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KEY FACTS

Terminology
- Spinocerebellar ataxia (SCA)
Imaging
- Cerebellum atrophy always, brainstem often
- Supratentorial atrophy variably in volumetric analysis
- Cerebellum & pontine tegmentum (dorsal pons) atrophy in SCA1, SCA3 [Machado-Joseph disease (MJD)], DRPLA
- Cerebellum & pontine base (ventral pons) atrophy in SCA2
- Pontine base:tegmentum distance ratio (BT-ratio) useful
- Cerebellum atrophy purely/predominantly in SCA5, SCA6, SCA11, SCA26, SCA30, SCA31, SCA37
- Superior cerebellar peduncle atrophy in MJD, SCA6, SCA8, DRPLA; severe cerebral atrophy in juvenile-onset DRPLA - Medulla & upper cervical cord atrophy in SCA3 (MJD); relative lack of cord involvement in SCA6
- Hot cross bun sign in pons in SCA2 & rarely MJD
- Anteroposteriorly oriented pontine midline linear T2-hyperintensity (PMH) in SCA1, SCA2, SCA3 (MJD), DRPLA
- Bilateral bright middle cerebellar peduncle (MCP) sign rarely in SCA2, SCA3 (MJD), SCA6, DRPLA
- Cerebral white matter (WM), brainstem, & thalamic hyperintensities in adult-onset DRPLA
- Cerebral WM signal abnormalities usually absent in juvenile-onset DRPLA - Periventricular WM changes may be seen in very late stage
Top Differential Diagnoses
- Multiple system atrophy-cerebellar (MSA-C)
- Friedrich ataxia
- Ataxia with oculomotor apraxia types 1 & 2
- Ataxia telangiectasia
- Fragile X-associated tremor/ataxia syndrome (FXTAS)
- Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
Pathology
- Autosomal dominant ataxia; many SCAs due to PolyQ expansion of coding CAG repeats
- Various other gene loci & proteins in remaining SCAs
- Commonest mutant genes: ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3/MJD),CACNA1A (SCA6), ATN1 (DRPLA)
Clinical Issues
- Young to middle-aged patient with slowly progressing cerebellar ataxia & other typical associated symptoms
Diagnostic Checklist
- Atrophy of cerebellum ± brainstem
- Evaluate axial T2WI for characteristic hyperintense signal in SCA types, especially pons, MCP, periventricular WM

TERMINOLOGY

Abbreviations
- Spinocerebellar ataxia (SCA)
- Polyglutamine repeats (PolyQ)
- Cytosine-adenine-guanine (CAG)
- Machado-Joseph disease (MJD)
- Dentatorubropallidoluysian atrophy (DRPLA)
- Distance ratio of pontine base:tegmentum (BT-ratio)
Synonyms
- MJD = Spinocerebellar ataxia type 3 (SCA3)
Definitions
- Slowly progressive cerebellum and cerebellar interconnection neurodegenerative diseases
- Autosomal dominant ataxia; many SCAs [SCA1, SCA2, SCA3 (MJD), SCA6, SCA7, SCA12, SCA17] due to PolyQ expansion of coding CAG repeats, similar to Huntington disease
- SCA8 shows CTG expansion and complementary CAG repeat
- Various other gene loci and proteins in remaining SCAs
- SCA type number as per order in which disease identified (by linkage analysis initially and gene discovery lately)
- SCA types now 1-40 and beyond; but SCA9, SCA33, and SCA39 not been assigned to specific clinical disorders
- SCA1, SCA2, SCA3, SCA6 relatively common types with SCA3 (MJD) being most common among these worldwide
- DRPLA, CAG repeat PolyQ expansion disorder that resembles SCA, usually discussed along with SCA

IMAGING

General Features

Best diagnostic clue

- Atrophy of cerebellum ± brainstem
- Atrophy difficult to detect in early stage, careful MR analysis needed

Location

- Cerebellum always, brainstem often, supratentorial structures variably on volumetric analysis
- Early stages of any SCA may show pure cerebellar atrophy and later show brainstem atrophy

Size

- Atrophy of involved structures
        - Cerebellum and **pontine tegmentum (dorsal pons)** atrophy: SCA1, SCA3 (MJD), DRPLA
        - Cerebellum and **basal pons (ventral pons)** atrophy: SCA2
        - Cerebellum atrophy purely/predominantly: SCA5, SCA6, SCA11, SCA26, SCA30, SCA31, SCA37
        - Superior cerebellar peduncle (SCP) atrophy mainly in SCA3 (MJD), SCA6, SCA8, DRPLA
                  - Medulla and upper cervical cord atrophy in SCA3 (MJD); relative lack of cord involvement in SCA6
        - Severe cerebral atrophy in juvenile-onset DRPLA
- Pontine **BT-ratio** useful in diagnostic decision tree
        - Distance from ventral edge of pons to medial lemniscus (ML): Distance from ML to its dorsal edge

