CNS nontumor
Motor neuron disorders
Amyotrophic lateral sclerosis
Topic Completed: 1 September 2016
Minor changes: 22 February 2021
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: Amyotrophic lateral sclerosis CNS [title]
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Genetic factors | Clinical features | Diagnosis | Radiology description | Prognostic factors | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Differential diagnosisCite this page: Flanagan ME, Montine TJ, Plowey E. Amyotrophic lateral sclerosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnsals.html. Accessed March 3rd, 2021.
Definition / general
- Progressive neurodegenerative disorder characterized by degeneration of upper and lower motor neurons resulting in progressive skeletal muscle wasting and weakness leading to respiratory failure and death (Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014)
- Can be associated with variable degeneration of nonmotor systems
Essential features
- Spinal cord and anterior spinal root atrophy
- Upper and motor neuron loss with associated loss of myelinated axons
- Neuronal inclusions:
- Skein-like inclusions
- Hyaline (Lewy-like) inclusions
- Bunina bodies
Terminology
- Popularly known as Lou Gehrig disease (Wikipedia: Lou Gehrig)
- Progressive bulbar palsy (PBP) and progressive muscular atrophy (PMA) are generally considered to be variants of a single clinicopathologic syndrome (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- PBP: syndrome of progressive dysarthria and dysphagia
- ~25% of patients who develop other features of ALS initially present with PBP
- PMA: condition where lower motor neuron signs correlating with loss of anterior horn cells occur in absence of upper motor neuron signs
- Upper motor neurons are preserved
- PBP: syndrome of progressive dysarthria and dysphagia
- Primary lateral sclerosis (PLS) is usually regarded as a distinct entity because of the lack of lower motor neuron (LMN) involvement (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- PLS: upper motor neuron signs occur in the absence of lower neuron signs
- Pathologic changes are confined to motor cortex and cortical spinal tracts
- PLS: upper motor neuron signs occur in the absence of lower neuron signs
Epidemiology
- Incidence: 2/100,000 (Arh Hig Rada Toksikol 2015;66:285)
- Prevalence: 5/100,000
- Mean age of sporadic ALS is 60 years
- Male:female ratio is 1.5:1
- Due to familial ALS in ~10% of cases (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
Sites
- Anterior spinal roots
- Spinal cord
- Hypoglossal nucleus
- Primary motor cortex
- Brain stem motor nuclei
Pathophysiology
- Cause of sporadic ALS is unknown but recent research has provided insights into the role of genetic factors, proteins involved in RNA processing and excitotoxic damage (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Pathological aggregation of TDP43 (RNA / DNA binding protein) is central to development of neurodegeneration (Science 2008;319:1668, Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Some patients have mutation in TDP43 gene (TARDBP on chromosome 1) causing ALS
- Several other proteins likely interact along a pathway leading to TDP43 linked neurodegeneration
- Protein FUS is involved in some cases (Science 2009;323:1205, Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014, Arh Hig Rada Toksikol 2015;66:285)
- Pathologic aggregation of FUS (a protein involved in RNA processing) is seen in a proportion of cases linked to a mutation in the gene
- Hexanucleotide repeat expansion in C9Orf72 gene was discovered to be the most frequent genetic cause of frontotemporal dementia (FTD) ALS (Acta Neuropathol 2011;122:673, Arh Hig Rada Toksikol 2015;66:285)
- Becomes pathogenic at greater than 30 repeats with most patients having expansions greater than 500 repeats
- Excitotoxic neurotransmitter glutamate has been implicated in ALS (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Auto antibodies to L type calcium channels have been described in ALS (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
Genetic factors
- 5 - 10% of patients with ALS have an autosomal dominant inherited form of the disease
- Typically presents 10 years earlier than sporadic form of disease
- Median survival time is ~24 months
- Most common form is mutation of copper / zinc superoxide dismutase (SOD1) gene on chromosome 21 (Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014, Arh Hig Rada Toksikol 2015;66:285)
- Autosomal recessive and X linked forms of ALS have also been described.
