Diagnosis and management of progressive ataxia in adults

Abstract

Progressive ataxia in adults can be difficult to diagnose, owing to its heterogeneity and the rarity of individual causes. Many patients remain undiagnosed (‘idiopathic’ ataxia). This paper provides suggested diagnostic pathways for the general neurologist, based on Ataxia UK’s guidelines for professionals. MR brain scanning can provide diagnostic clues, as well as identify ‘structural’ causes such as tumours and multiple sclerosis. Advances in molecular genetics, including the wider and cheaper availability of ‘next-generation sequencing’, have enabled clinicians to identify many more cases with a genetic cause. Finally, autoimmunity is probably an under-recognised cause of progressive ataxia: as well as patients with antigliadin antibodies there are smaller numbers with various antibodies, including some associated with cancer. There are a few treatable ataxias, but also symptomatic treatments to help people with the spectrum of complications that might accompany progressive ataxias. Multidisciplinary team involvement and allied health professionals’ input are critical to excellent patient care, including in the palliative phase. We can no longer justify a nihilistic approach to the management of ataxia.

Full text

196 de SilvaRN, etal. Pract Neurol 2019;19:196–207. doi:10.1136/practneurol-2018-002096
REVIEW
1Department of Neurology,
Essex Centre for Neurological
Sciences, Queen’s Hospital,
Romford, UK
2Ataxia UK, London, UK
3Department of Clinical and
Movement Neurosciences,
Ataxia Centre, UCL Institute of
Neurology, London, UK
4Academic Department of
Neurosciences, Sheffield
Teaching Hospitals NHS Trust
and University of Sheffield,
Sheffield, UK
Correspondence to
Dr Rajith Nilantha de Silva,
Department of Neurology,
Essex Centre for Neurological
Sciences, Queen’s Hospital,
Romford RM7 0AG, UK;
desilva63@ aol. com
Accepted 17 December 2018
Published Online First
2May2019
To cite: de SilvaRN,
VallortigaraJ, GreenfieldJ,
etal. Pract Neurol
2019;19:196–207.
Diagnosis and management of
progressive ataxia inadults
Rajith Nilantha de Silva,1 Julie Vallortigara,2 Julie Greeneld,2
Barry Hunt,2 Paola Giunti,3 Marios Hadjivassiliou4
© Author(s) (or their
employer(s)) 2019. Re-use
permitted under CC BY.
Published by BMJ.
ABSTRACT
Progressive ataxia in adults can be difcult to
diagnose, owing to its heterogeneity and the
rarity of individual causes. Many patients remain
undiagnosed (‘idiopathic’ ataxia). This paper
provides suggested diagnostic pathways for
the general neurologist, based on Ataxia UK’s
guidelines for professionals. MR brain scanning
can provide diagnostic clues, as well as identify
‘structural’ causes such as tumours and multiple
sclerosis. Advances in molecular genetics,
including the wider and cheaper availability of
‘next-generation sequencing’, have enabled
clinicians to identify many more cases with a
genetic cause. Finally, autoimmunity is probably
an under-recognised cause of progressive
ataxia: as well as patients with antigliadin
antibodies there are smaller numbers with
various antibodies, including some associated
with cancer. There are a few treatable ataxias,
but also symptomatic treatments to help
people with the spectrum of complications
that might accompany progressive ataxias.
Multidisciplinary team involvement and allied
health professionals’ input are critical to excellent
patient care, including in the palliative phase. We
can no longer justify a nihilistic approach to the
management of ataxia.
