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SPORADIC ALS

Sporadic ALS: Common forms   Clinical features     Weakness     Upper motor neuron     Spontaneous activity     Behavioral     Prognosis     Treatment   Diagnostic criteria   Differential diagnosis   Discussion of diagnosis   Epidemiology     Clinical     Genetic   History   Laboratory features     Susceptibility loci   Pathology

ALS Variants   Hereditary ALS   Primary lateral sclerosis   Primary muscular atrophy   Pseudobulbar paralysis   Flail arm Multisystem disorders   ALS + PNL   + EOM & Extrapyramidal Δ   Fronto-Temporal Dementia   Multiple system atrophy   Polyglucosan body disease   Western Pacific ALS     ALS-PD1     ALS-PD2

MRI: FLAIR Motor Neuron Disease (Late) Cerebral Peduncles: Hyperintense

From NLM Jean Martin Charcot

Lou Gehrig & Babe Ruth

Sporadic ALS: Common forms

• ALS: Epidemiology ⁷
  • Frequency statistics
    • Incidence/100,000/year
      • Overall: 0.4 to 3; Male = 2.1; Female 1.8
      • 65 to 74 years: Male = 10.2; Female = 7.4
      • Increases in 1990's in: Females; Patients > 75 years; Southern Europe
    • Prevalence: 3 to 8 per 100,000
    • Risk
      • Increases with age: Up to 74 years
      • Less common > 80 years
      • Reduced with
        • High BMI
        • Increased exercise in Males ¹⁰⁴
      • Increased with
        • Metabolic syndrome with normal BMI: Hypertension; Triglycerides high ¹⁰⁵
    • Life-long risk of ALS (Living to 70 years)
      • General: 1:350 to 1:2000
      • Sex: Females 1:400-450; Males 1:300-350
    • Mortality
      • Causes 1 in 700 (350 to 1,000) deaths
      • Rate: 1.9/100,000/year
    • Geography: World-wide distribution
      • General frequency: Uniform
      • Exception: Variants on Guam (Chamorro) & Kii peninsula of Japan
  • Male:Female
    • Western countries 1.5:1
    • India 3:1
    • Younger onset patients: Male predominance
  • ALS: Familial
    • Frequency vs all ALS: 10% to 20% ³⁶
    • Genes mutated in some "sporadic" ALS patients (5% to 20%): c9orf72; TDP-43; SOD1
    • "Sporadic" patients with FALS mutations more likely to have FH of Dementia
  • Sporadic ALS: Heritability ⁵⁴
    • ALS concordance in monozygotic twins with no known ALS gene mutations ⁶⁷
      • Range 38% to 78%; Mean 60%
      • Affected twin, WBCs
        • Higher epigenetic age
        • More CpG methylation
          • Glutamate-induced neuronal excitation
          • GABA-mediated neuronal inhibition
    • ALS concordance in parent offspring trios: Range 40% to 60%; Mean 50%
    • ALS heritability in genome-wide complex trait analysis (GCTA): 10% to 23%; Mean 21%
  • ALS associations: Disease & History
    • Habitus
      • Lifelong slim: 2.2x higher
      • BMI higher: Decreased risk for ALS several decades later
      • Genetically predicted associations with lower ALS risk ⁸⁴
        • 1 SD increase in predicted body fat % in adult
        • 1 SD increase in predicted BMI in childhood
    • Exercise
      • Varsity athletics: 1.7x higher
      • Physical activity in leisure or occupation: 7% higher ⁷⁸ to 30% lower in men ¹⁰⁷
    • Military service (World War II): 1.26x to 2.03x ⁵⁸
    • Smoking ²¹
      • More with: Increased smoking
      • Current smoking in females: 1.7x higher
      • Less with increased time after quitting
    • Medical
      • Diabetes ⁵⁵
        • Type 2: 48% reduced risk, more with increased age at ALS diagnosis
        • Type 1: Risk factor
      • Drugs & Medicaions
        • Hormonal exposure: ALS reduced with ⁶⁸
          • Oral contraceptives (0.65)
          • Hormone replacement (0.57)
        • High carotenoid intake: 25% reduced ALS risk
        • Immunosuppressive drugs: 75% reduced ALS risk
        • Statin use: 55% reduced ALS risk
      • Trauma: Antecedent, Repeated, Severe ⁸⁵
        • Trauma definition
          • Severity: Injury requiring medical care
          • Time: > 3 to 5 years before symptom onset
        • 2x to 3x increased ALS risk
        • Head & Neck injuries
          • Mildly younger disease onset
          • Repetitive concussive head & cervical spinal trauma
          • Professional sports
      • Parents: Less frequent cardiovascular deaths ⁶³
      • Lovostatin treatment ⁹⁸
        • Humans: ALS risk lower (14%)
        • SOD1 mice: Longer survival
      • Hyperlipidemia ²⁵
        • Total cholesterol or LDL high: 2x more frequent in ALS than controls
        • Hypercholesterolemia: 25% reduced risk fo ALS
        • LDL/HDL ratio high: 12 month longer survival in ALS
      • Neoplasm ⁶¹
        • ? Lymphoma with M-protein or CSF protein elevated
        • Decreased risk: Lung cancer (HR 0.23); Any site (HR 0.80)
        • Increased risk: Salivary (HR 5.27); Testicular (HR 3.82)
  • ALS associations: Genes ¹⁰
    

