amyotrophic lateral sclerosis (ALS); Lou Gerig's disease

Etiology

• degeneration of motor neurons at all levels of the CNS
  • anterior horn cells in the spinal cord
  • brainstem motor nuclei
  • neurons in the motor cortex
  • variants in TP73 correlate with risk for ALS& suggest a role for apoptosis in pathology of ALS
• frontotemporal dementia sometimes a comorbidity
• familial forms
• risk factors
  • pesticides (RR=5.1)
    • pentachlorobenzene, cis-chlordane, polychlorinated biphenyl (PCB) 175, PCB 202, & polybrominated diphenyl ether (PBDE) 47
  • lead exposure, PCB 151 & PBDE 66 with protective effects
  • exposure to diesel exhaust (RR=1.2-1.4)
  • physical activity (RR=1.06-1.07)
  • professional soccer, 3.2 cases per 100,000 person-years (RR=2)

Epidemiology

• 5.0 per 100,000 Americans, 1.7 per 100,000
• 20 per 100,000 among Americans in their 70s

Pathology

• upper & lower motor neuron degeneration in cranial, cervical, thoracic & lumbosacral regions
• the most striking changes are seen in affected muscles & anterior spinal nerve roots
• some cases show selective atrophy of the precentral gyrus
• loss of large motor neurons with gliosis most easily seen in anterior horns of the lumbar & cervical spinal cord
• neurofilament (NF)-rich inclusions in neurons of the spinal cord & brain, colocalization of MAP6
• spinal cord:
  • degeneration of crossed & uncrossed pyramidal tracts
  • diffuse loss of myelin in anterior & lateral columns
  • intact posterior columns, sometimes some cell loss in Clarke's column
• neurochemical changes:
  • antiganglioside antibodies
  • reduced muscarinic cholinergic, glycinergic, benzodiazepine, & TRH receptors
  • decreased fibers containing enkephalin, neurokinin, somatostatin, substance P, & TRH in some cases
  • accumulation of cholesterol esters & ceramides (globosides ?)

Genetics

• mutation in SOD1 in one familial form
• genetic variation in DPP6 may influence susceptibility to ALS
• defects in NEFH are a cause of susceptibility to ALS
• defects in ANG are the cause of susceptibility to ALS type 9
• defects in TARDBP/TDP43 are the cause of ALS type 10
• pathogenic mutation in ARPP21 identified in 12 patients from Spain
• variants in TP73 correlate with risk for ALS & suggest a role for apoptosis in pathology of ALS
• hexanucleotide-repeat expansion in the C9ORF72 gene in ~10% of patients
• other implicated genes: RNF19A
• relative of patients with ALS at increased risk of schizophrenia & other psychiatric disorders

Clinical manifestations

• onset usually mid-life
• most cases rapidly progressive with death in 3-5 years
• upper motor neuron signs + lower motor neuron signs
• presentation may be asymmetric with single limb involvement
• hands & arms involved more than legs
  • hand muscles involved early
  • muscle weakness
  • muscle wasting/muscle atrophy (lower motor neuron sign)
  • muscle stiffness, muscle rigidity may be asymmetric
  • muscle cramping, muscle spasms
  • muscle twitching
  • hyperreflexia/hyporeflexia, reflexes may be preserved
  • spasticity
  • + Babinski's sign
  • fasciculations (lower motor neuron sign)
    • fasciculations occur in association with muscle weakness or muscle atrophy
  • clonus
• brainstem involvement
  • dysarthria
  • dysphagia
  • pseudobulbar palsy
  • wasting of tongue
  • fasciculations of tongue
• preserved intellect
• lack of sensory abnormalities
• extraocular muscles intact, no weakness
• absence of bowel or bladder dysfunction
• progressive respiratory deterioration

Laboratory

• cerebrospinal fluid (CSF): normal
• elevated muscle enzymes:
  • serum creatine kinase
  • serum aldolase
• serology:
  • antibodies to gangliosides: anti-GM1 & anti-GD1b
  • dipeptidyl peptidase 6 IgG in CSF
  • dipeptidyl peptidase 6 IgG in serum
• arterial blood gas (ABG): hypercapnia
• lipid panel
  • higher HDL cholesterol in serum & higher HDL/total cholesterol associated with reduced risk for ALS
  • higher apolipoprotein A1 in serum associated with reduced risk for ALS
• exclusion testing:
  • heavy metals in urine & serum
    • serum copper
  • thyroid function tests
  • serum protein electrophoresis
  • lysosomal enzyme activities
  • serum vitamin B12 & serum folate levels
  • serologic tests for syphilis
  • Lyme serology
  • complete blood count (CBC)
  • erythrocyte sedimentation rate (ESR); serum C-reactive protein (CRP)
  • chemistry profile:
    • serum glucose
    • serum calcium, serum PTH if elevated
    • serum chloride
• genetic testing
  • SOD1 gene mutation