INTRODUCTION
Ataxia, or lack of coordination, is a
common manifestation of various neuro-
logical conditions, including stroke, brain
tumour, multiple sclerosis, traumatic
brain injury, toxicity, infection (including
following varicella) and congenital cere-
bellar defects. Its evolution can be acute,
subacute, episodic or chronic. Progressive
ataxias frequently cause diagnostic uncer-
tainty in general neurological practice,
and many cases remain undiagnosed (or
‘idiopathic’). This review aims to provide
general neurologists with helpful path-
ways for diagnosing and managing adults
with progressive ataxias. Recent advances
in molecular genetics have enabled the
diagnosis of many more cases with a
genetic cause. Autoimmunity may also
be important (but under-recognised)
in causing some progressive cerebellar
ataxias. There are no current treatments
to halt the progression of most forms of
chronic ataxia (with a few notable excep-
tions) but there have been recent advances
in disease-modifying interventions. Ataxia
management warrants a broad and multi-
disciplinary approach.
In this review, we explore in detail the
progressive ataxias in adults, providing
guidance on how to diagnose and to
manage patients (and their families). Our
advice is based on Ataxia UK’s guide-
lines on the management of the ataxias
(third edition July 2016), to which we
have contributed (https://www. ataxia.
org. uk/ Handlers/ Download. ashx?
IDMF= 261e0aa4- 5ca0- 4b90- 9db0-
1ecb6ef8738a).1 Our emphasis is clinical,
guiding the busy general neurologist to
a precise diagnosis, identifying pitfalls
to avoid and outlining best practice in
managing patients.
Types of ataxia
The ataxias may be broadly divided into
those that are genetic (with or without
a family history) and those that are
acquired/degenerative. ‘Sporadic’ ataxia
implies there is no family history. Acquired
progressive ataxias can be immune medi-
ated (eg, paraneoplastic spinocerebellar
degeneration, gluten ataxia), degenerative
(eg, cerebellar variant of multiple systems
atrophy (type C)), caused by deficiency
states (eg, vitamin B12, vitamin E, and so
on), toxicity (eg, alcohol-related ataxia,
phenytoin), or associated with infections
(HIV, sporadic Creutzfeldt-Jakob disease,
progressive multifocal leucoencephalop-
athy, and so on). Inherited ataxias can have
autosomal dominant, autosomal recessive,
X-linked or mitochondrial (maternal)
inheritance. Metabolic disorders (eg,
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Niemann-Pick type C, Tay-Sachs disease), even though
‘inherited’, can present as late-onset ataxia with no
family history, emphasising the need for careful clin-
ical scrutiny and comprehensive and appropriate labo-
ratory testing.
Clinical presentation
Patients with ataxia report clumsiness, unsteadiness,
incoordination and slurred speech. Rarely, they expe-
rience oscillopsia. When examined, there may be one
or more of the following signs2:
►Gait ataxia and impaired sitting balance (usually late in
the disease).
►Gaze-evoked nystagmus, jerky (saccadic) pursuit and
hypo/hypermetropic saccades.
►Dysarthria.
►Intention tremor.
►Dysmetria.
►Dysdiadochokinesis.
The signs rarely indicate the cause of the patient’s
ataxia but occasionally there are very helpful hints.
►Reflexes are usually reduced or absent in Friedreich’s
ataxia, ataxia associated with vitamin E deficiency,
ataxia with oculomotor apraxia type 2 and spinocere-
bellar ataxia (SCA) type 2. Reflexes are present, even
brisk, in patients with most of the dominant SCAs and
patients with multiple systems atrophy type C.
►Eye movements. Oculomotor apraxia can develop in
ataxia-telangiectasia and in ataxia with oculomotor
apraxia type 1 (although rare in this condition) and type
2. Slow saccades are typical of SCA type 2.
►Postural hypotension (often with impotence and urinary
urgency/incontinence) points towards multiple systems
atrophy type C.
►Tendon xanthomas (and early-onset cataracts) suggest
cerebrotendinous xanthomatosis.
►Abnormal visually enhanced vestibulo-ocular reflexes
(and pathological head impulse test responses) are
characteristic of cerebellar ataxia with neuropathy and
vestibular areflexia syndrome (CANVAS), which also has
a sensory neuropathy/neuronopathy.39
The age of onset and the rate of ataxia progres-
sion are perhaps the two most useful clinical features
pointing to the cause.