    Transcriptome patterns: Cortex pathology 94 ALS-Ox: Oxidative & Proteotoxic stress; snRNP70 splicing change; Most common pattern ALS-Glia: Glial activation increased ALS-TE: Retrotransposon expression high; TDP-43 dysfunction Han Chinese: ALS 47 Onset age: Mean 49 years; 10 years younger than European population Onset region: Spinal (87%) more frequent than European population (70%) Susceptibiliy loci 1q32 (CAMK1G, rs6703183) OR 1.31 22p11 11 (CABIN1 & SUSD2, rs8141797) OR 1.52 No association with many European loci ITPR2; FLJ10986; DPP6; UNC13A; MOBKL2B FALS: PFN1 & c9orf72 rare; SOD1 reported FALS genes: Mutations & variants occurring in "sporadic" ALS 51 General Frequency: 28% Common: C9orf72 (9%); ATXN2 (3%); SETX (9%); DCTN1 (3%) Multiple mutations in one patient Frequency: 3.8% ALS onset age: 10 years earlier "Sporadic" patients with FALS mutations More likely to have FH of Dementia C9orf72 mutations Frequency in "sporadic" ALS Usual: 4% to 8% Range: 0% to 21% More common: Finnish & Western populations Family history: May include dementia without ALS Chromosomal rearangements 14 Frequency: 5.9% vs 0.05 to 0.1% in general population Types: Balanced translocations (3/85); Pericentric inversions (2/85) EAAT2 (glutamate transporter) : RNA processing errors APOE Plasma levels high Correlate with rapid deterioration & shorter survival time Relative risk = 0.647 APOE phenotype: No clear correlations Vascular endothelial growth factor (VEGF) 18 Low VEGF producing homozygous haplotypes 1.8-fold higher risk of ALS Haplotypes: -2578A/-1,154A/-634G; -2578A/-1,154G/-634G Associated with low circulating VEGF levels Association found for both sporadic & familial ALS Earlier death in SOD mutant mice with impaired VEGF expression Granulin precursor (Progranulin; PGRN; GRN) 31 ● Chromosome 17q21.31; Dominant with other CNS syndromes in family Allelic disorders ALS ALS-FTD Frontotemporal lobar degeneration with TDP43 & Ubiquitin inclusions : Dominant Genetics Inheritance: Dominant Mutations: Often produce haploinsufficiency 20% of FTD with TDP43 inclusions Aphasia, primary progressive : Dominant Ceroid lipofuscinosis, neuronal, 11 (CLN11) : Recessive ALS ALS mutations Types: Missense; 5' regulatory; DNA variants ALS clinical associations Mutations: IVS2 + 21G>A or IVS3-47-46insGTCA Younger ALS disease onset Shorter ALS survival FTD-ALS Epidemiology: > 40 patients Genetics Mutations: A9D & missense Mutation effect: Haploinsufficiency due to loss of GRN secretion Clinical Onset age: 48 to 67 years; Later than c9orf72 Amyotrophic lateral sclerosis, atypical: Some patients Motor Dystonia: Focal Extrapyramidal disorder, atypical: Dysarthria; Hypomimia Apraxia Frontotemporal dementia: Behavioral variant Aphasia EOM: Limited or Apraxic Laboratory NCV: Mild slow; CMAP amplitudes small EMG: Fibrillations; Fasciculations MRI: Subcortical atrophy Pathology Motor neuron loss: Upper & Lower Neuronal or Glial cytoplasmic inclusions TDP43 pathology GRN variant: Ceroid lipofuscinosis, neuronal, 11 (CLN11) Genetics: Recessive inheritance Clinical Retinal dystrophy: Visual loss Seizures Cerebellar ataxia Cognitive decline Course: Rapidly progressive Laboratory Brain MRI: Cerebellar atrophy SMN1 & SMN2 SMN1 & SMN2 Copy numbers 89 No differences: ALS vs controls No effect: ALS onset age or survival FIG4 32 ALS Mutations Heterozygous Missense or Termination Frequency: 1% to 2% of ALS patients ALS type Family history: Familial or Sporadic Clinical pattern: ALS or PLS; Brisk tendon reflexes Also see: CMT 4J SLC11A2 37 Genetics Chromosome locus: 12q13.12 Feature: rs407135 with C allele SLC11A2 protein Divalent metal transporter (DMT1) Carries iron, manganese, cobalt, nickel, cadmium, lead, copper & zinc Clinical correlation: Shorter sporadic ALS disease duration with leg onset Sequestome 1 (SQSTM1; p62) 43 ● Chromosome 5q35.3 Genetics: Allelic disorders ALS FTDALS3 Paget disease of bone 3 (PDB3) Some C-terminus mutations: (P392L & Other) Myopathy, Distal with Vacuoles, Digenic Childhood Neurodegeneration SQSTM1 protein Autophagy receptor Mediates protein-protein interactions by binding to phosphotyrosine Part of dynactin complex: Associated with retrograde axonal transport Ubiquitin binding protein: Coordinates ubiquitin-proteasome system Clinical: Associated syndromes ALS Genetics Inheritance: Usually Sporadic SQSTM1 Mutations Some mutations only in ALS or FTLD ALS: Ala53Thr; V259L; P348L; P438L; Pro439Leu FTLD: K344E; -1221 G>A Types: Most often Heterozygous Missense or Promoter Variants more in ALS or FTLD Present in 2% to 3% of familial & sporadic ALS Also occur in controls K238E; E274D; E319K Clinical Onset Age: 33 to 69 years Site: Bulbar or Limb Weakness: Bulbar & Limbs Tendon reflexes: Increased or Decreased Course: Progressive; 1 to 16 years EMG: Denervation, diffuse Frontotemporal Lobar Degeneration (FTDALS3; FTLD) : Behavioral variant Inheritance: Dominant Clinical Intrafamilial variation Behavior Aggressiveness Mood changes Social detachment Motor: Some patients Weakness Tendon reflexes: Increased or Decreased Paget disease Laboratory MRI: Frontotemporal atrophy CSF: Phosphoτ increased in one patient Speech apraxia Atypical behavior Visuo-constructional deficits SQSTM1/p62 variant: Myopathy, Distal + Vacuoles (DMRV; MSP4) 56 Nosology: Multisystem proteinopathy 4 Epidemiology: 24 patients; Male 75% SQSTM1 Genetics Inheritance: Sporadic, Dominant or Digenic 53 Mutations Common TIA1 mutation: Asn357Ser SQSTM1 (p62) mutation: Pro392Leu most common Splice site (c.1165+1 G>A;): May have additional TIA1 mutation 103 c.1175C>T Frameshift (c.542_549delACAGCCGC) Clinical Onset Age: 4th to 7th decade; Median 52 years Weakness: Distal legs Weakness: More in legs at onset than Welander Distal legs: Foot & toe dorsiflexion; Gait disorder Distal arms: Wrist & finger extensors Other: Pectorals; Scapular Asymmetric: Some patients Proximal predominant & neck weakness: Frameshift mutation Tendon reflexes: Reduced or Absent Sensory loss: Distal; Some patients Laboratory Serum CK: 100 to 500; High in 80% Muscle biopsy Fiber sizes Varied Groups of small fibers Internal nuclei Vacuoles: Rimmed Aggregates in fibers: SMI-31, TDP-43, LC3, SQSTM1 COX- fibers: Few; Scattered Ultrastructure: Myofibril disorganization & Aggregates Muscle MRI Lower extremity: distal > Proximal Thigh: Quadriceps femoris & Posterior compartment in the thighs Legs: Medial gastrocnemius ± Anterior tibial EMG: Myopathic Possible association: Sensory-Motor neuropathy SQSTM1/p62 variant: Childhood Neurodegeneration (NADGP) 62 Epidemiology: 7 families, 20 patients Genetics Inheritance: Recessive Mutations: Truncation SQSTM1 defect: Autophagy impaired Clinical Onset age: 6 to 15 years CNS Ataxia (100%): Gait disorder; Dysarthria Extrapyramidal (40%): Dystonia; Athetosis EOM: Vertical gaze palsy Cognitive (100%): Decline Pyramidal signs (10%) Hypogonadism, Hypergonadotropic Laboratory Muscle biopsy: Morphology: Unremarkable Complex IV activity: Mildly reduced Brain MRI Cerebellar atrophy: With disease progression Globus pallidus iron (10%) Epha4 45 Chromosome locus: 2q36.1 Epha4 expression levels: Lower in ALS patients correlate with Onset age: Later Survival length: Greater EPHA4: Loss-of-function mutations Associated with long survival in 2 ALS patients Mutations: C1540T, R514X Inhibition of Epha4 expression Rescues motor neuron disorders in animal models: SOD1; TDP43; SMN1 UNC13A 34 Genetics Chromosome locus: 19p13.3 Common intron 21 variant rs12608932 Polymorphisms: Variably associated with ALS susceptibility ALS & FTD-TDP susceptibility Shorter ALS survival Time: 1 year less rs4808092: G>A only in short survivors (4/25) Longer ALS survival rs10419420: G>A (3/25) Longer ALS survival with Lithium carbonate treatment 69 rs12608932 86 C allele Higher age symptom onset More bulbar onset C/C More ALS-FTD Lower forced vital capacity at diagnosis Shorter survival More upper motor neuron features: AA genotype Allelic disorder Congenital Myasthenia + Microcephaly & Cortical hyperexcitability UNC13A protein: Presynaptic Low density lipoprotein receptor-related protein 10 (LRP10) 87 China ALS c.1721G>A (p.R574Q) associated with Bulbar ALS onset Worse prognosis Pathogenic variants found in 2% of ALS Associated with: Alzheimer; Parkinson ZNF512B 46 Genetics: SNP rs2275294 C allele ALS Survival: Shorter TREM2 50 Genetics Chromosome locus: 6p21.1 ALS: Risk factor Modification: p.R47H (rs75932628) sALS allele frequency: 0.45 Control allele frequency: 0.19 R47H: Also Risk factor in Alzheimer disease Frontotemporaldementia Parkinson disease TREM2 Mutations Polycystic lipomembranous osteodysplasia +   Sclerosing leukoencephalopathy (PLOSL) TREM2 protein Simultaneous activation of TREM2/TYROBP Potentially neuroprotective microglial state Improved phagocytosis of apoptotic cellular debris Downregulation of inflammatory cytokines TREM2 expression in ALS Increased in spinal cord ALS survival: Negative correlation NIMA-related Kinase 1 (NEK1) 60 ● Chromosome 4q33; Dominant or Sporadic Epidemiology > 25 patients May be more common in China Genetics Mutations: Heterozygous Loss-of-function Missense (Arg261His common); Frameshift Allelic disorder Short-rib thoracic dysplasia 6 ± Polydactyly Inheritance: Probably Dominant Increased frequency of NEK1 mutations in sALS & fALS: ~3% Additional variants in other ALS-related genes (Up to 32%) ? Oligogenic disorder NEK1 protein functions Cilia formation DNA-damage response Microtubule stability Neuronal morphology Axon polarity Clinical: ALS 24 Onset age: 6th to 8th decade Weakness Bulbar: Common Respiratory Limbs: Upper > Lower Asymmetric Upper motor neuron Tendon reflexes: Brisk Bulbar dysfunction Cognitive: Normal Course: Progressive; Death in 2 to 5 years CX3CR1 65 Genetics: V249I & T280M polymorphisms Protein Microglia-specific Involved in: Microglia-neuron crosstalk; Neuroinflammation Clinical Disease course Shorter: V249I VV & T280M MM genotypes No increased risk of ALS or change in onset age V249I Variant Neurofibrillary pathology progression in late-onset Alzheimer's disease c21orf2 70 Genetics Non-synonymous & Loss-of-function mutations Allelic disorders Retinal dystrophy with macular staphyloma Spondylometaphyseal dysplasia, axial (SMDAX) c21orf2 protein Basal body & Cilia ALS relation Increased risk: 6x more frequent in ALS than controls DNAJC7 82 Genetics Mutation types: Protein-truncating variants Mutation frequency: 0.16% pf ALS patients DNAJC7 protein Molecular chaperone DNAJ heat shock protein family ALS relation Increased risk: Mutations more frequent in ALS than controls Sporadic ALS in Japan Mutation frequency: 0.87% Mutation type: Missense Mutation location: Near TRP domain