Morphology

- Variable abnormal T2/FLAIR hyperintense signal
        - **Hot cross bun sign** (**HCBS**; cruciform ↑ T2 in pons)
                  - 8.7% overall prevalence in SCA; 25.7% SCA2, 1.3% SCA3 (MJD); extremely rare SCA7, SCA8
        - Anteroposteriorly oriented **pontine midline** linear T2-**hyperintensity** (**PMH**) in SCA1, SCA3 (MJD), DRPLA
        - Bilateral **bright middle cerebellar peduncle (MCP) sign** rarely in SCA2, SCA3 (MJD), SCA6, DRPLA
        - Cerebral white matter (WM), brainstem, and thalamic hyperintensities in adult-onset DRPLA
        - Cerebral WM usually normal in juvenile-onset DRPLA
                  - Periventricular WM changes may occur very late

CT Findings
- Atrophy of involved structures
MR Findings
- SCA types 1 and 3 (SCA1 and SCA3/MJD) - Pontine tegmentum (dorsal pons) atrophy in early stage - In contrast to multiple system atrophy with predominant cerebellar ataxia (MSA-C) - Important, more common differential diagnosis - MSA-C mainly pontine base (ventral pons) atrophy - Cerebellum and brainstem atrophy prominent later - PMH in later stage on axial T2WI MR; HCBS in 1.3% MJD - In contrast to pontine HCBS in MSA-C commonly - Slightly shrunken neurons of pontine nuclei with preserved cell architecture - Relatively preserves myelinated transverse pontocerebellar fibers - Fiber loss seen only in pontine midline where fibers from right and left pontine nuclei cross - Considered early change of HCBS - Volumetric MR: Caudate/putamen and temporal lobe atrophy in SCA1 - Volumetric MR: Temporofrontoparietooccipital, limbic, SCP, basal ganglia, thalamus atrophy in MJD - Medulla/upper cervical cord atrophy, bright MCP in MJD - Progressive linear ↑ T2 just outside ICs (inner segments of globi pallidi) in SCA3 (MJD)
- SCA2 - MR findings mimicking MSA-C in young ataxic patient - Prominent cerebellum and brainstem atrophy, more severe than SCA1 and SCA3 - Pontine atrophy more prominent in pontine base (ventral pons) than tegmentum (dorsal pons) - Characteristic pontine HCBS in 25%; PMH earlier - Inconsistently, T2 hyperintensities of basal ganglia - Rarely, bilateral MCP focal hyperintensities - Volumetric data shows no cerebral gray matter (GM) or WM atrophy
- SCA5, SCA6, SCA11, SCA26, SCA30, SCA31, SCA37 - Pure/predominantly cerebellar atrophy
- DRPLA - Cerebellum, brainstem, SCP atrophy - Pontine atrophy is more prominent in pontine tegmentum (dorsal pons) than base (ventral pons) - Rarely, PMH and/or bilateral MCP focal hyperintensities - Adult-onset DRPLA: ↑ T2 cerebral WM, brainstem, thalamus - Juvenile-onset DRPLA: Cerebral WM usually normal - ↑ T2 periventricular WM in very late stage - Severe cerebral atrophy in juvenile-onset DRPLA
- MRS - Significantly lower NAA/Cr, Cho/Cr, and NAA/Cho in cerebellar hemispheres/vermis in SCAs, especially SCA2 - MSA-C also shows similar findings

Imaging Recommendations

Best imaging tool
```
- MR
```

Protocol advice

- Volumetric 3D T1 MR sequences, such as MPRAGE or SPGR
- Axial T2WI and FLAIR to evaluate ↑ T2 like PMH, HCBS