►Age of onset. Ataxia may appear first in infancy (reflecting
a congenital or developmental cause, often genetic) or
develop before aged 20 years (early-onset ataxia). Most
early-onset ataxias prove to be genetic (usually auto-
somal recessive or mitochondrial inheritance), even if
there is no family history. Dominant ataxias (including
the SCAs) tend to present later (from the third and
fourth decades onwards). However, this rule does not
always hold: Friedreich’s ataxia can have a late onset
(with intact or even brisk reflexes) and also some SCAs
have very young-onset forms (associated with large CAG
repeat expansions). CANVAS, despite recessive inher-
itance, presents unusually late (in middle age).39
►Rapid progression (within weeks to months) is character-
istic of paraneoplastic spinocerebellar degeneration and
sporadic Creutzfeldt-Jakob disease. Multiple systems
atrophy type C can also advance faster than other
progressive neurodegenerative ataxias (including inher-
ited types), which generally progress over many years.
There are validated measures (such as the ‘scale
for the assessment and rating of ataxia’, table 1) to
monitor the rate of progression serially.3 Therapeutic
trials require researchers to use rating scales, which
have as their endpoint the improvement or the halting
of progression of ataxia.
Investigation
Brain imaging with MRI (or CT, if MRI is contrain-
dicated) is essential in almost everyone with ataxia.
While it is rarely diagnostic, it often provides helpful
diagnostic clues, as well as ruling out structural
pathology (table 2). The MR scan usually shows cere-
bellar atrophy, in line with the clinical appraisal.
Diagnostic tests
Table 3 shows the investigations useful for patients
presenting with ataxia, listed as first, second and third
lines, based on the guidelines.
First-line studies, such as checking thyroid function,
serum B12 and folate (and homocysteine) and coeliac
serology, could be undertaken in primary care. Most
people with ataxia require evaluation in secondary care,
preferably by a neurologist. At this point, in addition to
cranial (with/without spinal) imaging, patients may need
(depending on clinical context) lumbar puncture, elec-
trophysiological testing, CT scan of thorax, abdomen
and pelvis, and muscle biopsy. Genetic testing (even if
there is no family history) may also be considered at
this stage, given how commonly genetic factors cause
progressive ataxia. Rapid progression of ataxia (within
months) should prompt a search for underlying malig-
nancy, including with serological testing for parane-
oplastic antibodies.4 A fluorodeoxyglucose positron
emission tomography study may be indicated, even if the
CT scan of thorax, abdomen and pelvis is normal. The
responsible malignancy may be occult and easily missed
in the initial imaging. Its identification may enable earlier
diagnosis of the cancer, and possibly cure. Some forms
of Creutzfeldt-Jakob disease (including inherited forms,
such as Gerstmann-Straussler syndrome) can present
with progressive ataxia, when again the tempo of deteri-
oration may be relatively rapid. Neurologists frequently
infer that alcohol toxicity is causing a patient’s progres-
sive cerebellar ataxia but such cases usually justify
further investigation, which often identifies alternative/
additional explanations for their ataxia.
Genetic testing
Genetic diagnoses among patients with progressive
inherited ataxia are still evolving, especially with recent
rapid advances in molecular genetics. The advent and
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Table 1 Scale for the assessment and rating of ataxia (SARA)
1. Gait 2. Stance
Proband is asked (1) to walk at a safe distance parallel to a wall
including a half-turn (turn around to face the opposite direction of gait)
and (2) to walk in tandem (heels to toes) without support.