    ALS: Possible Susceptibility & Modifier Genes 26 Gene Locus Variant ACSL5 -   ZDHHC6 88 14q11.2 Mutations ALKBH3 106 11p11.2 Polymorphism Protective APEX1 10q25.2 Mutations ApoE ε4 19q13 ε4 genotype Ataxin-1 6p22.3 PolyQ expansions   Mild: ≥ 32 Ataxin-2 12q24.1 PolyQ expansions   Mild: 27–33 Reduced survival Ataxin-7 3p14.1 PolyQ expansion     ALS patient ATXN8OS 13q21 Non-coding expansion     Japanese ALS c9orf72 9p21 Mutations → ALS Repeat length = 2   Longer survival c21orf2 21q22 ALS risk CACNA1A 19p13.2 CAG repeat   Few patients CAMLG 99 5q31 ALS risk CAMTA1 1p36 Reduced survival CHRNA3 CHRNA4 CHRNB4 15q25, 20q13, 15q24 Mutations 33 CNBP 3q21 CCTG repeat CNTF 11q12 Null allele CTIF 18q21 Onset age 100 CX3CR1 3p22.2 Polymorphism DHTKD1 10p14 Mutations DMPK 19q13 CTG repeat in 3' UTR DNAJC7 17q21 Mutations DPP6 7 Linkage Dynactin 2p13 Mutations EAAT2 11p13 Low expression ELP3 8p21 Polymorphism ERBB4 2q34 Insertion EPHA4 2q36.1 Disease modifier FGGY 1q32 Linkage FIG4 6q21 Mutations FMR1 Xq27 CCG repeat in promoter FXN 9q21 GAA repeats in intron GluR2 4q32 RNA editing Δ HTT 4p16 CAG repeat IL18RAP 95 2q12 3'UTR Δ; Protective ITPR2 12p11 Linkage KANK1 9p24 Mutations KIF1A 2q37 Variants LRP10 14q11 Mutation   Risk LRP12 8q22 CGG repeat MTHFR 1p36.22 Polymorphism   Female risk ↑ NEFH 22q12 KSP deletions NEK1 4q33 Loss of function   Haploinsufficiency NIPA1 15q11 GCG repeat; Copy number NOP56 20p13 GGCCTG expansion NOTCH2NLC 1q21 CGG, GGC expansions NUP50 97 22q13 Variants; ALS risk PON1 PON2 PON3 7q21.3 Linkage Progranulin 17q21.3 Mutations RFC1 4p14 Expansions SARM1 17q11 Gain function Polymorphisms SCFD1 14q12 Risk factor SLC11A2 12q13 rs407135: C allele Faster progression SMN1 5q12 Copy number SMN2 5q12 Copy number SQSTM1 (p62) 5q35 Mutations STMN2 8q21 CA repeat expansion TBP 6q27 CAG/CAA repeat expansion Titin 2q31.2 Reduced levels Rapid progression TREM2 6p21.1 R47H UNC13A 19p13.3 Intron 21 link 34 Reduced survival VEGF 6p12 Promoter SNPs VCP 9p13 Inversion ZNF512B 20q13.33 Mutation:   Reduced expression

• ALS: Clinical features
  

  Behavior Dx criteria Onset Patterns Spontaneous activity Survival Upper motor neuron Weakness   ALS specificty   Bulbar   Course   Respiratory