- Some gene variants act as risk factors for ALS (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013):
- Deletions within C terminal domain of NEFH gene coding for neurofilament heavy subunit have been found in several sporadic ALS patients
- May be a susceptibility factor
- Short expansions of glutamine forming a polyglutamine tract in the ataxin2 protein are associated with increased risk of ALS
- Deletions within C terminal domain of NEFH gene coding for neurofilament heavy subunit have been found in several sporadic ALS patients
Clinical features
- Weakness and muscular atrophy throughout the body due to degeneration of upper and lower motor neurons (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014, Neurol Clin 2015;33:855)
- Patients ultimately lose ability to initiate and control all voluntary movements
- Bladder / bowel function and muscles responsible for eye movements are usually spared until final stages of disease (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Most common presenting symptom is asymmetric extremity weakness (80% of patients) followed by dysphagia and dysarthria (20% of patients) (Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014)
Diagnosis
- Diagnosis of ALS requires (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013):
- Presence of:
- Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiological or neuropathological examination
- Evidence of upper motor neuron (UMN) degeneration by clinical examination
- Progression of the motor syndrome within a region or to other region, as determined by history or examination
- Absence of:
- Electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN or UMN degeneration
- Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs
- Presence of:
Radiology description
- MRI usually normal
- Increased signal in corticospinal tracts on T2 and FLAIR may be seen
- Hypointensity of motor cortex on T2 images has been reported (Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014)
Prognostic factors
- Progressive disease with median survival 3 - 5 years after onset of symptoms (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- ~10% of patients survive > 10 years
Treatment
- Glutamate inhibitor and sodium channel blocker (riluzole) may slow disease progression (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014)
Gross description
- Anterior nerve roots may appear shrunken and grey when compared with posterior sensory nerve roots (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014, Neurol Clin 2015;33:855)
- Spinal cord may be atrophic
- Brain usually appears grossly normal (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014, Neurol Clin 2015;33:855)
- May show atrophy of the precentral gyrus
- In ALS patients with clinical dementia, the frontal and temporal lobes may be atrophic
Gross images
Contributed by Hannes Vogel, M.D.
ALS
Microscopic (histologic) description
- Most characteristic finding is loss of anterior horn motor neurons and gliosis in the spinal cord, brain stem and motor cortex (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014, Neurol Clin 2015;33:855)
- This occurs with associated lateral and anterior corticospinal tract degeneration, characterized by myelinated axon loss which is visualized as pallor on myelin and axon stains with associated macrophages and gliosis; usually more severe distally
- Remaining neurons in the spinal cord and brain stem may show cytoskeletal abnormalities including abnormal inclusions containing neurofilaments (NF) or perpherin, reduced mRNA levels for the NF light protein and mutations in the NF heavy gene (J Neurol Sci 2000;180:7, Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Inclusion bodies may be seen on H&E stained sections but distinctive ALS inclusions are more easily identified with immunostaining
- Bunina bodies: round to oval shaped eosinophilic granular cytoplasmic deposits (3 - 6 μm) seen most frequently within motor neurons and often in chains (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Neurol Clin 2015;33:855)
- May occasionally be found in dendrites
- Cystatin C positive
- Transferrin positive (Neurol Clin 2015;33:855)
- Partially colocalize with peripherin (Neurol Clin 2015;33:855)
- Ubiquitin negative
- Skein-like inclusions: intracytoplasmic thread-like structures within neurons (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Ubiquitin and TDP43 positive; there is no TDP43 positivity seen with FUS or SOD1 mutation cases
- Phosphorylated neurofilament protein negative
- Spherical hyaline (Lewy-like) inclusions (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014): pale eosinophilic intracytoplasmic deposits within neurons
- Alpha synuclein negative
- Inclusions are seen in both sporadic and familial ALS
- Bunina bodies: round to oval shaped eosinophilic granular cytoplasmic deposits (3 - 6 μm) seen most frequently within motor neurons and often in chains (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Neurol Clin 2015;33:855)
- TDP43 aggregation and displacement from nucleus to cytoplasm is seen (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013, Yachnis: Neuropathology - A Volume in the High-Yield Pathology Series, First Edition, 2014, Arh Hig Rada Toksikol 2015;66:285, Neurol Clin 2015;33:855)
Microscopic (histologic) images
Contributed by Hannes Vogel, M.D.
Various images
Positive stains
- Bunina bodies: cystatin c and transferrin positive (Neurol Clin 2015;33:855)
- Skein-like inclusions: ubiquitin and TDP43 positive
- Hyaline (Lewy-like) inclusions: ubiquitin and TDP43 positive
Negative stains
- Bunina bodies: ubiquitin, tau and alpha-synuclein negative (Neurol Clin 2015;33:855)
- Skein-like inclusions: phosphorylated neurofilament protein negative
- Hyaline (Lewy-like) inclusions: alpha-synuclein negative
Differential diagnosis
- Hereditary spastic paraplegia
- Myasthenia gravis
- Secondary causes of motor neuron disease (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013):
- Infectious
- Acute poliomyelitis
- HIV infection
- Metabolic
- Immune
- Paraproteinemia
- Infectious
- Spinal muscular atrophy
- X linked bulbar spinal atrophy (Kennedy disease)
