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KEY FACTS

Terminology
- Amyotrophic lateral sclerosis (ALS)
- Selective degeneration of somatic motor neurons of brainstem/spinal cord & large pyramidal neurons of motor cortex - Eventual loss of corticospinal tract (CST) fibers
Imaging
- Small percentage demonstrate CST hyperintensity
- As CST is normally slightly hyperintense, especially at 3.0 T, this finding lacks sensitivity & specificity
- T2-hyperintense CST may be specific for ALS when seen on corresponding PD images
- Consider FLAIR & PD in suspected ALS
- DWI hyperintensity (↓ diffusivity) in CST
- Hypointense gray matter in precentral gyrus (motor cortex)
Top Differential Diagnoses
- Primary lateral sclerosis
- Wallerian degeneration
- Hypertrophic olivary degeneration
- Metabolic diseases involving bilateral CSTs
- Demyelinating & inflammatory diseases
- Neoplasms: Brainstem glioma, malignant lymphoma
- CST can appear hyperintense on 3T MR normally
Pathology
- Majority of ALS cases are sALS
- 5-10% are familial (fALS)
Clinical Issues
- UMN signs: Babinski sign, spasticity, hyperreflexia
- LMN signs: Asymmetric muscle weakness, atrophy, fasciculations, hyporeflexia
- Bulbar signs: Slurred speech, dysphagia
- Classic ALS: Both UMN & LMN affected
- Peaks in 6th-8th decades of life
- Complete disability & death within 1 decade
- Some patients with familial, juvenile-onset ALS survive for longer periods (2-3 decades)

TERMINOLOGY

Abbreviations
- Amyotrophic lateral sclerosis (ALS)
Synonyms
- Lou Gehrig disease, motor neuron disease (MND)
Definitions
- Selective degeneration of somatic motor neurons of brainstem/spinal cord {lower motor neurons (LMN) & large pyramidal neurons of motor cortex [upper motor neurons (UMN)]} - Eventual loss of corticospinal tract (CST) fibers

IMAGING

General Features

Best diagnostic clue

- Bilateral hyperintensities along CST extending from corona radiata to brainstem on T2WI/PD/FLAIR

Location

- Hallmark is CST & LMN degeneration
        - LMN in anterior horn of spinal cord & brainstem
        - Corticospinal UMN in precentral gyrus (motor cortex)
- White matter (WM) & gray matter (GM)
- Frequently, prefrontal motor neurons involved in planning or orchestrating work of UMN & LMN

Size

- Atrophy of motor system, particularly pyramidal tract, in advanced stages of ALS

Morphology

- Oval or thin, curvilinear hyperintensities conforming to CST

CT Findings

NECT

- Serial CT exams may show progressive atrophy
        - Frontal, anterior temporal lobes → precentral gyrus → postcentral gyrus, anterior cingulate gyrus, corpus callosum, tegmentum

MR Findings
- T1WI
```
- Different T1 appearances of CST
        - Isointensity (most common) may reflect ↑ content of free radicals
        - Hypointense or mild hyperintense signal
        - CST differs between ALS patients & normal subjects only at internal capsule
- T1 hyperintensity in anterolateral cervical cord is associated with younger patients & rapid disease progression
```
- T2WI
```
- Hyperintense CST
- Hyperintensity can occur anywhere from subcortical WM of precentral gyrus to posterior limb internal capsules, cerebral peduncles, & pons
- As CST is normally slightly hyperintense especially at 3.0 T, this finding lacks sensitivity & specificity
- T2 hyperintense CST may be specific for ALS when seen on corresponding PD images
- Hypointense GM in precentral gyrus (motor cortex)
        - Nonspecific; may be due to iron & heavy metals accumulating in cortex of aged patients
```
- PD/intermediate
```
- Hyperintense CST
```
- FLAIR
```
- More sensitive & less specific than T2 FSE for detecting hypointensity in precentral gyrus
- Hyperintense CST
        - More frequently seen on FLAIR than on T2/T1/PD
```
- T2* GRE
```
- Hypointensity in precentral gyri
```
- DWI
```
- Hyperintensity in CST
        - May be seen in absence of T2 hyperintensity
```
- Diffusion tensor imaging (DTI) - ROI-based approaches & tractography demonstrates significant changes in diffusion parameters along CST - Most common finding: ↓ fractional anisotropy (FA) in CST due to UMN degeneration - ↓ FA in CST; most significant in posterior limb internal capsule & correlates with disease severity - ↑ mean diffusivity (MD) along CST which correlates with disease duration - ↑ MD in corpus callosum, frontal & temporal WM - ↓ FA & ↑ MD in cervical cord correlate with disease severity & duration respectively
- ¹H-MRS useful for assessing UMN involvement - ↓ NAA, ↓ NAA/Cr, ↓ NAA/Cho, & ↓ NAA/(Cr + Cho) in motor cortex - NAA present primarily in neurons; these metabolic changes reflect loss or dysfunction of motor neurons - ↓ NAA/Cr:NAA/Cho ratio along CST; most pronounced in precentral gyrus & corona radiata - ↓ NAA in pons & upper medulla in patients with prominent UMN or bulbar signs - ↑ Cho in posterior limb internal capsule - ↑ myo-inositol (mI) in motor cortex - ↓ NAA:mI ratio has better sensitivity & specificity in detecting ALS than any other metabolites
- Magnetization-transfer ratio (MTR) measurements - ↓ MTR in CST - CST hyperintensity on T1 MT contrast-enhanced images: 80% sensitivity, 100% specificity - May detect CST degeneration of ALS at early stage
- Voxel-based morphometry (VBM) - Regional GM loss in motor cortex, frontal, temporal, parietal, & limbic regions - Frontal severe atrophy in ALS & frontotemporal dementia - WM loss in corpus callosum, cerebellum, frontotemporal, & occipital regions - ↓ Brain parenchymal fraction (BPF) & very mild global brain atrophy
- Functional MR - Pattern of cortical reorganization - ↑ activation of contralateral sensorimotor cortex, supplementary motor area, basal ganglia, & cerebellum during motor tasks
Nuclear Medicine Findings
- PET, Tc-99m HMPAO SPECT - ↓ regional cerebral metabolism/perfusion throughout brain with marked changes in sensorimotor cortex & putamen - ↑ ALS severity correlated with ↓ GM perfusion
Imaging Recommendations
- Best imaging tool: MR with T2, PD, FLAIR, DTI

