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motorneurondiseases-130425105529-phpapp01.pptx
1.
2. ⚫Upper motor neurons (UMN) are responsible for
conveying impulses forvoluntary motoractivity
⚫UMN send fibers to the LMN, and thatexertdirector
indirect supranuclearcontrol overthe LMN.
⚫Lowermotor neurons (LMN) directly innervate the
skeletal muscle
3. Motorcortex: the UMNs are located in the primary motor
cortex, Brodmann’sarea 4, and the premotorareas, Brodmann’sarea 6
(secondary motorcomplex and premotorcomplex).
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 musclesand control the forceand contraction.
4.
5. ⚫Axons from thecortical areas form thecorticospinal and
corticobulbar tracts.
⚫1/3 from primary motorcortex (Betz’s cell axons -3-
5%, and other 95% from small neurons)
⚫1/3 from Brodmann’sarea 6
⚫1/3 from the somatic sensory cortex (areas 1, 2, and
3), and adjacent temporal lobe region.
6. •Thecorticobulbar tract projects bilaterally to CNs
V
, VII, IX, X and XII.
•Thecorticospinal tractdecussates (75-90%) in the
lower medulla and forms the lateral corticospinal
tract. The remaining fibers form the ventral
corticospinal tract.
•Thesecorticospinal axons providedirectand strong
glutamatergic excitatory input to alpha
motorneurons.
7. •Basal gangliaand cerebellum-No direct input to the LMNs and
thusare NOT considered partof the UMNs.
•Basal Ganglia modulates
•Higherorder functions,
•Cognitiveaspect of motorcontrol,
•Planning and execution of complex motor strategies.
•Thecerebellum 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.
•Pseudobulbarpalsy is hallmark of the UMN
disorder, which is characterized by sudden unmotivated
crying or laughing
9. ⚫ The LMNs -Located in the brainstemand spinal cord
⚫ The spinal LMNs are also known as anterior horn cell. The
neuronsareclustered in nuclei, forming longitudinal columns.
⚫ Dorsal anterior horncells -Innervatedistal muscles,
⚫ Ventral located cells- Proximal muscles,
⚫ Medially located neurons- Truncal and axial muscles.
⚫ Markedlyenlarged lateral partsof thecervical and lumbar (lower
thoracic) anterior horns innervatearm, hand, and leg muscles.
⚫ Largespinal cord LMNs arecalled alpha neurons.
11. ⚫Weakness: Reduction in overall muscles strength.
⚫Muscle atrophy and Hyporeflexia
⚫Muscle hypotonicityand flaccidity
⚫Fasciculations
⚫Muscle cramps
12. ⚫Importanttodifferentiate the terms MND and ALS from
the “Motor Neuron Disorders” which is used for a
heterogenousgroupof diseaseordisorders of neuronsof
varied etiology having in common the involvementof
UpperAND/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
14. Theses share a molecular and cellular pathology along
with intraneuronal inclusions.(ubiquitin-
immunoreactivityand TAR-DNAbinding protein-43)
⚫Sporadicand Familial ALS
⚫Primary lateral sclerosis
⚫Progressive pulbarpalsy
⚫Progressive muscularatrophy
⚫JuvenileALS
⚫Western Pacific ALS
⚫Madras variant MND
15.
16. JeanMartin Charcot
⚫Named by Jean Martin Charcot in 19th century
⚫Also known as Lou Gehrig’s diseaseafterthe famous baseball
playerdiagnosed of ALS in 1930.
⚫Degeneration of the motor neuron(UMN & LMN) in motor
cortex,brainstem & spinal cord.
⚫Amyotrophy-Atrophyof muscle fibres consequentof
denervation due toanterior horn cell degeneration
⚫Lateral sclerosis-Sclerosis of the anterior and lateral
corticospinal tractswhich are replaced by progressivegliosis.
17.
