaginations……..