Motor neuron diseases


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Motor Neuron Diseases/Disorders-A Simple Understanding.

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Motor neuron diseases

  1. 1.  Upper motor neurons (UMN) are responsible forconveying impulses for voluntary motor activity UMN send fibers to the LMN, and that exert direct orindirect supranuclear control over the LMN. Lower motor neurons (LMN) directly innervate theskeletal muscle
  2. 2. Motor cortex: the UMNs are located in the primary motorcortex, 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 5and other smaller neurons initiate the contraction of the small groups of theskeletal muscles and control the force and contraction.
  3. 3.  Axons from the cortical areas form the corticospinal andcorticobulbar 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, and3), and adjacent temporal lobe region.
  4. 4. •The corticobulbar tract projects bilaterally to CNsV, VII, IX, X and XII.•The corticospinal tract decussates (75-90%) in thelower medulla and forms the lateral corticospinaltract. The remaining fibers form the ventralcorticospinal tract.•These corticospinal axons provide direct and strongglutamatergic excitatory input to alphamotorneurons.
  5. 5. •Basal ganglia and cerebellum-No direct input to the LMNs andthus 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 movementsbecause it receives input from the sensorimotor cortex and thespinal cord.
  6. 6. •Loss of dexterity•Stiffness, slowness, and clumsiness, in particular, rapidrepetitive motions.•Weakness is mild.•Spasticity is hallmark of the UMN disease•Pathological hyperreflexia.•Pseudobulbar palsy is hallmark of the UMNdisorder, which is characterized by sudden unmotivatedcrying or laughing
  7. 7.  The LMNs -Located in the brainstem and spinal cord The spinal LMNs are also known as anterior horn cell. Theneurons 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 (lowerthoracic) anterior horns innervate arm, hand, and leg muscles. Large spinal cord LMNs are called alpha neurons.
  8. 8. LOWER MOTOR NEURONSpinal 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 fromthe “Motor Neuron Disorders” which is used for aheterogenous group of disease or disorders of neurons ofvaried etiology having in common the involvement ofUpper AND/OR Lower motor neuron systems. The Motor Neuron Disorders includeinflammmatory/immune disorders ,sporadic/familialdisorders and disorders of undetermined cause. ALS or MND is ONE of the Motor neuron disorders
  11. 11. Motor NeuronDisordersUMNDisordersUMN & LMNDisordersLMNDisordersNeurodegenerativeDisorder(Primary lateralSclerosis)Toxins(Neurolathyrism)Infections(HIV-1/2 asso.Myelopathy)Amyotrophic LateralSclerosis• Sporadic ALS• Familial ALSNeurodegenerative(ProgMus Atrophy;Benign focalamyotrophy/brachialmonomelic amyotrophy)Infections(Polio;PostPolio;Subacute motorneuropathy oflymphoproliferative diseases)Inherited(SMA;Kennedydisease;Hexaminidasedeficiency)Post radiation
  12. 12. Theses share a molecular and cellular pathology alongwith 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 baseballplayer diagnosed of ALS in 1930. Degeneration of the motor neuron(UMN & LMN) in motorcortex,brainstem & spinal cord. Amyotrophy-Atrophy of muscle fibres consequent ofdenervation due to anterior horn cell degeneration Lateral sclerosis-Sclerosis of the anterior and lateralcorticospinal 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 likeChamorro people of Guam and Kii penninsula ofJapan.
  15. 15. • Cases from India with distinct features-Madras variant MND• Peak onset-sixth to seventh decade(oneto two decades earlier in India)• 20%- live for 5 &10%-Live for 10 yrs(Indian data suggests longer mediansurvival 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,immuneactivation & hormonal dysfunctions. Sporadic ALS with predominantly autosomal dominant inheritance Molecular pathway proposed are due to excitotoxicity,oxidativestress,mitochondrial dysfunction,impaired axonaltransport,neurafilament aggregation. Genetic susceptibility include APOE,SMN,peripherin,VEGF,paraoxonasegene alteration
  17. 17.  Western Pacific ALS(ALS parkinsonism dementia complex)-Exposure to toxin β-N-methylamino-l-alanine, which is present inseeds of theCycas circinalis in people of Chamorro natives ofGuam & Kii Peninsula of Japan. Familial ALS(FALS)-(Type 1-10)(Type 2 & 5 have AR,rest have ADinheritance)i)Cu/Zn superoxide dismutase 1 (SOD1) in 20% of FALScases(autosomal recessive inheritance)ii) Expansions of a GGGGCC hexanucleotide repeat in anoncoding region of chromosome 9 is present in 37% to 46% ofFALS and 6% to 20% of sporadic ALS of European descentiii)mutations in two RNA binding proteins, TAR DNA-bindingprotein-43 (TDP-43) and fused in sarcoma (FUS)
  18. 18.  2/3rd -Typical/Spinal form of ALS with focal motor weaknessof distal or proximal upper or lower limbs. Spread of weaknes tocontiguous muscles in the same region before another region isinvolved. Pseudoneuritic pattern-Involvement of muscles in theapparent 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 ofthe body Bulbar/pseudobulbar palsy