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 increaseswith age up to 74 years
⚫ Geographical distribution-In regions like
Chamorro peopleof Guam and Kii penninsulaof
Japan.
19. • Cases from India with distinct features-
Madrasvariant MND
• Peak onset-sixth toseventh decade(one
to twodecades earlier in India)
• 20%- live for 5 &
10%-Live for 10 yrs
(Indian data suggests longer median
survival time may be due toearlieronset)
20. ⚫ Undetermined aetiology.
⚫ Complex genetic-environmental interaction for neuronal degenration.
⚫ 90-95% aresporadic.
⚫ Proposed hypothesis of degeneration isviral infection,immune
activation & hormonal dysfunctions.
⚫ Sporadic ALS with predominantlyautosomal dominant inheritance
⚫ Molecularpathway proposed aredue toexcitotoxicity,oxidative
stress,mitochondrial dysfunction,impaired axonal
transport,neurafilamentaggregation.
⚫ Geneticsusceptibility include APOE,SMN,peripherin,VEGF,paraoxonase
genealteration
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 superoxidedismutase 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 sporadicALS 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 motorweakness
of distal or proximal upperor lower limbs. Spread of weaknes to
contiguous muscles in thesame region beforeanotherregion is
involved.
⚫ Pseudoneuriticpattern-Involvementof muscles in the
apparentdistribution of a peripheral nerve
⚫ Monomelic-Involvementof one limb
⚫ Pseudopolyneuritic-Weakness in the both distal lower limbs
⚫ Mill’s Hemiplegicvariant-Weakness restricted toone half of
the body
⚫ Bulbar/pseudobulbar palsy
23. ⚫ 1-2% -Weakness of respiratorygroupof muscles
⚫ 10% - Bilateral upper limbweakness and wasting, flail arm of
flail person in barrel syndrome.
⚫ Head drop
⚫ Fasiculations-(Not the initial presenting symptom butalmost
seen in all patients at presentation)
⚫ Cramps-thighs,abdomen,back oreven tongue
⚫ Non motorsymptoms-Sleepdisturbance, Subtle cognitive
Dysfunctionand mood changes.
⚫Rarely involved: Bladder; bowels; Autonomic; Extraocular
movements; Sensory
24. ⚫ Morecommon in older females: 50% with bulbar
presentation
⚫ Bulbaronset in 20% to 30% of all ALS cases
⚫ Features
⚫ Dysarthria
⚫Speech rate: Slow
⚫Voice quality: Reduced
⚫ Dysphagia
•Coticobulbar tracts involvement
•Spasticdysarthria,dysphonia,dysphagia
•Emotional lability(forced crying or laughter)
•Brisk jaw jerk
•Hyperactivegag ref lex
26. ⚫Clinical examinationand electrophysiological
assesement.
⚫Differentiated from ALS mimickers-
⚫ Paraneoplastic
⚫ Hyperthyroidism
⚫ Parathormone dysfunction
⚫ Vit B12 Deficiency
⚫ HIV Infection(may presentwith 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 whitearrows) forming a 'wineglassappearance'.
29. ⚫ELECTROPHYSIOLOGY-
⚫ Nerve Conduction Study-Normal in ALS except for low
amplitudeof compound muscleaction potential(CMAP)
which is due to wasting of muscles being
recorded.Sensory nerve conduction is normal
⚫ Electromyogram- signsof denervation include
fibrillations, positivesharp
waves,fasciculations, neurogenic units, and a neurogenic
pattern of recruitment.
30. ⚫Transcranial Magneticstimulation –Measures the
central central motorconductionand so the upper
motor neuron involvementcould be documented
#’SPLIT HAND’ Phenomenon-In cases of Severechanges
in the thenar eminence and the relative sparing of
hypothenareminence ,observed on the EMG study
⚫MotorUnit Number Estimation-Quantitative
assesmentof progressive motoraxon loss.