  • Onset age
    • Mean: 46 to 63 years
      • US & Europe: 56 to 63 years
      • India: 46 years
    • Before 20 years: Rare patients
      • Male predominance
      • Spinal onset more common
      • Sporadic gene mutations common
    • Genetics
      • MAO-B5 allele ²: Higher (60 years) with allele; Lower (52 years) with others
      • Homozygous CNTF gene defect ⁸
        • Present in 2% of normals
        • Earlier onset of sporadic & SOD ALS: 48 vs 58 years; Normal disease duration
        • Associated with loss of 15% to 20% of neurons in postnatal mice
      • Associated with variants in SMN2 gene number
      • SOD1: 50 bp deletion in promoter region ³⁰
        • ALS onset age: Increased
        • SOD1 activity: Reduced
        • SP1 binding: Reduced
  • Typical clinical pattern: Upper + Lower motor neuron signs with normal sensation
    • Male > Female
    • More common in younger ALS patients
    • Course: General patterns of decline ⁵⁹
      • Rapid: Associated with reduced Titin expression (OR = 5.5)
      • Intermediate
      • Moderate
      • Sigmoidal
      • Slow: Survival > 5 years
    • Survival: Intermediate
      • Median: 32 months (23 to 48 months)
      • 5 years: 20%
      • 10 years: 5% to 10%
      • Shorter: Bulbar onset
      • Longer: Earlier onset age; ALS family history; PLS presentation; Supportive care
  • Weakness
    • Patterns of weakness & dysfunction: Common features ⁴⁰
      • Limb weakness
        • Early patterns
          • Asymmetric
          • May involve proximal or distal musculature
        • Specific patterns
          • Upper > Lower extremity (Flail arm)
            • Higher frequency in patients of African descent
            • Male > Female
            • More common in younger patients
            • Distributions of weakness
              • Flail arm
              • Weak shoulder & 1st dorsal interosseus with Arm (Biceps & Triceps) sparing ⁹³
            • Longer survival
          • Distal lower extremity (Flail leg)
            • More common at disease onset in hereditary ALS
            • Male = Female
          • Pure lower motor neuron (PMA)
            • Male > Female
            • Onset age: Younger
            • No associated dementia
            • Longer survival
          • Split hand atrophy
            • Definition: More atrophy of lateral hand than medial hand
            • Muscles
              • More involved: Abductor pollicis brevis (APB); 1st dorsal interosseous (FDI)
              • Less involved: Abductor digiti minimi (ADM)
            • May be defined by: CMP differences; Ultrasound echo intensity ⁷³
      • Bulbar dysfunction ²⁸
        

        From Bramwell:  Atlas of Clinical Medicine ALS with Bulbar involvement

        • Usual pattern: Upper > Lower motor neuron involvement
        • Associations
          • Females
          • Older age
          • Other upper motor neuron dysfunction
          • Shorter survival
          • ALS in older females: 50% with bulbar presentation
          • Bulbar signs at ALS onset
            • 20% to 30% of all sporadic ALS cases
            • More common with
              • Older females
              • ALS-FTD1 (C9orf72) mutations
            • Also see: Selective bulbar UMN dysfunction
        • Features
          • Dysarthria
            • Speech rate: Slow
            • Speech pattern
              • Slurred
              • Short phrases
              • Inappropriate pauses
            • Voice quality
              • Reduced
              • Hypernasality
              • Reduced range of pitch & loudness
          • Dysphagia
            • Aspiration
              • Fall in O₂ saturation, or
              • Increased respiratory rate after oral intake
            • Food types: Dry, Tough-textured or Crumbly; Thin liquids
            • Eating time: Increased
            • Saliva: Poor swallowing; Droolong
          • Emotional lability
            • "Pseudobulbar" affect ⁴⁴
              • Excessive laughing or crying in response to stimuli
              • Laugh or cry usually appropriate to stimulus
              • Inability to suppress laugh or cry response
            • Bulbar onset or involvement: 95% association
            • Anatomy: ? Related to dorsolateral prefrontal disease
            • Treatment
          • Other bulbar features

            Tongue in ALS: Weak with little wasting At rest & Attempted protrusion

            • Difficulty with voluntary coughing
            • Laryngospasm (20%)
            • Difficulty using external respiratory support
          • Jaw
            • Reflex: Brisk
            • Difficulty closing
          • Tongue
            • Movements: Slow
            • Bulk: Often relatively preserved for degree of dysfunction
      • ALS: Respiratory failure ⁹¹
        • May occur in isolation: Male > Female
        • Symptoms
          • Dyspnea: With mild exertion
          • Sleep: Nightmares; Frequent awakening
          • Daytime: Sleepy; Fatigue; Morning headache
          • Behavior: Depression; Hallucinations; Poor concentration
          • GI: Poor appetite; Taste sense loss; Dry mouth
        • Signs
          • Tachypnea
          • Orthopnoea
          • Auxiliary respiratory muscles: Activation
          • Abdomen: Paradoxical movement
          • Chest wall movement: reduced
          • Cough: Ineffective; Weak expiratory muscles
          • Oral: Difficulty clearing secretions
          • Respiratory infections: Frequent
          • Sweating
          • Weight loss
          • Voice volume: Reduced
          • Sighs or Deep breathing: At rest
        • Associations
          • Weight loss
          • Arm weakness
          • Shorter survival
        • Early stages
          • Often asymptomatic
          • Hypoventilation
          • Occurs first in REM sleep
          • Accessory muscles of respiration become flaccid
        • Treatment: External respiratory support (NIV)
          • Indications for initial discussion
            • Vital capacity
              • < 60% of Predicted value
              • < 80% of Predicted value + Symptoms or signs of respiratory impairment, especially orthopnea
            • Sniff nasal inspiratory pressure (SNIP) or Maximal inspiratory pressure (MIP)
              • < 40 cmH₂O
              • < 65 cmH₂O for men or < 55 cmH₂O for women + Symptoms or Signs
              • Rate of decrease of SNIP or MIP >10 cmH₂O over 3 months
          • Less effective: Bulbar onset diesase ⁹²
          • Other necessary aspects
            • Caregiver support
            • Patient education
            • NIV mask fit & acceptance
            • Sialorrhea control
          • Patient Utilization of NIV
            • 33% Decline treatment
            • Adherence: 50% to 60%
            • NIV duration: Often > 9 hours/day; Longer with ALS disease progression
      • Areas of weakness with some specificity for ALS
        • Very proximal denervation
          • Paraspinous
          • Posterior neck
        • Jaw weakness: Closure; Opening
        • Voice
          • Nasal, slurred speech
          • Continuous emission of sound
        • Tongue
          • Weak
          • Movement
            • Slow
            • Reduced amplitude
          • Relatively preserved bulk: Often
          • Associated signs
            • Movement of jaw with tongue
            • Jaw reflex: Hyperactive
        • Isolated respiratory failure
    • Muscle wasting
      • Often present early in disease course
      • Usually associated with Weakness