0—Normal, no difficulties in walking, turning and walking tandem (up
to one misstep allowed)
1—Slight difficulties, only visible when walking 10 consecutive steps in
tandem
2—Clearly abnormal, tandem walking >10 steps not possible
3—Considerable staggering, difficulties in half-turn, but without support
4—Marked staggering, intermittent support of the wall required
5—Severe staggering, permanent support of one stick or light support
by one arm required
6—Walking >10 m only with strong support (two special sticks or
stroller or accompanying person)
7—Walking <10 m only with strong support (two special sticks or
stroller or accompanying person)
8—Unable to walk, even supported
Proband is asked to stand (1) in natural position, (2) with feet together
in parallel (big toes touching each other) and (3) in tandem (both feet
on one line, no space between heel and toe). Proband does not wear
shoes, eyes are open. For each condition, three trials are allowed. The
best trial is rated.
0—Normal, able to stand in tandem for >10 s
1—Able to stand with feet together without sway, but not in tandem
for >10 s
2—Able to stand with feet together for >10 s, but only with sway
3—Able to stand for >10 s without support in natural position, but not
with feet together
4—Able to stand for >10 s in natural position only with intermittent
support
5—Able to stand >10 s in natural position only with constant support
of one arm
6—Unable to stand for >10 s even with constant support of one arm
Score Score
3. Sitting 4. Speech disturbance
Proband is asked to sit on an examination bed without support of feet,
eyes open and arms outstretched to the front.
0—Normal, no difficulties sitting >10 s
1—Slight difficulties, intermittent sway
2—Constant sway, but able to sit >10 s without support
3—Able to sit for >10 s only with intermittent support
4—Unable to sit for >10 s without continuous support
Speech is assessed during normal conversation.
0—Normal
1—Suggestion of speech disturbance
2—Impaired speech, but easy to understand
3—Occasional words difficult to understand
4—Many words difficult to understand
5—Only single words understandable
6—Speech unintelligible/anarthria
Score Score
5. Finger chase 6. Nose–finger test
Rated separately for each side
Proband sits comfortably, if necessary with their feet and trunk
supported. Examiner sits in front of proband and performs five
consecutive sudden and fast-pointing movements in unpredictable
directions in a frontal plane, at about half of proband’s reach.
Movements have an amplitude of 30 cm and a frequency of one
movement every 2 s. Proband is asked to follow the movements with his
index finger, as fast and precisely as possible. Average performance of
last three movements is rated.
0—No dysmetria
1—Dysmetria, under/overshooting target <5 cm
2—Dysmetria, under/overshooting target <15 cm
3—Dysmetria, under/overshooting target >15 cm
4—Unable to perform 5 pointing movements
Rated separately for each side
Proband sits comfortably, if necessary with their feet and trunk
supported. Proband is asked to point repeatedly with the index finger
from his nose to examiner’s finger, which is in front of the proband at
about 90% of proband’s reach. Movements are performed at moderate
speed. The average performance of movements is rated according to the
amplitude of the kinetic tremor.
0—No tremor
1—Tremor with an amplitude <2 cm
2—Tremor with an amplitude <5 cm
3—Tremor with an amplitude >5 cm
4—Unable to perform
5—Pointing movements
Score Right Left Score Right Left
Mean of both sides (R+L)/2 Mean of both sides (R+L)/2
7. Fast alternating hand movements 8. Heel–shin slide
Rated separately for each side
Proband sits comfortably, if necessary, with the feet and trunk
supported. The proband is asked to perform 10 cycles of repetitive
alternation of pronations and supinations of the hand on the thigh
as fast and as precisely as possible. The examiner demonstrates the
movement at about 10 cycles within 7 s. Exact times for movement
execution have to be taken.
1. 0—Normal, no irregularities (performs <10 s)
2. 1—Slightly irregular (performs <10 s)
3. 2—Clearly irregular, single movements difficult to distinguish or relevant
interruptions, but performs <10 s
4. 3—Very irregular, single movements difficult to distinguish or relevant
interruptions, performs >10 s
5. 4—Unable to complete 10 cycles
Rated separately for each side
Proband lies on examination bed, unable to see his/her legs. Proband
is asked to lift one leg, point with the heel to the opposite knee,
slide down along the shin to the ankle, and lay the leg back on the
examination bed. The task is performed three times. Slide-down
movements should be performed within 1 s. If proband slides down
without contact to shin in all three trials, rate 4.