31. Definite ALS
⚫ Clinical orelectrophysiologicevidence of LMN *** and UMN signs in the bulbarregion
AND
⚫ At least two spinal regions or the presenceof LMN and UMN signs in threespinal
regions
ProbableALS
⚫ Clinical orelectrophysiologicevidence by LMN and UMN signs in at least two regions
with some UMN signs necessarily rostral to (above) the LMN signs
PossibleALS
⚫ Clinical orelectrophysiologicsignsof UMN and LMN dysfunction are in onlyone
region,
OR
⚫ UMN signs alone in twoor more regions,
OR
⚫ LMN signs rostral to UMN signs
(ALS mimics should beexcluded by EMG, appropriate neuroimaging, and clinical
laboratorystudies)
*** EMG evidence fordenervation hasequal value toclinical 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. ⚫Nocure is presentlyavailable 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 twicea day, improves 1-yearsurvival byabout
15% and prolongs overall survival by 2 to 3 months
⚫Thecornerstones of symptomatic treatmentof ALS
include walking assists,management of respiratory
impairment, nutritional support, treatment of
sialorrhea,and palliativecare.
34. ⚫Early institution of noninvasive positive pressure
ventilation probably improves survival and slows the
rateof declineof 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 nervesand diaphragm
36. ⚫Presentation <25yrsof age
⚫Both LMN and UMN symptomsand sign
⚫Choreic movements,cerebellarataxiaand
mental retardation in the absence of
deafness
⚫Patientsdon’t have bulbar involvement till
late in thedisease
⚫Mutation in the ALSIN gene has been
recognised
38. ⚫Reported from South India.
⚫Casesare sporadic;Familial MMND appaers to be Aut.
Recessive
⚫Youngerage of onset(1st and 2nd decade)
⚫Wasting and weaknessof predominatelydistal musclesof
limbs
⚫Bulbardysfunction(IX & XII cranial nerve nuclei) and
facial muscle involvement
⚫Pyramidal dysfunction
⚫Sensorineural hearing loss
⚫Opticatrophy(if present,its named as Madras MND
variant)
39. ⚫ Majorityof patientswereadultsengaged in heavy manual work.
⚫ Strictly unilateral wasting of thewhole lower limb
⚫ The nerveconduction studies and the electromyographicpattern
suggested anterior horn cell disorder.
⚫ Neurogenicatrophy is seen in muscle biopsies
⚫ Suggested that possibly thesecases representan entity, clinically
differentfrom otheranterior 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. ⚫Hirayamadisease is also knownas juvenile muscular
atrophyof thedistal upperextremity
⚫Affects predominantly males in either their 2nd or
theirearly 3rd decadeof life
⚫Typical clinical features-Muscularweaknessand
atrophy in the hand and forearm
⚫Unilateral involvement in the majorityof patients, but
asymmetricand symmetric bilateral involvementare
alsoobserved .
⚫Since the brachioradialis muscle is spared, the pattern
of forearm involvement is also referred to as an oblique
amyotrophy.
41.
42. ⚫Primary Lateral sclerosis: adiagnosisof
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. ⚫Diagnosisof exclusion
⚫Account for 2-4% of ALS
⚫Absenceof LMN Invovement
⚫Presentation in early 50’s
⚫Slowlyevolving spastic paresis after involving upper
limbs.
⚫Median diseaseduration:19yrs
⚫Fasiculation,cramps,bladderdysfunction,cognitive
deficits & abnormal voluntaryeye movement
⚫Striking loss of Betz cells in layer 5 of frontal and
prefrontal cortex with laminargliosis 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 occurat anyage Forpatientswith uncomplicated
HSP, the life expectancy is typically unchanged.
45. ⚫Caused bya human T-cell leukemiavirus type I
(HTLV-I) aftera long incubation period.
⚫Characterized bya chronic progressive paraparesis
with sphincterdisturbances, 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. ⚫Variantof adrenoleukodystrophy, an X-linked
recessivedisorder (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 sphincterdysfunctions.