        Wasting of hands & arms in ALS

    • Progression: Regional (Arms, Legs or Bulbar)
      • Symptoms usually progress first in already affected region
      • Continuous progression once region (bulbar,arms, or legs) involved
      • Other regions involved later
        • Spread usually to adjacent region
        • No predictor of time of involvement
      • Periods of symptomatic stabilization may occur
      • Remissions in symptoms or signs rare
  • Spontaneous motor activity
    • Cramps ⁵⁷
      • Frequency in ALS: Up to 95% of patients
      • Locations: Legs (Calf & Thigh) > Hands & Feet
      • Temporal
        • Few to 100 per month
        • Variable frequency over days & months
        • At night: May interrupt sleep
      • Other associations
        • Discomfort or Pain: Some patients
        • Often resolve, or reduce in frequency, spontaneously with disease progression
        • May be severe: Later in disease: Associated with prominent spasticity
        • More frequent: Disease onset > 60 years; Limb-onset disease; ? Early in disease course
        • No relation to disease severity
      • Treatment
    • Fasciculations
      • Locations: Proximal & Distal muscles; Arms & Legs
      • ALS rarely presents with fasciculations in the absence of weakness
      • Pathogenesis ⁴¹
        • Reduced K⁺ currents in axons
        • K⁺ channels (K_v1.2) reduced in ventral roots
  • Upper motor neuron
    • Anatomic patterns
      • Bulbar
        • Causes most tongue & bulbar dysfunction
        • Tongue: Slow movement
        • Jaw jerk: Increased
        • Dysarthria & Dysphagia
        • At disease onset: More common in
          • Older females
          • ALS-FTD1 (C9orf72) mutations
      • Paraparesis
      • Asymmetry: Common in limbs, especially early in disease
      • Cortical hemiparetic: Occasional
    • Tendon reflexes
      • Hyperactive (100%): In areas with normal strength and weakness
      • More common sign than upgoing toes (30% to 50%)
    • Plantar reflex: Less often extensor than with other causers of spasticity
    • Bulbar involvement: Associated with emotional lability (75%)
    • May cause disability without associated weakness: Especially in legs
    • Laboratory correlates: Abnormal ²⁰
      • MR spectroscopy
      • Transcranial magnetic stimulation
    • Some patients have relatively selective upper motor neuron involvement
      • Onset: Younger
      • Survival: Longer
  • Pain: Related to immobility
  • Behavioral
    • Cognitive
      • Frontal lobe dysfunction (mild); 20%
      • Dementia ⁶⁶
        • Fronto-temporal; 3% to 15%
        • ALS in FTD: Poor prognosis; Median survival < 1.5 years
        • May precede or follow diagnosis of ALS
          • 5% of FTD patients develop ALS: More common with
            • Progressive non-fluent aphasia
            • Mixed behavioral FTD variant
            • ALS onset
              • Time: Within 1st 5 years of FTD, especially 1st year
              • Region: Especially bulbar
            • Rule out: c9orf72 mutation
      • Rule out: ALS-FTD
    • Pseudobulbar affect
      • Unprovoked laughing & crying
      • Common with bulbar involvement
    • Neuropsychiatric
    • Cortical atrophy
      • Associated with presence of neuropsychiatric & cognitive features
  • Rarely involved: Bladder; Bowels; Autonomic; Extraocular movements; Sensory
  • Skin ¹⁰¹
    • Collagen IV immunoreactivity: Reduced
    • Meissner corpuscles: Reduced; Inverse correlation with serum NfL levels
    • Intra-epidermal axons: Reduced; Then increase with disease course
  • Survival ²⁹
    • Mean
      • Overall survival: 3 to 4 years
      • Survival after diagnosis: ~2 years
      • Time from initial symptom to diagnosis: ~1 year
    • Longer survival ¹⁷
      • Frequency (> 10 years): 4% to 10%
      • Features at onset
        • More frequent than general ALS population
          • Younger age: Mean 43 years; 14 years younger than average
          • Pure upper motor neuron signs
        • No difference from general ALS population: Sex; Site of onset
        • Both UMN & LMN signs at onset: 70%
      • PLS: Longer survival
      • Younger onset: Longer survival
      • Indian ²⁷ & African patients: Longer survival; Mean 115 months
      • Drugs: Calcium intake
    • Poorer prognosis for survival
      • Clinical
        • Rapid rate of functional decline ⁹
        • Age: Increasing
        • Weight loss: Prominent recent
        • BMI : Low
        • Onset to diagnosis: Short time
        • Respiratory failure
        • No gastrostomy: Varied evidence
        • Depression
        • Drugs: Aspirin; Acetaminophen
      • Laboratory
        • Pulmonary function: Poor; < 60% of predicted
        • Serum
          • Chloride: Low; ? Relation to poor nutrition
          • Bicarbonate: High
          • Creatine: Low
          • CK decline: More rapid
          • Alkaline phosphatase: Increasing
          • Albumin: Decreasing
        • EMG
          • Low CMAPs
          • Decrement on RNS
          • SFEMG: Marked jitter; Low fiber density
        • Sensory cortex hyperexcitability: Survival reduced by 50% ⁷¹
        • ? Homozygous deletion of SMN2 gene ⁵
          • More common in sporadic ALS
          • Survival time: 2 years shorter
          • Effect not replicated in other reports
        • Disease progression more rapid
          • Titin expression, Reduced
          • COL19A1 expression in muscle: Increased ⁷⁹
    • Death
      
      • Cause of death: Respiratory failure most common
      • Respiratory failure with reduced consciousness: 2° to hypercapnea
      • Death: Usually peaceful & occurs in sleep
      • Choking unusual
• Diagnostic criteria (by clinical exam, EMG and pathology)
  • Definite ALS: Progressive disease with
    • Upper & lower motor neuron signs in bulbar & 2 spinal regions, or
    • Upper & lower motor neuron signs in 3 spinal regions
  • Probable ALS: Progressive disease with
    • Upper & lower motor neuron signs in 2 regions and
    • Upper motor neuron signs in a region rostral to the lower motor neuron signs
• Variant syndromes
  • Primary muscular atrophy (PMA): Lower motor neuron signs only
  • Primary lateral sclerosis (PLS): Upper motor neuron signs only
  • ALS-FTD
• Possible differential diagnoses
  • Spondylitic myelopathy or radiculopathy
  • Motor neuron disease variant with only lower or upper motor neuron signs
    • Primary lateral sclerosis (upper motor neuron only)
      • ? Rare association with breast cancer
    • Lower motor neuron disorders, motor neuropathies & motor syndromes
    • Localized pseudobulbar palsy: Older females
  • Polymyositis
  • Benign fasciculations
  • Multiple sclerosis
  • Cerebrovascular disease
    