DIFFERENTIAL DIAGNOSIS

Primary Lateral Sclerosis
- Neurodegeneration restricted to UMN - T2WI shows changes in motor pathways
- ALS2 mutations reported
- Autosomal recessive disease with juvenile onset
- Infantile-onset hereditary spastic paraplegia - Spastic paralysis with ascending progression, only UMN involvement - Mutations described in alsin & spastin genes
Wallerian Degeneration
- Dynamic signal intensities change along CST in patients with various cortical/subcortical lesions
Hypertrophic Olivary Degeneration
- Secondary degeneration of inferior olivary nucleus (ION), usually caused by primary lesions in dento-rubro-olivary pathway
Conditions With T2-Hyperintense Lesions Along CST
- Metabolic diseases may involve CST bilaterally - X-linked adrenoleukodystrophy, Wilson disease - Hypoglycemic coma: Reversible CST changes
- Demyelinating & inflammatory diseases - Multiple sclerosis, ADEM, Behçet disease, AIDS, cervical myelopathy
- Neoplasms: Brainstem glioma, malignant lymphoma
- Intoxication: Heroin inhalation
Normal Individuals
- CST can appear hyperintense on 3T MR (normal fully myelinated brain at any age) & mimic ALS

PATHOLOGY

General Features

Etiology

- Sporadic ALS (sALS) etiology is largely unknown
- Proposed potential mechanisms include
        - Abnormal RNA processing, SOD1-mediated toxicity, excitotoxicity, cytoskeletal derangements, mitochondrial dysfunction
        - Viral infections, apoptosis, growth factor abnormalities, & inflammatory responses
- Pathological hallmarks include loss of MNs with intraneuronal ubiquitin-immunoreactive inclusions in UMN & TDP-43 immunoreactive inclusions in degenerating LMN
- ↑ expression of cyclooxygenase-2 in spinal cord, frontal cortex, & hippocampus
- Apoptosis, free radical-mediated oxidative stress, excessive glutamate-mediated excitotoxicity
- Dopamine deficiency probably has important role
- Biochemical studies have shown ↓ glutamate levels in CNS tissue & ↑ levels in CSF
- Mutations in single gene can lead to selective degeneration of motor neurons

Genetics

- 90-95% of cases are sALS
- 5-10% of cases are familial (fALS)
        - Most common ALS-related gene mutation occurs in *C9ORF72*, *SOD1*, *TARDBP*, & *FUS*
                  - In European population: Most common is *C9ORF72*repeats
                  - In Asian population: Most common is *SOD1* mutation
- Rare autosomal recessive juvenile-onset ALS
        - *ALS2* gene on chromosome 2q encodes alsin

Associated abnormalities

- ALS-plus syndrome: MND with other symptoms or signs outside of voluntary motor system
        - 2–3% of cases, ALS is accompanied by frontotemporal dementia
        - ~ 50% of cases show cognitive impairment
- Can be associated with frontotemporal dementia (FTD), autonomic insufficiency, parkinsonism, supranuclear gaze paresis, &/or sensory loss
- ALS-like MND can occur as paraneoplastic syndrome