⚫88% presents with Addison’s disease
47. ⚫ Chronic neurogenicdisease –long term ingestion of chickpeas
(Lathyrus sativus) containing β-N-oxalylamino-L-
alanine(BOA), which isan glutamate receptoragonist.
⚫ Theonset isacute orchronic
⚫ Musclespasm and leg weakness
⚫ Spastic paraparesiswith orwithout some sensory and bladder
dysfunction.
⚫ Leg motor neurons in the motorcortex and thecorresponding
pyramidal tracts are predominatelyaffected.
⚫ Found in Bangladesh, China, Ethiopia, India, Romania, Spain
51. ⚫ Electromyography: loss of CMAP amplitude, diminished
conduction velocity, SNC studiesare normal in pure LMN
disorder.
⚫ Muscle biopsy: muscle fibers denervation could be seen early
than needle EMG examination
52. ⚫Acute poliomyelitis is prototypical disorderof 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 maycontinue over the
ensuing 18-24 months.
54. ⚫ Antecedentpoliomyelitis
⚫ Residual paralysis was generally absent or only
minimal.
⚫ Both polio-affected and unaffected siteof the limb
areequally 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 Definitecause 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 muscularatrophyare
used todescribe this intriguing entity.
⚫ Etiology is unknown.
⚫ Hirayama'sdisease: 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 toa 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 fingerextension; 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, theageof onset for
spinal muscularatrophies is as follows:
⚫SMA type I (acute infantileor 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 1stsymptom
⚫ Weakness
⚫ Proximal; Symmetric
⚫ Variabledegreesof severity
⚫ Some neverwalk
⚫Poorprognosis
⚫Scoliosis early
⚫ Lateronset: Betterprognosis
⚫ Progression
⚫ Most have lossof function overtime
⚫ ? Change in strength overtime
⚫Difficult to measure
⚫ Tremor
⚫ Tendon ref lexes: Reduced
61. ⚫Laboratory
⚫Serum CK: Normal
⚫Electrophysiology
⚫EMG: Fibrillations; Largeamplitude
action potentials
⚫NCS: Small amplitude CMAPs;
Mild slowing; Sensory normal
⚫Muscle biopsy
⚫Grouped atrophy
⚫Type I muscle fiber predominance
62. ⚫ Mostcommon adultonset SMA
⚫ BSMA: Long, 40-65 CAG repeats
⚫ CAG repeat length effects
⚫ Longer therepeats
⚫Earlierdiseaseonset
⚫? More severe SBMA disease
⚫Impaired spermatogenesis
⚫Noeffecton specificclinical features
⚫ Length inverselycorrelated with transcriptional activity
by theandrogen receptor
63. ⚫Age: Mean 27 years; Range 15 to 60 years
⚫Earlysymptoms & signs:Adolescence but
symptoms usually at 30 years
⚫Musclediscomfort: Crampsor Pain
⚫Fatigue: General; Chewing
⚫Gynecomastia: May be asymmetric
⚫Weakness: Not common early; May bedistal
⚫Lower > Upper limbweakness
64. ⚫Tremor: Hands; Postural & Action
⚫Tongue
Wasted; Weak; Moves rapidly
⚫NO upper motor neuron signs
⚫Androgen insensitivity related
⚫Gynecomastia (50% to 70%)
⚫Reduced fertility
⚫Testicularatrophy
⚫Groin hernia: 33%
Otherendocrine
⚫Diabetes mellitus in some patients
⚫Pituitary microadenoma: Rare
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 motoractivity
⚫Cramps: Common in legs, at night
⚫Fasciculations
⚫Noupper motor neuron signs
⚫Pain: Related to immobility
⚫Timecourse
⚫Progressive
⚫Similarto, more rapid, orslowerthan, 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 muscularatrophy
Notewasting, including
paraspinal muscles