• Laboratory features
  

  NCV Motor: CMAP amplitudes progressively reduced SNAPs: Relatively preserved; Slow NCV in 12% to 25% EMG: Denervation Spontaneous activity Fibrillations Positive sharp waves Fasciculations 35 Lower motor neuron disorder associated with Fasciculation firing rate: Increased Double fasciculations: More common Complex & Unstable fasciculations Occur in both ALS & Benign syndromes ALS: Shorter duration & More turns than benign syndromes Motor unit size: Normal or Large Distribution Proximal & Distal In several body regions Specificity for ALS higher: Denervation in ≥ 3 regions "Split hand" Lateral hand (Median & Ulnar innervation) Weaker & more Denervated vs Medial hand Thoracic paraspinous denervation Some specificity for motor neuron diseases May also occur in motor neuropathies Repetitive Nerve Stimulation (RNS): Decrement at 3 Hz 64 Decrement magnitude: > 5% Frequency of abnormal RNA decrement in ALS General Varies according to disease pattern & muscle tested 5% decrement: 30% to 100% 10% Decrement: 24% to 60% Muscles (5% decrement): APB 32%; Trapezius 51%; Deltoid 75% More frequent: With ALS onset in region tested Specificity for ALS vs Cervical spondylosis: Highest in trapezius Presence of decrement suggests: Lower motor neuron involvement in ALS Serum CK: Normal to 8x elevated Neurofilament light chain, serum 102 High in most ALS patients Highest: Bulbar ALS Lowest: PLS High levels correlate with Rapid disease progression Shorter survival May be high up to 2 years before diagnosis No change in levels during disease course Angiogenin: Mean level 20% elevated, especially spinal ALS 23 VEGF: Normal Lipids: Cholesterol, LDL & Triglycerides mildly reduced with FVC < 70% Antibody: High mobility group box 1 (HMGB1) 48 Titers: 2.45x higher than healthy controls Higher titers in severely affected patients (Low ALS-FRS-R scores) Plasma pro-hepcidin expression: High in ALS with bulbar onset Iron metabolism Plasma L-ferritin: High Plasma transferrin: Low ALS CSF General testing: Usually normal Cystatin C & Native Transthyretin: Low CRP & Post-translationally modified Transthyretin: High Neurofilament Heavy Chain levels (NFH) 80 ALS NFH levels commonly high, even early in disease course Higher NFH levels More LMN & UMN involvement More rapid disease progression Disease course Stable during most of ALS progression SOD1 ALS: May slowly increase Before disease onset With disease progression ALS with Upper motor neuron features: Higher than PLS, or HSP c9orf72 ALS: May have higher pNFH levels Other disorders: CSF NFH may also be high in Parkinson disease Dementias Multiple sclerosis: Patients with more disability CNS inflammatory disorders Spinal cord ionjury MRI & Brain Imaging MRI: General patterns 96 Motor, Pure Males = 73% Median onset: 56 years Bulbar onset = 13% Upper motor neuron: More severre Orbitofrontal & Temporal Males = 56% Median onset: 62 years Bulbar onset = 30% ALS-FTD: Cognitive impairment Other Regions Posterior cingulate cortex Parietal white matter Temporal operculum, Cerebellum Median onset = 62 years Cognitive impairment bulbar onset = 31% c9orf72 mutations present in all 3 subgroups Cortex changes Reduced T2 signal intensity in motor (1° & 2°) cortex Not specific for ALS Reduced N-acetylaspartate by MRI May correlate with spasticity: Reduced finger tap rate C9orf72-negative ALS Anterior cingulate & temporal cortex relatively spared Subcortical white matter abnormalities Corticospinal tract regions: Increased T2 Signal; Especially rostral Probably 2° to axon loss Corpus callosum No strong relation to clinical upper motor neuron involvement ? Relation to mirror movements C9orf72-negative ALS Prominent locations: Corticospinal, Corpus callosum, Cerebellar Limited extramotor involvement

  ALS: Anterior horn Oppenheim 1894

  Pathology Anterior horn cells Shrinkage & Loss of cell bodies Course of cell body loss 22 Early: Rapid Late: Slower ? Associated with Apoptosis Sparing: Nucleus of Onufrowicz, or Onuf Parasympathetic neurons in the sacral spinal cord Innervation of bowel & bladder Aggregates in ALS spinal motor neurons 52, 102 SOD1 containing SOD1 ALS: Hyaline conglomerate inclusions Misfolded (normal) SOD1: May aggregate in sALS FUS & TDP-43 containing Sporadic ALS Hereditary ALS: Except SOD1 ALS Ubiquitin: All ALS; Often also contain TDP-43 Spheroids (Neurofilaments): In proximal axons Bunina bodies 49 Histochemistry: Round, Eosinophilic, 1–5 μm in diameter Ultrastructure Homogeneous Electron-dense Granular matrix Surrounded by: Vesicular & Tubular structures Components: Cystatin C, Transferrin, Peripherin More common in neurons with TDP-43 inclusions Location: Brainstem & spinal motor neurons in ALS Location, subcellular: Neuron cell body cytoplasm Hirano bodies Rod shaped inclusions with ubiquitinated parallel filaments Most prominent in lower motor neurons TDP-43 aggregates Component of ubiquitinated inclusions in ALS & FTLD-TDP Inclusions Filamentous (Skein-like) Neuronal: Compact, Round Cytoplasmic Sporadic ALS: TDP-43 neuronal cytoplasmic inclusions (NCIs) TDP-43 aggregates: Insoluble Relatively confined to upper & lower motor neuron systems Widely distributed through CNS, including non-motor systems ALS-TDP pathology spread May propagate Through corticofugal axonal pathways Cell-cell transmission TDP-43: May be relased by damaged cells Via CSF: Extracellular TDP-43 seeds Toxic TDP-43 Possibly misfolded, insoluble protein Pallido-Nigro-Luysian (PNL) system 83 PNL areas Globus pallidus Substantia nigra Subthalamic nucleus Frequency of selective involvement in ALS: 5% to 11% Most ALS: No TDP43 lesions in PNL Locked in state: May have extesive PNL lesions ALS + Selective PNL lesions (Subthalamic nucleus) Younger onset Extrapyramidal signs Motor: Lower motor neuron predominant course: Slower progression Hereditary ALS: All except ALS1 ± ALS6 RANT Dipeptides From: GGGGCC repeats in c9orf72 Present in: ALS1; c9orf72 p62: c9orf72; All sporadic & hereditary ALS Ubiquilin-2: All sporadic & hereditary ALS Other proteins in aggregates in neurons & axons Optineurin Neurofilament subunits p38MAPK Galectin-1 Smad2/3 RBM4514 p54nrb/NONO γ-Synuclein Autophagy: Autophagosomes & Autolysosomes in motor neuron cell bodies 38 Other spinal cord Pathology Corticospinal tracts: Loss of myelinated axons Posterior columns: Spared except in familial ALS Astroglial proliferation Inflammation: Little or None Inclusions: Ubiquitin & TDP-43 positive 24 Present in cytoplasm of neurons & glia of sporadic ALS Filamentous or round Also found in: ALS with dementia; non-SOD1 FALS Not present in SOD1 FALS Spinal cord biochemistry 12 Increased levels of Ceramide C16:0, ceramide C24:0, & sphingomyelin Cholesterol esters C16:0 & C18:0 Similar changes: Presymptomatic SOD/ALS mice; Oxidative stress Other CNS Brainstem: Loss of motor neurons: Sparing of extraocular nuclei Precentral cortex: Loss of Betz & other pyramidal cells Sural nerve 39 Axons: Normal or Mildly reduced number Vessels, Epineurial: Some patients with perivascular inflammation Muscle Grouped, angular, atrophic muscle fibers: Many small regions Atrophic muscle fibers in individual groups: Often varied types Little type grouping: Except in chronic, slowly progressive cases Largest fibers: Mildly hypertrophic miRNA: miR-4429 & miR-1825 increased, or miR-638 decreased 90