Gross Pathologic & Surgical Features
- Focal atrophy of motor cortex & along course of CST
- Atrophy of anterior & lateral portions of spinal cord
Microscopic Features
- Loss of cortical motor neurons (pyramidal & Betz cells) & astrocytosis
- Retrograde axonal loss & gliosis in CST
- "Senescent changes" with lipofuscin pigment atrophy
- Various cytoplasmic inclusions with chromatolysis
- Proximal & distal axonopathy with axonal spheroids
- Surviving motor neurons are smaller & abnormal
- Frequently undetected CST pathology in progressive muscular atrophy variant of ALS
- Bunina bodies (eosinophilic aggregates are positive for cystatin C) are unique for ALS
- Other intracellular inclusions: Neurofilament inclusions, ubiquitinated inclusions, TDP-43 inclusions, & immunoreactive inclusions toFUS

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- UMN signs: Babinski sign, spasticity, hyperreflexia
- LMN signs: Asymmetric muscle weakness, atrophy, fasciculations, hyporeflexia
        - Split-hand syndrome: Frequent pattern of weakness & atrophy in ALS involving thenar muscles more than hypothenar muscles
- Bulbar signs: Slurred speech, dysphagia
- Difficulty walking, unexplained weight loss
- Hypoxia, cardiac arrhythmia

Other signs/symptoms

- El Escorial criteria diagnosis of ALS: Evidence of UMN findings, LMN findings, & progression
        - 4 regions or levels: Bulbar, cervical, thoracic, lumbosacral

Clinical profile

- Classic ALS: Both UMN & LMN affected
- UMN-dominant ALS can be difficult to distinguish from primary lateral sclerosis
- Predominantly bulbar form usually leads to more rapid deterioration & death
- fALS associated with *SOD1* abnormality has mean age at 42 years limb onset, slow evolution

Demographics

Age

- Peaks in 6th to 8th decades; can occur in young adults

Sex
```
- M:F = 1.5:1.0
```

Ethnicity

- Slightly higher in Non-Hispanics white population

Epidemiology

- Incidence: 1-3 cases/100,000 people
- Prevalence: 2.7-7.4 cases/100,000 people

Natural History & Prognosis
- Progressive (distal to proximal) - Median survival from diagnosis to death: 3-4 years - 10% of patients survive > 10 years
- Some patients with familial, juvenile-onset ALS survive for longer periods (2-3 decades)
Treatment
- Riluzole (glutamate release inhibitor & insulin-like growth factor) may prolong survival - ↑ NAA/Cr in precentral gyrus & supplementary motor area after riluzole therapy - This suggests population of sublethally injured, metabolically compromised neurons that are amenable to therapeutic rescue
- No improvement in perirolandic neuronal integrity (no change in NAA:Cr ratio) was detected after gabapentin treatment, which agrees with equivocal clinical effectiveness
- Baclofen, dantrolene, or diazepam for spasticity

DIAGNOSTIC CHECKLIST

Consider
- FLAIR & PD MR in all patients with suspected ALS
Image Interpretation Pearls
- High T2 signal intensity in posterior limb of IC is suggestive for ALS when also visible on PD MR
- T1- & PD-weighted images differentiate real degeneration from normal areas
- DTI can assess CST lesions before pyramidal symptoms

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References

Selected References

Tables

European Federation of Neurological Societies Guidelines on Use of Neuroimaging in Management of Motor Neuron Disease

Role of MR in Diagnosis of Amyotrophic Lateral Sclerosis
Conventional MR is restricted to exclude other causes of signs and symptoms of motor neuron pathology
Corticospinal tract T2 hyperintensities and precentral gyrus T2-hypointense rim can support preexisting suspicion of motor neuron disease; specific search of these abnormalities for purpose of making firm diagnosis of motor neuron disease is not recommended
Currently advanced neuroimaging techniques (including DTI and MRS) have no role in diagnosis/routine monitoring of motor neuron diseases
Advanced neuroimaging techniques are strongly recommended to be incorporated into new clinical trials

Images

Selected Images

A 56-year-old man with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) presents with progressive bilateral lower extremity weakness (he has been wheelchair bound for 6 months of symptom onset). Axial DWI MR shows hyperintense signal in posterior limb of bilateral internal capsules .

Coronal T2 MR in the same patient shows hyperintense signal along the bilateral corticospinal tract (CST) , more prominent in the internal capsule and cerebral peduncles.

Axial FLAIR MR in the same patient shows hyperintense signal in the posterior limbs of bilateral internal capsule along the CSTs .

Axial 3D SWI in the same patient at the level of vertex shows rim of low signal in bilateral precentral gyri (motor cortex) . This finding is nonspecific and may be due to iron and heavy metals accumulating in the cortex of older patients.