  19. 19.  1-2% -Weakness of respiratory group of muscles 10% - Bilateral upper limb weakness and wasting, flail arm offlail person in barrel syndrome. Head drop Fasiculations-(Not the initial presenting symptom but almostseen in all patients at presentation) Cramps-thighs,abdomen,back or even tongue Non motor symptoms-Sleep disturbance, Subtle cognitiveDysfunction and mood changes. Rarely involved: Bladder; bowels; Autonomic; Extraocularmovements; Sensory
  20. 20.  More common in older females: 50% with bulbarpresentation 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 alternatingmovements Spasticity, clasp knifephenomenon Hyperreflexia Pathologic reflexes, includingBabinski and Hoffmann Presence of reflexes inatrophic limbs Pseudobulbar palsy (labileaffect, spasticspeech, dysarthria,brisk jawjerk, and gag reflex)LMN Weakness Muscle atrophy Fasciculations Cramps Attenuated or absentreflexes Bulbar palsy)
  22. 22.  Clinical examination and electrophysiologicalassesement. 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 symmetricalhyperintensity along corticospinal tract (thinwhite arrows) forming a WINE GLASSAPPEARANCE‘ 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 lowamplitude of compound muscle action potential(CMAP)which is due to wasting of muscles beingrecorded.Sensory nerve conduction is normal Electromyogram- signs of denervation includefibrillations, positive sharpwaves,fasciculations, neurogenic units, and a neurogenicpattern of recruitment.
  26. 26.  Motor Unit Number Estimation-Quantitativeassesment of progressive motor axon loss. Transcranial Magnetic stimulation –Measures thecentral central motor conduction and so the uppermotor neuron involvement could be documented#’SPLIT HAND’ Phenomenon-In cases of Severe changesin the thenar eminence and the relative sparing ofhypothenar eminence ,observed on the EMG study
  27. 27. Definite ALS Clinical or electrophysiologic evidence of LMN *** and UMN signs in the bulbar regionAND At least two spinal regions or the presence of LMN and UMN signs in three spinalregionsProbable ALS Clinical or electrophysiologic evidence by LMN and UMN signs in at least two regionswith some UMN signs necessarily rostral to (above) the LMN signsPossible ALS Clinical or electrophysiologic signs of UMN and LMN dysfunction are in only oneregion,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 clinicallaboratory studies)*** EMG evidence for denervation has equal value to clinical LMN signs; when there isclinical suspicion for ALS, fasciculations have equivalent value to fibrillations andpositive waves in determining denervation
  28. 28. General: Hereditary vs Sporadic ALSFeatureHereditary ALSSporadicALSMales:Females 1:1 1.7:1Disease DurationBimodal< 2 & > 5yearsUnimodal3 to 4 yearsOnsetAge distribution More younger More olderMean age 46 years56 to 63yearsBulbar features 20% to 30% UnusualLegs Common Occasional
  29. 29.  No cure is presently available for ALS,so the goal oftherapy is improving the quality of life. Riluzole(blocks TTX-sensitive sodium channels) isthe only medication that has been shown to beeffective in ALS 50 mg twice a day, improves 1-year survival by about15% and prolongs overall survival by 2 to 3 months The cornerstones of symptomatic treatment of ALSinclude walking assists,management of respiratoryimpairment, nutritional support, treatment ofsialorrhea,and palliative care.
  30. 30.  Early institution of noninvasive positive pressureventilation probably improves survival and slows therate 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 patientswith ALS with moderately impaired respiratory functionand viable phrenic nerves and diaphragm
  31. 31.  Percutaneous endoscopic gastrostomy(before FVCdrops <50%) Stem cell transplantation Transplantation of precursor neural cells Antisense oligonucleotides and RNA interferencehave been proposed
  32. 32.  Presentation <25yrs of age Both LMN and UMN symptoms and sign Choreic movements,cerebellar ataxia andmental retardation in the absence ofdeafness Patients don’t have bulbar involvement tilllate in the disease Mutation in the ALSIN gene has beenrecognised
  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 oflimbs Bulbar dysfunction(IX & XII cranial nerve nuclei) andfacial muscle involvement Pyramidal dysfunction Sensorineural hearing loss Optic atrophy(if present,its named as Madras MNDvariant)
  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 patternsuggested anterior horn cell disorder. Neurogenic atrophy is seen in muscle biopsies Suggested that possibly these cases represent an entity, clinicallydifferent from other anterior horn cell disorders.(*Prabhakar S, Chopra JS, Banerjee AK, Rana PV. Wasted leg syndrome: a clinical, electrophysiologicaland histopathological study. Clin Neurol Neurosurg. 1981;83(1):19-28. PubMed PMID: 6273041.)