  ALS: Spinal Cord Oppenheim 1894

• Treatment
  • Symptomatic
    • Respiratory failure ¹⁶
      • Nasal-Facial (Non-invasive) ventilation
        • Initially nocturnal
        • Starting criteria
          • Related symptoms
            • Respiratory: Dyspnea; Tachypnea; Orthopnea; Auxiliary respiratory muscle use at rest; Paradoxical respiration
            • Sleep-related: Nocturnal desaturation/arousals; Morning headache; Daytime Fatigue or Sleepiness
          • Measurements
            • Sleep oximetry: O₂ saturation < 88%, For five continuous minutes
            • Vital capacity (Sitting ot Supine) ≤ 50% to 80%
            • Sniff nasal pressure < 40 cmH₂O
            • PI max < 60 mmH₂O
            • Nocturnal desaturation overnight
            • Morning blood gas pCO₂ > 45 mmHg
        • End point
          • Oximetry without supplemental oxygen 95% or greater
        • Benefits
          • May improve: Survival (20% to 30% longer; Mean 11 months) & Quality of life
          • Less effective: With bulbar symptoms
          • Longer survival: Slow ALS progression; Better PFTs (> 30%); No bulbar features
        • Prognosis: Majority ALS patients who start NPPV do not decide to go on to tracheostomy
      • Tracheostomy
        • Less commonly chosen after longer non-invasive ventilatory support
        • Elective types
          • Percutaneous dilatational tracheostomy
          • Open surgical
      • Safety
        • Training & drills for all caregivers
        • Resuscitation bag for back-up. People
        • Second ventilator system: For patients who require 20- to 24-h ventilation
      • Avoid
        • Supplemental oxygen
        • Continuous positive airway pressure: Increases burden on weak inspiratory muscles;
      • Cough: Mechanical assistance
      • Reduction of dyspnea anxiety: Lorazepam, sublingual 0.5 to 1 mg
      • Treatment of terminal dyspnea
        • Morphine 2.5 to 5 mg q4h
        • Associated anxiety: Lorazepam 1 to 2.5 mg; Midazolam 1 to 2 mg
    • Bulbar dysfunction: Gastrostomy ⁷⁶
      • Before gastrostomy: Change diet to easily chewed, high caloric foods
      • Decision for gastrostomy: Based on clinical, not radiological, assessment
      • Gastrostomy methods: Similar complication rates
        • Radiographically-introduced gastrostomy (RIG) tubes: Most often recommended ⁷⁴
          • Smaller
          • Requires less anesthesia to place
        • Percutaneous endoscopic gastrostomy (PEG) tubes
      • Gastrostomy benefits
        • Better quality of life
        • Most effective & safe: Performed before significant weight loss or respiratory compromise
        • May improve survival: Varied results in different studies at different times
      • Gastrostomy risks
        • Discomfort
        • Wound issues
        • Aspiration with over feeding
        • May require intubation or NPPV in patients with vital capacity < 50%
    • Slower decline in early ALS stages: Edaravone (Radacava; 3-methyl-1-phenyl-2-pyrazolin-5-one) ⁷²
      • Mechanisms & Properties
        • Neutralizes free oxygen species by adding spare electron
        • Lipophilic
        • Serum half-life 4 to 6 hours
      • Drug regimen
        • Initial: Daily for 14 days; 1st cycles in hospital settings
        • Follow-up: Daily for 10 of 1st 14 days each month
      • Effects
        • Beneficial in early stages of ALS
          • Disease duration: < 24 months
          • Forced vital capacity: ≥ 80%
          • ≥ 2 points on ALSFRS-R
            • Bulbar: Mild
            • Self-feed, &-dressing
            • Walk without assistance
            • No need for gastrostomy or ventilation support
        • Benefit
          • Smaller decline of ALSFRS-R score vs control group but not historical data
          • Present in patients with bulbar or limb ALS
          • Can be safely used for at least 12 months
          • More severe ALS: No benefit
          • Italian study: No benefit ⁸¹
        • Concomitant drug to use: Riluzole
    • Cramps: May resolve spontaneously
      • Mexiletine: 150 mg bid; Reduced cramp frequency & severity ⁷⁷
      • Quinine sulfate: 200 mg bid
      • Carbamazepine: 200 mg bid
      • Riluzole treatment: No effect
    • Spasticity
      • Baclofen in some patients: 10 to 80 mg; May increase weakness
      • Other: Tizanidin; Memantine; Tetrazepam
      • Rarely: Dantrolene, Usually increases weakness
    • Pseudobulbar affect
      • Amitriptyline: 10 to 150 mg
      • Neudexta (Avanir): Dextromethorphan (20mg) & Quinidine (10mg) together
      • Other: Fluvoxamine; Lithium; L-DOPA
    • Weakness: Splints, Supports....
    • Care type: Multidisciplinary clinics
      • Survival: Longer
      • Quality of life: Improved
    • General: Information & Discussion
      • Provide clear diagnosis & information that disease is progressive in most cases
      • Allow patient to retain some hope
      • Encourage development of support systems
      • Late: Initiate contact with hospice
  • Survival
    • Longer time in late ALS stages: Riluzole ⁷⁵
      • Drug mechanism: Glutamatergic antagonist
      • Dose: 50 mg po q12h
      • Benefits
        • General: May increase survival by an average of 3 months
        • ? More effective ¹⁵: Bulbar disease onset; Older age; Earlier in disease course
        • Benefit type: Prolongs survival in late clinical stage of ALS No relation to time drug was started
        • No effect on strength, respiration or quality of life
      • Other issues
        • High cost: ~ $10,000 per year
        • Avoid with: Hepatic disease
        • Side effects: GI disturbance, Liver FT high, Fatigue, Hypersensitivity pneumonitis (Rare)
        • Safety monitoring: Liver function tests
    • Respiratory support
  • Caregiver support

ALS-like disorders with Fronto-Temporal Dementia (FTD) ¹¹

• Genetics
• Clinical
  • Onset age: 4th to 8th decade
  • Fronto-Temporal Dementia (FTD)
    • Dementia
    • Language disorders
    • Personality changes
    • Behavioral disorders
  • Amyotrophic lateral sclerosis syndrome (ALS)
    • Bulbar dysfunction: Dysphagia
    • Limb denervation
    • Upper motor neuron signs in limbs
      • Hyperreflexia
      • Spasticity less prominent in some patients
    • Fasciculations: May occur without signs of ALS
• Course & associations
  • ALS or FTD may present first
    • Time between onset of syndromes may be years
    • Most commonly dementia presents first
  • Association
    • 14% of FTD patients meet criteria for definite ALS
    • 36% of FTD patients meet criteria for posible ALS
• Laboratory
  • EMG: Denervation; Fasciculations
  • CNS Pathology
    • Neuronal loss in frontotemporal lobes
    • Intraneuronal ubiquitin-immunoreactive inclusions
      • Frequency
        • ALS-Dementia: 100%
        • Non-demented ALS patients: 20% to 50%
        • Frontotemporal dementia lacking motor symptoms: Some patients
      • Locations
        • Hippocampal dentate granular cells
        • Neurons in layer II of frontotemporal (extra-motor) cortex
        • Dystrophic cortical neurites
        • Motor neurons
      • Histochemistry
        • Ubiqutin: Staining
        • Tau & α-Synuclein: No staining
    • Cortex: Astrocytosis (Layer V); Loss of Betz cells
    • Loss of pyramidal tract axons: More distally
    • No pathological evidence of other dementing conditions