0—Normal
1—Slightly abnormal, contact to shin maintained
2—Clearly abnormal, goes off shin up to three times during three cycles
3—Severely abnormal, goes off shin four or more times during three
cycles
4—Unable to perform the task
Score Right Left Score Right Left
Mean of both sides (R+L)/2 Mean of both sides (R+L)/2
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Table 2 Diagnostic clues from MR scanning of the brain
Condition MR brain scan finding(s) MRI sequence
‘Diagnostic’
Multiple systems atrophy type C ‘Hot-cross bun’ sign*; pontine atrophy (figure1) T2/FLAIR
Fragile X tremor-ataxia syndrome Middle cerebellar peduncle sign† (figure2) T2/FLAIR
Superficial siderosis Deposition of haemosiderin; cerebellar atrophy (figure3) GRE/T2*
Sporadic Creutzfeldt-Jakob disease High basal ganglia signal; cortical high (and persistent DWI) signal T2/FLAIR, DWI/ADC
Autosomal recessive spastic ataxia of Charlevoix-
Saguenay
Hypointense pontine stripes (figure4); atrophy of superior cerebellar vermis;
thinning of posterior mid-body of corpus callosum
T2/FLAIR
SPG7 High dentate nuclei signal (figure5)38 T2/FLAIR
‘Suggestive’ (in familial forms)
Friedreich’s ataxia, vitamin E deficiency Upper cervical cord atrophy; cerebellar atrophy late (figure6) T1/T2
Ataxia-telangiectasia, ataxia with oculomotor
apraxia, types 1 and 2
Cerebellar atrophy T1/T2
Autosomal dominant spinocerebellar ataxia Cerebellar and pontine atrophy T1/T2
*Also occurs in autosomal dominant spinocerebellar ataxia.
†Can occur in multiple systems atrophy type C.
ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; GRE, gradient echo; SPG7, spastic
paraplegia 7.
Figure 1 Fluid-attenuated inversion recovery (FLAIR) axial
image of the brain, showing pontine and cerebellar atrophy,
and ‘hot-cross bun’ sign, in a patient with multiple systems
atrophy type C (MSA-C). Note the narrow middle cerebellar
peduncles.
Figure 2 Axial T2-uid-attenuated inversion recovery (FLAIR)
image of the brain, showing high signal in the middle cerebellar
peduncles, in a case of fragile X tremor-ataxia syndrome
(FXTAS).
impact of next-generation sequencing is such that
targeted searches for known gene mutations (other than
in family members, where this is already fully charac-
terised) may soon become obsolete. Candidate gene
testing is still available, for example, in the UK via the
UK Genetics Testing Network (https:// ukgtn. nhs. uk).
Next-generation sequencing panels allow the search for
a wider array of ‘ataxia genes’, available from specialist
genetic laboratories (Oxford and Sheffield, in the UK).
When the diagnosis remains elusive, clinicians should
consider exome or whole-genome sequencing.
When undertaking genetics tests, even for diagnostic
purposes, clinicians should counsel people with ataxia
about the potential implications of a positive result for
other family members. Genetic counselling services
should be made available for asymptomatic relatives
who wish to be tested, after identifying a pathological
genetic variant in a patient with progressive ataxia. There
may also be important implications on the reproductive
choices that patients and at-risk relatives make, based on
this knowledge, including in relation to prenatal testing
and preimplantation genetic diagnosis.5 These services
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Figure 3 Axial T2-weighted MRI of the brain, showing
haemosiderin deposition around the medulla and cerebellum, in
a case of supercial siderosis. (Gradient echo (GRE)/T2* imaging
would have demonstrated these changes more vividly.)
Figure 4 Axial T2-weighted MRI of the brain in a case of
autosomal recessive spastic ataxia of Charlevoix-Saguenay
(ARSACS) showing pontine hypointense (‘tigroid’) stripes.