DIFFERENTIAL DIAGNOSIS

Multiple System Atrophy - Cerebellar
- Most cases sporadic; 6th decade
- Atrophy of pons, cerebellum, and inferior olives
- Pontine atrophy predominantly at itsbase (ventral pons)
- PMH or HCBS in pons on axial T2; bright MCP sometimes - Due to loss of myelinated transverse pontocerebellar fibers
- MR mimics SCA2 (consider SCA2 in younger patient)
- SCP spared in MSA-C; SCP may atrophy in MSA-P, PSP, SCA3/MJD, SCA6, SCA8, DRPLA, Friedrich ataxia, ARSACS
Friedrich Ataxia
- Autosomal recessive ataxic disorder
- Severe spinal cord atrophy with flat posterior aspect
- May show ↑ T2 in spinal cord posterior (fasciculus gracilis and cuneatus) and lateral (pyramidal tracts) columns
- Atrophic dorsal medulla, rostral vermis (culmen, declive), inferomedial cerebellar hemisphere, and SCP
- Conventionally, cerebellar involvement considered rare, but nowadays volumetric MR shows atrophy
- Scoliosis, cardiomyopathy, and stroke due to atrial fibrillation or mural thrombus
Ataxia With Oculomotor Apraxia Types 1 and 2
- Type 1: Autosomal recessive, mutation in APTX gene - MR shows cerebellar atrophy, mild brainstem atrophy - Cortical atrophy in advanced stages
- Type 2: Autosomal recessive, mutation in SETX gene - Peripheral neuropathy and ↑ serum α-fetoprotein - MR shows cerebellar atrophy
Ataxia Telangiectasia
- Autosomal recessive ataxic disorder
- Normal pons; initially cerebellum may also be normal
- MR between 3 and 7 years of age usually shows superior vermian and lateral cerebellar hemispheric atrophy
- Later, diffuse cerebellovermian atrophy, including dentate nuclei and cerebellar peduncles
- Subtle ↑ FLAIR signal of cerebellar cortex after atrophy
- Telangiectasias evident by late childhood and early adult stage using T2*/SWI/postcontrast MR
- Supratentorial WM hyperintensities due to spongiosis surrounding telangiectasias
Fragile X-Associated Tremor/Ataxia Syndrome
- Late-onset X-linked dominant neurodegeneration
- Variable penetrance; males between 50 and 80 years of age
- FMR1 gene mutation affecting CGG trinucleotide repeats
- Generalized cerebral, cerebellar, and brainstem atrophy
- Periventricular, deep WM and corpus callosum ↑ T2
- Characteristic bilateral MCP focal hyperintensities in 60%
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay
- Atrophy of anterior cerebellar vermis and SCP 1st
- Cerebellar hemisphere, medulla, and cervical cord later
- Bulky pons and MCP; subtle ↑ T2 in lateral pons and MCP
- Characteristic ↓ T2/FLAIR transverse striations (pontine tigroid hypointensities) in pontine base and tegmentum
- DTI shows interruption of thin pyramidal tracts by these hyperplastic pontocerebellar fibers
- Rim of T2 hyperintensity around thalami
- Straightened spine in radiographs

PATHOLOGY

General Features
- Autosomal dominant ataxia; many SCAs due to PolyQ expansion of coding CAG repeats
- Various other gene loci and proteins in remaining SCAs
- 60-75% SCA patients only have mutations in known loci
- Expansion of CAG repeats produce toxic gain of function
- PolyQ SCAs, such as other PolyQ disorders, symptoms manifest above particular CAG repeat threshold
- Threshold for symptoms variable for different genes
- Threshold in most SCA types > 36, for SCA3 (MJD) > 50
- Commonest mutant genes: ATXN1 (SCA1), ATXN2(SCA2), ATXN3 (SCA3/MJD), CACNA1A (SCA6), ATN1 (DRPLA)
Staging, Grading, & Classification
- SCA types currently numbered 1-40 and beyond
- Genetic anticipation: Earlier onset and progressive worsening of phenotype in successive generations
Gross Pathologic & Surgical Features
- Cerebellar atrophy, variable brainstem atrophy, flattening of facial colliculus in MJD
- Neuronal dysfunction and neuronal loss in 10-20 years
- Neurodegeneration of pontine reticulotegmental nucleus in SCA1, SCA2, SCA3 - Nucleus involved in horizontal smooth pursuit eye movements and accuracy of horizontal saccades

CLINICAL ISSUES

Presentation

Most common signs/symptoms
```
- Cerebellar ataxia in all SCAs
```

Other signs/symptoms

- SCA1: Pyramidal signs, peripheral neuropathy
- SCA2: Slow saccades, myoclonus, areflexia
- SCA3/MJD: Slow saccades, persistent stare, extrapyramidal signs, peripheral neuropathy
- SCA6: Nystagmus; mild, can be very late onset
- Juvenile-onset DRPLA: Myoclonus, seizures, behavioral changes, and intellectual deterioration
- Adult-onset DRPLA: Choreoathetosis, delusions, dementia

