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Motor neuron disease
Motor neuron disease
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Motor neuron diseases

  1. 1.  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
  2. 2. 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.
  3. 3.  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.
  4. 4. •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.
  5. 5. •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.
  6. 6. •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
  7. 7.  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.
  8. 8. LOWER MOTOR NEURON Spinal cord ventral horn (Cervical spinal cord cross section)
  9. 9.  Weakness: Reduction in overall muscles strength.  Muscle atrophy and Hyporeflexia  Muscle hypotonicity and flaccidity  Fasciculations  Muscle cramps
  10. 10.  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
  11. 11. 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
  12. 12. 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
  13. 13.  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
  14. 14.  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.
  15. 15. • 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)
  16. 16.  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
  17. 17.  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)
  18. 18.  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
  19. 19.  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
  20. 20.  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
  21. 21. 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)
  22. 22.  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
  23. 23.  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’
  24. 24. Coronal T2WI showing bilateral symmetrical hyperintensity along corticospinal tract (thin white arrows) forming a 'wine glass appearance'.
  25. 25.  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.
  26. 26.  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
  27. 27. 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
  28. 28. 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
  29. 29.  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.
  30. 30.  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
  31. 31.  Percutaneous endoscopic gastrostomy(before FVC drops <50%)  Stem cell transplantation  Transplantation of precursor neural cells  Antisense oligonucleotides and RNA interference have been proposed
  32. 32.  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
  33. 33.  Madras variant of MND  Wasted Leg Syndrome  Monomelic Amyotophy  Hirayama Disease
  34. 34.  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)
  35. 35.  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.)
  36. 36.  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.
  37. 37.  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
  38. 38.  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
  39. 39.  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.
  40. 40.  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
  41. 41.  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
  42. 42.  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
  43. 43.  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)
  44. 44.  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
  45. 45.  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.
  46. 46.  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.
  47. 47.  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
  48. 48.  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
  49. 49.  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
  50. 50.  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
  51. 51.  Werdnig and Hoffmann in 1891 independently described  SMN1 (Telomeric SMN (SMNT)) gene mutated in 95% of SMA
  52. 52. 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).
  53. 53.  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
  54. 54.  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
  55. 55.  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
  56. 56.  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
  57. 57.  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
  58. 58. Bulbo-Spinal Muscular Atrophy Gynecomastia
  59. 59.  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
  60. 60. 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
  61. 61. The Disease can Kill Your Body But Not Your Imaginations……..

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