Figure 5 Axial T2-weighted MRI of the brain in a case of
hereditary spastic paraplegia 7 (SPG7) showing hyperintensity
of the dentate nuclei (arrowed).
Figure 6 Sagittal T1-weighted MRI of the brain and upper
cervical cord in a 26-year-old woman with ataxia. There is
relative preservation of the brainstem and cerebellum, but
thinning of upper cervical cord. (Friedreich’s ataxia (FRDA) was
conrmed in her genetically.)
are delivered by clinical genetics services, in liaison with
specialist obstetrics/prenatal units.
Next-generation sequencing is already showing great
promise for investigating patients with ataxia. There
are already ‘ataxia panels’ using parallel sequencing
technology but they are limited because they seek only
known (ataxia) genes.6 Exome sequencing and whole-ge-
nome sequencing (the approach adopted by the 100,000
Genomes Project) are increasingly used in clinical prac-
tice, and will probably make major contributions to our
knowledge of the underlying genetic factors and mecha-
nisms causing ataxia, as well as expanding our diagnostic
acumen. A critical issue with these ‘novel’ techniques
is the generation of data in the form of variants of
unknown significance, and the interpretation of ‘results’
needs significant bioinformatics input. Technologically,
too, next-generation sequencing is still not sufficiently
reliable to identify large-scale genomic rearrangements,
including nucleotide expansions with certainty (or with
precision regarding the number of repeats, in the case of
expansions). Thus, at present, we need a combination of
conventional and novel techniques to investigate familial
ataxia.
Dominant ataxias
There are over 40 dominant currently identified SCAs,
some of which may be limited to a small number of
families or geographical areas.7 SCAs 1, 2 and 3 can be
‘complicated’ by the co-occurrence of cognitive decline,
slow saccades, ophthalmoplegia, pyramidal/extrapyra-
midal signs and neuropathy. Patients with SCA7 usually
also have macular degeneration and blindness. Some
forms—including SCA7 and dentato-rubro-pallido-luy-
sian atrophy—have extreme repeat expansion instability,
and hence a tendency for severe anticipation (particu-
larly when paternally inherited). SCA6 (a relatively
‘pure’ form of SCA) typically has stable CAG repeat
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Table 3 Diagnostic investigations in adults
Primary care Serum urea and electrolytes, serum
creatinine, full blood count
ESR/C-reactive protein
Liver enzymes, serum γ-GT, thyroid function
tests
Vitamin B12
Serum folate, plasma glucose, chest X-ray
Secondary care
(first line)
αFP
Blood film
Caeruloplasmin/copper
Coeliac disease screen, serum creatine
kinase
Genetic tests for Friedreich’s ataxia, SCA
1, 2, 3, 6, 7 (12, 17) and fragile X tremor-
ataxia syndrome
Lactate
Lipid-adjusted vitamin E and lipoproteins
Lumbar puncture (cells, protein, glucose,
cytology, oligoclonal bands, lactate, ferritin)
MR scan of brain and cervical spine
Anti-Hu/Yo and other paraneoplastic
antibodies
Anti-GAD antibody
Anti-voltage-gated calcium channel
antibody
CT scan of chest, abdomen, pelvis
14-3-3 and other proteins in CSF (prion
diseases)
Secondary care
(second line)
Cholestanol
Plasma oxysterols
Bile acids
Coenzyme Q10 (ubiquinone)
Electroencephalography
Very-long-chain fatty acids
Muscle biopsy
Ophthalmology/optical coherence
tomography
Peripheral nerve conduction studies
Phytanic acid
Remaining genetic tests (next-generation
sequencing)
Total body PET scan
White cell enzymes
CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; αFP, alpha-fetoprotein; GAD, glutamic acid decarboxylase; γ-GT, gamma-glutamyltransferase;
PET, positron emission tomography; SCA, spinocerebellar ataxia.