Diagnostic procedures

• electromyography is diagnostic test of choice
  • muscle denervation with chronic reinnervation
  • involvement of different peripheral nerves & nerve roots
  • fasciculation potentials
• pulmonary function tests (PFT) - ventilation management
• polysomnography may be helpful in titrating ventilation management (BiPap)
• swallowing evaluation if bulbar signs

Radiology

• magnetic resonance imaging (MRI) better than computed tomography
  • not diagnostic
  • T2 bright signal bilateral in corticospinal tract may be observed
  • exclude spinal cord lesions
    • spinal cord compression
    • cervical spondylosis
  • cervical spine lesions can produce bulbar signs & symptoms if the brainstem is also involved

Complications

• respiratory failure is the cause of death in most cases
• nocturnal ventilatory impairment may precede awakend-state hypoventilation
• aspiration
• 20% of patients with develop frontotemporal dementia

Differential diagnosis

• secondary motor neuron disorders (see motor neuron disease)
• chronic traumatic encephalopathy
• Lyme disease
• hyperparathyroidism
• thyroxicosis
• sensory symptoms or pain, cognitive impairment or extaocular muscle weakness suggest an etiology other than ALS
• fasciculations without muscle weakness or muscle atrophy or muscle weakness/muscle atrophy with fasciculations is not ALS

Management

• supportive care
  • goals
    • prolong independence
    • improve quality of life
  • non-invasive ventilatory support for symptoms of respiratory insufficiency (BiPap)
    • early diaphragm pacing hastens the need for BiPap & increases mortality
  • occupational therapy for energy-conservation techniques to maintain function
  • physical therapy for muscle stretching to maintain function
  • strength training, endurance exercise & balance training not helpful
  • enteral feeding (percutaneous encoscopic gastrostomy)
  • high-carbohydrate, high calorie diet may improve survival*
• riluzole may be effective in slowing the progression of ALS
  • increases survival by 3 months on average
• edaravone (Radicava) FDA-approved May 2017
  • may benefit mildly symptomatic patients
• lithium carbonate, therapeutic range 0.4-0.8 meq/L {investigational}
• IV or intrathecal thyrotropin-releasing hormone (TRH)
• dextromethorphan/quinidine (Nuedexta) may be useful for treatment of pseudobulbar palsy
• agents in clinical trials
  • ciliary neurotrophic factor (CNTF)
  • insulin-like growth factor-1 (IGF-1)
  • sodium phenylbutyrate/taurursodiol (AMX0035)
• other investigational therapies
  • repeated intrathecal antisense oligonucleotides that selectively blunt expression of G4C2 repeat-containing transcripts & effectively suppress CSF levels of poly(GP) dipeptides (see C9ORF72)

* mildly obese patients with ALS have longer survival

More general terms

• motor neuron disease
• neurodegenerative disease

More specific terms

• amyotrophic lateral sclerosis type 17
• amyotrophic lateral sclerosis type 2; juvenile amyotrophic lateral sclerosis
• amyotrophic lateral sclerosis with dementia
• familial amyotrophic lateral sclerosis (ALS)
• juvenile amyotrophic lateral sclerosis with dementia
• pagetoid amyotrophic lateral sclerosis (inclusion body myopathy with early-onset Paget disease & frontotemporal dementia, IBMPFD, muscular dystrophy limb-girdle with Paget disease of bone, pagetoid neuroskeletal syndrome, lower motor neuron degeneratio...
• primary juvenile lateral sclerosis
• sporadic amyotrophic lateral sclerosis (ALS)

Additional terms

• alsin; amyotrophic lateral sclerosis 2 chromosomal region candidate gene 6 protein; amyotrophic lateral sclerosis 2 protein (ALS2 ALS2CR6 KIAA1563)
• amyotrophic lateral sclerosis [ALS] 2 chromosomal region candidate gene
• hospice guidelines for determining prognosis, amyotrophic lateral sclerosis (ALS)

Patient information

amyotrophic lateral sclerosis patient information

Database

• Kegg: http://www.genome.jp/dbget-bin/www_bget?
• OMIM: https://mirror.omim.org/entry/611895