A 52-year-old male patient with ALS presenting with progressive bilateral lower extremity weakness followed by upper extremity weakness is shown. Axial T2WI (top) and FLAIR (bottom) show hyperintense signal involving the internal capsules posterior limb.

Axial SWI in same patient shows linear low signal along bilateral motor cortex . EMG shows degeneration and chronic reinnervation in a multisegmental distribution, consistent with motor neuron disease.

$Axial DWI MR shows oval hyperintensities corresponding to CSTs in the pons . DWI/DTI can help differentiate progressive muscular atrophy [no change in fractional anisotropy (FA) or mean diffusivity (MD)] from ALS (↑ MD, ↓ FA), which can be clinically difficult.$ Axial DWI MR shows oval hyperintensities corresponding to CSTs in the pons . DWI/DTI can help differentiate progressive muscular atrophy [no change in fractional anisotropy (FA) or mean diffusivity (MD)] from ALS (↑ MD, ↓ FA), which can be clinically difficult.

Sagittal T1WI MR shows atrophy of the posterior corpus callosum body . DTI showed ↓ FA in the corpus callosum. Voxel-based morphometry has high sensitivity in detecting local tissue atrophy in the motor cortex and along the CSTs.

Axial T2WI FS MR shows central cortical hypointense signal intensity in the precentral gyri due to iron deposition. While this is common in ALS patients, it is nonspecific and may be seen in older patients due to iron and heavy metals accumulation.

Axial T2 SWI MR demonstrates curvilinear hypointensity along the cortical gray matter of bilateral precentral gyri . The T2* SWI technique accentuates the T2 hypointensity seen in the precentral gyrus gray matter of ALS patients.*

Additional Images

Axial ADC map in the same ALS patient appears normal.

Axial DWI MR shows increased signal involving subcortical white matter of both precentral (motor) gyri, extending caudally into CSTs (not shown). These findings are typical for ALS.

Axial T2WI MR in the same patient shows hyperintense CSTs at the level of the cerebral peduncle. (Courtesy O.Q. Castro, MD.)

Coronal T2WI MR shows hyperintense CSTs in a patient with ALS. (Courtesy O.Q. Castro, MD.)

Axial T2WI MR in the same patient shows symmetrical high signal intensity in corona radiata fibers corresponding to CSTs.

Axial T2WI MR in the same patient demonstrates bilateral low signal intensity in the precentral (motor) cortex .

Axial T2WI MR in the same patient with ALS shows symmetric hyperintense CSTs at the level of the cerebral peduncle.

Axial T2WI MR in a young man with ALS shows symmetric hyperintense CSTs at the level of the internal capsule.

Axial DWI MR shows small foci of hyperintensity in the posterior limbs of bilateral internal capsules in this ALS patient.

Axial T2 MR in a patient with ALS shows hyperintensity along the course of the CST bilaterally. Important to note that CST is typically slightly hyperintense on T2 especially at 3.0 T.

Axial DTI trace image shows symmetric hyperintensity in the internal capsule posterior limbs . FA correlates with measures of disease severity and UMN involvement, whereas the MD correlates with disease duration.

Axial T2WI FS MR demonstrates ovoid hyperintensity along the CSTs bilaterally . Atrophy and hyperintense foci is due to myelin loss and gliosis. There is frequently involvement of prefrontal motor neurons that play a role in planning or orchestrating the work of the upper and lower motor neurons.

Coronal FLAIR MR shows linear hyperintensity along the CST from the precentral gyrus to the cerebri crus. Right CST signal abnormality is out of this imaging slice. Hyperintensity of the precentral gyrus subcortical white matter on FLAIR is a potentially useful and specific sign of ALS that is not seen in healthy, asymptomatic patients.

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KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Pathology

Clinical Issues

TERMINOLOGY

Abbreviations

Synonyms

Definitions

IMAGING

General Features

Best diagnostic clue

Location

Size

Morphology

CT Findings

NECT

MR Findings

T1WI

T2WI

PD/intermediate

FLAIR

T2* GRE

DWI

Nuclear Medicine Findings

Imaging Recommendations

DIFFERENTIAL DIAGNOSIS

Primary Lateral Sclerosis

Conditions With T2-Hyperintense Lesions Along CST

Normal Individuals

PATHOLOGY

General Features

Etiology

Genetics

Associated abnormalities

Gross Pathologic & Surgical Features

Microscopic Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Other signs/symptoms

Clinical profile

Demographics

Age

Sex

Ethnicity

Epidemiology

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

References

Selected References

Tables

European Federation of Neurological Societies Guidelines on Use of Neuroimaging in Management of Motor Neuron Disease

Images

Selected Images

Additional Images

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