Figure 7 How often is a genetic cause of progressive ataxia identied? Dx, diagnosis; ANO10, ANO10-associated ataxia; AOA1/
AOA2, ataxia with oculomotor apraxia types 1 and 2; AT, ataxia-telangiectasia; EA2, episodic ataxia type 2; FRDA, Friedreich’s ataxia;
FXTAS, fragile X tremor-ataxia syndrome; Mit, mitochondrial cytopathy; SCA6, spinocerebellar ataxia type 6; SPG7, hereditary spastic
paraplegia 7.
expansions during meiosis. The causative gene of SCA6
is also implicated in another form of dominant ataxia,
episodic ataxia type 2, and a form of familial hemiplegic
migraine (both of which, like SCA6, manifest with
progressive ataxia, usually after 50 years). SCA6/episodic
ataxia type 2 is the most common dominant ataxia in the
British Isles (see figure 7). The genetic mutations under-
pinning the SCAs are diverse, and include trinucleotide
repeat expansions (eg, SCAs 1–3 and 6), non-trinucle-
otide repeat expansions (eg, SCA10, where there is an
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intronic pentanucleotide repeat expansion of ATXN10),
deletions/insertions and missense/nonsense mutations.
Recessive ataxias
Friedreich’s ataxia is the most common inherited
ataxia in Caucasian populations, with a prevalence
of around 1 per 20 000–50 000. Spastic paraplegia
7 (SPG7), a classical cause of hereditary spastic para-
paresis, is the next most common recessive ataxia in
the UK.8 Patients with SPG7 may have only minimal
spasticity. Spastic ataxia is also a feature of autosomal
recessive spastic ataxia of Charlevoix-Saguenay. In
terms of frequency, Friedreich’s ataxia and SPG7 are
followed by ataxia with oculomotor apraxia type 2 and
ataxia-telangiectasia (which presents less commonly
in adulthood). MRI may provide useful clues on the
genetic cause (table 2). Clues to ataxia-telangiectasia
(and ataxia with oculomotor apraxias) include a high
serum alpha-fetoprotein and creatine kinase, and a low
serum albumin. Optical coherence tomography can
provide support for a diagnosis of autosomal recessive
spastic ataxia of Charlevoix-Saguenay.
Despite the growing emphasis on next-generation
sequencing in helping to diagnose inherited ataxia,6
accurate clinical phenotyping (incorporating relevant
laboratory data) remains important. This is especially
so when there are ‘variants of uncertain significance’:
knowledge and experience must then supplement the
bioinformatics pipeline. ‘Deep phenotyping’ is an
emerging field where promising biomarkers are used
to target genetic testing (which is still expensive).
For example, retinal fibre layer thickening (identified
using optical coherence tomography) appears to be
a sensitive and specific indicator of autosomal reces-
sive spastic ataxia of Charlevoix-Saguenay.9 Periph-
eral electrophysiology may also help define the cause
of (recessive) ataxias. There are four categories (after
eliminating Friedreich’s ataxia) based on:
1. The absence of neuropathy (mutations in SYNE1,
ANO10 and ADCK3).
2. The presence of a pure sensory neuronopathy (mutations
in POLG1, AVED and RFC1).
3. The presence of an axonal sensorimotor neuropathy
(ataxia with oculomotor apraxia types 1 and 2, and cere-
brotendinous xanthomatosis).
4. The presence of a demyelinating neuropathy (autosomal
recessive spastic ataxia of Charlevoix-Saguenay).10
Relative frequency of genetic forms of ataxia
Figure 7 shows data from two specialist ataxia centres
in Sheffield and Dublin, giving an insight to the rela-
tive frequencies of the different inherited ataxias in the
British Isles. The data also suggest the likelihood of
making a specific diagnosis in the specialist setting.11
12 However, these proportions vary with geography,
reflecting founder gene mutations on different
populations.