Western Pacific ALS-like disorders (ALS-PD) ⁶

• Etiology
  • ? Related to environmental toxins in cycad nut (Cycas circinalis): Possibilities include
    • β-Methylamino-L-alanine (BMAA) toxin
      • Consumption of cycad nut containing BMAA toxin
      • Consumption of Guamanian flying fox: Concentrate BMAA to high levels ¹⁹
    • Methylazoxymethanol (MAM): Alkylating agent, could produce long latency disease
  • Other environmental associations
    • Deficient calcium & magnesium
  • Genetics
    • Tau (MAPT) : May be a modifying gene increasing risk for ALS-PD
    • TRPM 7 mutation: Thr1482Ile
      • Present in some ALS-Guam & PD-Guam patients
        • Amyotrophic lateral sclerosis-Parkinsonism/Dementia complex 1 (ALS-PD1)
    • Other mutations in Guam Chamorro population ⁵³
      • Homozygous: PINK1 L347P
      • Heterozygous: DCTN1 T54I; FUS P431L; HTT
• Epidemiology
  • Occurs in high incidence foci
    • Mariana islands & South Guam; Kii peninsula of Japan
    • Frequency in Guam in 1960: Males 179/10⁵; Females 60/10⁵
    • Familial grouping
      • Chammoros
      • No clear Mendelian patterns of inheritance
      • ? Dominant with reduced penetrance
  • Onset mean: 52 years
  • Male:Female = 2:1 to 3:1
  • Changes over past 2 decades ¹³
    • Incidence: Decreasing; 8 to 10 fold reduction; No, or few, new cases in 2020's
    • Onset age: Increasing
    • Male predominance: Less
• Clinical features
  • Motor neuron disease
    • Upper & Lower motor neuron features: 90%
    • Lower motor neuron syndrome only: 10%
    • Bulbar features common
  • Other CNS
    • Parkinsonism: 15%
    • Dementia: 10%
    • ? Segregates as separate disease: Occurs in other family members
  • Pigmentary retinopathy: 50%
  • Disease duration
    • Mean: 4 years
    • Age at death: 48 to 68 years
  • Positive family history (ALS or PDC): 45%
• Pathology
  • Neurofibrillary tangles (NFT)
    • Location: Mesial temporal cortex; Basal ganglia; Brainstem
    • Contain: Tau protein & prions
    • Like Alzheimer (AD): Include both 3R & 4R tau isoforms with phosphorylated epitopes
    • Unlike AD: tau NFTs distributed in both neuronal and glial cells in gray & white matter
  • Granulovacuolar bodies
  • β-amyloid (Aβ)
    • No extracellular plaques
    • Intracellular inclusions may occur
    • Aβ prions present
  • Anterior horn cells
    • Loss (100%)
    • Ubiquitin positive inclusions (50%)

Atypical Motor Neuron Disease with Ophthalmoplegia & Extrapyramidal Disorders ⁴

• Clinical
  • Onset
    • 4th to 7th decade
    • Often bulbar dysfunction: Dysarthria
  • Motor
    • Weakness: Bulbar, Arms & Legs
  • Upper motor neuron signs
    • Variably present
    • Tendon reflexes: Brisk or Normal
  • Ocular
    • Gaze paresis: Especially vertical; Supranuclear
    • Saccades: Abnormal
  • Extrapyramidal signs: Variable
    • Rigidity
    • Ballism
    • Tremor
  • Progression: Often rapid; Death in 1 to 3.5 years
• Pathology
  • Anterior horn cell loss: With Bunina bodies
  • Brainstem change: Dentate; Collicular nuclei; Periaqueductal gray gliosis
  • Substantia nigra: Neuronal loss
  • Putamina & globus pallidus: Neuronal loss

Amyotrophic Lateral Sclerosis (ALS): Discussion of the Diagnosis ¹

• Provide information
  • Information appropriate to what the patient wants & can understand
  • Information appropriate to degree of certainty of ALS diagnosis
  • Avoid imposition of information that the patient does not want
• Respond to the patient's reaction to the information

• Setting
  • Private area
  • Avoid interruptions
  • Relative or friend of patient also present
  • Physician is seated & at level of patient
• Communication style: Direct & empathetic
• Find out what patient knows: "What have you been told is the problem?"
• Provide information gradually: Small pieces of information with increasing seriousness
  • Initial general negative comment: "I'm afraid that the test results not what I was hoping for."
  • Descriptive hierarchy: Do not give very pessimistic message all at once
    • "Your weakness is caused by damage to the telegraph wires (nerves) that tell muscles to contract"
    • "The nerves are being gradually damaged"
    • "The condition is called amyotrophic lateral sclerosis (ALS), Lou Gehrig's disease or motor neuron disease"
    • "Unfortunately, there is no cure, at the moment."
    • "A drug Riluzole may slow the problem down slightly."
    • "Yes, the disease is often eventually fatal, but progression can be slow in some patients"
  • Most patients are more comfortable with a "label" for their condition
• Respond to the patient's reaction to the information
• Ask patients
  • If they have had enough information, or would like more
  • If they have further questions
• Other information
  • Brochure with information about ALS in lay language
  • Organizations that can give additional help
• Contract for further care
  • Short term follow-up appointment
  • Treatment: Dependent on disease stage
    • "A drug Riluzole may slow the problem down slightly."
    • Occupational & Physical therapy
    • Nutrition
    • Respiratory
    • Social work: For patient and caregiver
    • Clinic resources for helping patient cope with ALS
    • Ongoing clinical and research studies in ALS
  • Emphasize availability for future questions

Motor Neuron Disease: MRI changes

• Focal signal in corticospinal tract, cerebral peduncle & internal capsule
• MRI changes occur in some but not all ALS patients

Medulla

Pons

Midbrain

Internal capsule

ALS: Early history of concepts

• 1830 Charles Bell: Reports case of middle aged woman with
  • Progressive paralysis of limbs and tongue
  • Preservation of sensation
  • Pathology: Anterior portion of spinal cord showed degeneration
  • Conclusion: ""Anterior column ...of the spinal marrow is for motion, the posterior column is for sensation...""
• 1850 Aran: Describes progressive muscular atrophy (PMA)
  • Thought to be a primary disease of muscle
• 1853 Cruveilhier: Attributes PMA to atopy of anterior horns of spinal cord
• 1870 Fritsch and Hitzig: Identify the cortical motor strip of the brain by electrical stimulation
• 1874 Charcot: Establishes clinical entity of Amyotrophic Lateral Sclerosis (ALS)
  • Based on 20 cases and 5 autopsies
• 1879 Kahler and Pick: Identify atrophy of motor cortex in ALS
• 1883 Dejerine: Relates Progressive Bulbar Palsy (PBP) to ALS
• 1884 Kahler: PMA, ALS and PBP grouped as "primary degnerations of the motor system"

Creatine Protocols: For ALS & Neuromuscular Disorders

• NOTE
  • There is some evidence that this treatment produces a small (3%) short-term improvement in strength in Dystrophinopathies and FSH.³
  • There is evidence that creatine is of NO benefit in ALS
• Prior to initiation of Drug Protocols: Measure strength by quantitative dynamometry
• Drug Protocols
  1. Creatine monohydrate: Dissolved in fluid,with small meal ³
     • Adults: 10 grams/day
     • Children: 5 grams/day
  2. Creatine monohydrate
     • Days 1 to 5: 12 grams 3 times a day
     • Days 6 to 30: 2 grams once a day
  3. Creatine and carbohydrate: Phosphagen HP
     • Concentration: 5 grams of creatine in 43 grams of Phosphagen (1 scoop)
     • Days 1 to 5: 7 scoops per day
     • Days 6 to 30: 1 scoop per day
• After 30 days: Measure strength by quantitative dynamometry