Demographics
- **SCA3 (MJD)****:**Portuguese Azorean, William Machado family in New England 1st to be diagnosed with MJD - Azorean Californian Joseph family also had MJD
- SCAs usually present in middle age
- SCA1, 37 years (range: 5-65); SCA2, 35 years (range: 7-66); SCA3, 37 years (range: 5-66); SCA6, 55 years (range: 31-77)
- Earlier age of onset and more severe disease with increasing number of CAG repeats on expanded alleles
Natural History & Prognosis
- Average SCA disability progression over 1-2 decades
- Wheelchair bound by 10-15 years after symptom onset
- Higher baseline scores on Scale for the Assessment and Rating of Ataxia (SARA) associated with shorter survival
- SCA1 (mean age of death 56 years) more rapid disease progression and shorter survival than SCA2, SCA3, SCA6
Treatment
- No effective or curative treatment
- Zolpidem: Transient improvement in cerebellar symptoms
- Varenicline (partial nicotine agonist): Improvement in some measures of cerebellar dysfunction
- Polyglutamine neurotoxicity suppressed by overexpression of heat shock proteins in animal studies
- Gene silencing with RNA interference promising in SCA mouse model

DIAGNOSTIC CHECKLIST

Consider
- Young to middle-aged patient with slowly progressing cerebellar ataxia and other typical associated symptoms
Image Interpretation Pearls
- Atrophy of cerebellum ± brainstem
- Evaluate axial T2WI for characteristic hyperintense signal in SCA types, especially pons, MCP, periventricular WM

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References

Selected References

Images

Selected Images

Flow chart shows a diagnostic decision tree for cerebellar ataxia.

Axial routine T1WI MR shows BT-ratio measurement at the axial slice with largest visualization of MCP. The medial lemniscus is identified as lines of low intensity . The distance of pontine base (B) is measured from ventral edge of pons to ventral edge of medial lemniscus (blue line). The distance of pontine tegmentum (T) is measured from ventral edge of medial lemniscus to dorsal edge of pons (red line). BT-ratio is B/T.

Axial T2WI MR in a SCA3/MJD patient shows pontine midline linear T2-hyperintensity (PMH) . PMH is also seen in SCA1, DRPLA, & other cerebellar ataxias with brainstem involvement. Bilateral bright MCP sign is seen; it is also described in SCA2, SCA6, DRPLA, MSA-C, FXTAS, Wilson disease, ischemia, demyelination, etc.

Axial FLAIR MR in a SCA2 patient shows hot cross bun sign (HCBS) ; it is also characteristic of MSA-C and rarely in MJD. Note bright MCP sign .

Axial NECT in a SCA1 patient shows cerebellum and pontine tegmentum (dorsal pons) atrophy.

Axial NECT in same SCA1 patient shows atrophy of the caudate nuclei bilaterally with convex margins of the frontal horns (boxcar appearance) due to atrophy of the caudate heads . Huntington disease, neuroacanthocytosis, and frontotemporal lobar degeneration with fused in sarcoma protein (FTLD-FUS) can also produce this appearance.

Sagittal T2WI MR in a SCA3/MJD patient shows atrophy of pontine tegmentum (dorsal pons) with a concave posterior pontine surface . Also notice the severe atrophy of cerebellum and superior cerebellar peduncle (SCP) . There is atrophy of medulla and upper cervical spinal cord .

Axial thin 3D T2 SPACE MR in the same SCA3/MJD patient shows tiny hyperintensities just outside the internal capsules, at the inner segments of globi pallidi .

Axial T2WI MR in a DRPLA patient shows midbrain atrophy with bilateral focal abnormal hyperintense signal . Patient also had pontine atrophy more prominent in the tegmentum than base (not shown). There is bilateral SCP atrophy , which can be also seen in SCA3/MJD, SCA6, SCA8, Friedrich ataxia, ARSACS, MSA-P, and PSP. Note that SCP is spared in MSA-C, an important mimic of SCAs.

Axial FLAIR MR in the same DRPLA patient shows subtle periventricular WM hyperintensities .

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KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Pathology

Clinical Issues

Diagnostic Checklist

TERMINOLOGY

Abbreviations

Synonyms

Definitions

IMAGING

General Features

Best diagnostic clue

Location

Size

Morphology

CT Findings

MR Findings

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

Friedrich Ataxia

Ataxia With Oculomotor Apraxia Types 1 and 2

Ataxia Telangiectasia

Fragile X-Associated Tremor/Ataxia Syndrome

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

PATHOLOGY

General Features

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Other signs/symptoms

Demographics

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

References

Selected References

Images

Selected Images

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