  36. 36.  Hirayama disease is also known as juvenile muscularatrophy of the distal upper extremity Affects predominantly males in either their 2nd ortheir early 3rd decade of life Typical clinical features-Muscular weakness andatrophy in the hand and forearm Unilateral involvement in the majority of patients, butasymmetric and symmetric bilateral involvement arealso observed . Since the brachioradialis muscle is spared, the patternof forearm involvement is also referred to as an obliqueamyotrophy.
  37. 37.  Primary Lateral sclerosis: a diagnosis ofexclusion Hereditary spastic paraplegia: AD disorder HTLV-1 associated myelopathy: X-linkedrecessive inheritance, increased serum of very-long-chain fatty acids Adrenomyeloneuropathy Lathyrism: history of consumption ofchickpeas
  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 upperlimbs. Median disease duration:19yrs Fasiculation,cramps,bladder dysfunction,cognitivedeficits & abnormal voluntary eye movement Striking loss of Betz cells in layer 5 of frontal andprefrontal cortex with laminar gliosis of layers 3 & 5 anddegeneration corticospinal tract
  39. 39.  Also called familial spastic paraparesis or Strumpell-Lorrain syndrome The common feature of this syndrome isprogressive, often severe, spasticity in the lowerextremities. Inheritance may be X-linked, autosomal recessive, orautosomal dominant (70-85%) May occur at any age For patients with uncomplicatedHSP, 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 paraparesiswith sphincter disturbances, no/mild sensoryloss,the absence of spinal cord compression andseropositivity for HTLV-I antibodies. Endemic in Caribbean, southern Japan, equatorialAfrica, South Africa, and parts Central and SouthAmerica
  41. 41.  Variant of adrenoleukodystrophy, an X-linkedrecessive 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 progressivespastic 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 bladderdysfunction. Leg motor neurons in the motor cortex and the correspondingpyramidal 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-asthmaticamyotrophy Spinal Muscular Atrophy Bulbo-Spinal Muscular Atrophy (BSMA; KennedysSyndrome; X-linked) Primary Muscular Atrophy (PMA)
  44. 44.  Electromyography: loss of CMAP amplitude, diminishedconduction velocity, SNC studies are normal in pure LMNdisorder. Muscle biopsy: muscle fibers denervation could be seen earlythan needle EMG examination
  45. 45.  Acute poliomyelitis is prototypical disorder of acuteLMN dysfunction. Caused by RNA poliovirus, genusEnterovirus, family Picornavirus. Small proportion -Either minor illness(gastroenteritis) or the major illness several daysafter the infection. Major illness resembles aseptic meningitis.Approximately 50% of patient progress to paralyticdisease within 2-5 days.
  46. 46.  Paralytic phase: localized fasciculations, severemyalgia, hyperesthesia, and usually fulminantfocal and asymmetrical paralysis. Leg muscle involvement is more frequent, thanarm, respiratory, and bulbar muscles. Recovery may begin during first week, but itestimated that 80% of recovery occurs in 6months. Further improvement may continue over theensuing 18-24 months.
  47. 47.  Antecedent poliomyelitis Residual paralysis was generally absent or onlyminimal. Both polio-affected and unaffected site of the limbare equally involved by PPMA Asymmetrical proximal muscular atrophy andflaccid motor paresis in one or two limbs withdecreased tendon reflexes. Fasciculation;myalgia, and hypesthesia No Definite cause has been determined
  48. 48.  Slowly progressive, asymmetrical muscle weaknessand atrophy Multifocal conduction block in motor nerveconduction studies Elevated titer GM1 antibodies May be mistaken with ALS, SMA, benign focalamyotrophy, progressive muscularatrophy, CIDP, GBS. Treatment: IVIG, and cyclophosphamide
  49. 49.  Monomelic amyotrophy, and juvenile muscular atrophy areused to describe this intriguing entity. Etiology is unknown. Hirayamas disease: Progressive weakness over 1 to 4years, then plateau OSullivan-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 innervatedmuscles; Hand & Forearm Proximal > Distal: 10% Side: Right = Left Atrophy: "Oblique amyotrophy"; Sparingbrachioradialis Tremor (80%): On finger extension; Irregular &Coarse (Minipolymyoclonus
  51. 51.  Werdnig and Hoffmann in1891 independentlydescribed SMN1 (Telomeric SMN(SMNT)) gene mutated in95% of SMA
  52. 52. According to the ISMAC system, the age of onset forspinal 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 between6 and 18 months. SMA type III (chronic juvenile): Onset is after 18months. 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 amplitudeaction potentialsNCS: Small amplitude CMAPs; Mildslowing; 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 activityby the androgen receptor
  56. 56.  Age: Mean 27 years; Range 15 to 60 years Early symptoms & signs:Adolescence butsymptoms 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 TongueWasted; 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 AtrophyGynecomastia
  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 syndromePathology Loss of motor neurons in anterior hornof spinal cord Shrinkage of remaining motor neurons Inclusion bodies:Intracytoplasmic, HyalinePrimary muscular atrophyNote wasting, includingparaspinal muscles
  61. 61. The Disease can Kill Your Body But Not YourImaginations……..