Immunological studies, including testing, for coeliac disease
Autoimmunity is increasingly recognised as a cause of
progressive cerebellar ataxia. A cohort of patients from
Sheffield with ataxia and positive antigliadin anti-
bodies (a serological marker of gluten sensitivity and
coeliac disease) is perhaps the best studied.13 In this
series, 25% of all sporadic cases were diagnosed with
gluten ataxia, although in other centres the proportion
recognised is considerably lower.11 Given Sheffield’s
interest and expertise, testing included serum antigli-
adin IgG and IgA, antiendomysium and antitransglu-
taminase antibodies (including TG6 antibodies) and
duodenal biopsy. Only half of patients with gluten
ataxia have small bowel enteropathy (coeliac disease)
and so antigliadin antibodies are essential for diag-
nosing the remainder. Antibodies against transglutam-
inase type 6 (TG6) are a potentially useful biomarker
of gluten ataxia, and such testing may become
commercially viable shortly ( zedira. com). Mutations
in the transglutaminase 6 gene (TGM6) meanwhile
are associated with a dominant SCA (SCA35), further
supporting a role for TG6 in cerebellar functioning.
There is also a well-characterised form of progres-
sive myoclonic ataxia (of Ramsay Hunt) in patients
with coeliac disease; most have refractory coeliac
disease and need aggressive immunosuppression and
chemotherapy.
Other immune-mediated ataxias include parane-
oplastic spinocerebellar degeneration, anti-glutamic
acid decarboxylase-associated ataxia, and ataxia asso-
ciated with several other antibodies (anti-voltage-gated
calcium channel, dipeptidyl-peptidase-like protein 6
(DPPX), and so on). These frequently present acutely
or subacutely. Taken together, these observations raise
the possibility that immunity plays a critical role in
causing cerebellar injury in some patients with ataxia.
Thus, immune modulation may have a possible role
in stabilising their disease and preventing progression.
The diagnostic pathway is summarised in the info-
graphic (figure 8).
Management
Neurologists traditionally have taken a nihilistic view
to managing ataxia, as with many other neurodegener-
ation diseases. However, this is no longer justified. In
addition to rehabilitation therapies, there are specific
complications of ataxia to seek and address. These
interventions can significantly alleviate the problems
of progressive ataxia and prevent complications,
which are even potentially life threatening. Finally,
there are some rare but treatable conditions that need
identifying early. An enthusiastic and well-informed
clinician can provide valuable support to a patient
with ataxia. Participation in research can be important
for patients and, when appropriate, they should be
offered opportunities for this at each clinical review (
www. clinicaltrials. gov and www. ataxia. org. uk). When
a patient with ataxia approaches end of life, specialist
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Figure 8 Infographic 1: The Diagnostic Pathway
palliative care services should be involved to help
address their specific needs.
Medical interventions
Treatable ataxias
Ataxias that are treatable are rare, except for gluten
ataxia and other immune-mediated ataxias. In people
with ataxia associated with antigliadin (and possibly
more specific antibodies), we recommend a gluten-free
diet even in the absence of enteropathy.14 The antibody
titres should be repeated every 6 months to confirm
their elimination (by strict adherence to the diet). Note,
however, that the symptoms may not stabilise or improve
for up to a year.
Ataxia with vitamin E deficiency mimics Friedreich’s
ataxia (clinically and on MRI) and can be confirmed
genetically. The serum vitamin E concentration is
significantly low but should be tested as ‘lipid-adjusted
vitamin E’, as free vitamin E concentrations are unre-
liable and potentially misleading. Malabsorption
of vitamin E, including in abetalipoproteinaemia,
can result in a similar phenotype. Patients may need
replacement doses of up to 1500 mg/day.15
Ataxia with CoQ10 (or ubiquinone) deficiency is
probably under-recognised. It is a recessively inherited
disorder (ADCK3 mutations) where patients have a
low concentration of CoQ10 in skeletal muscle.16 Its
severity is variable and some people have seizures and
mild mental retardation. CoQ10 supplementation can
potentially improve the ataxic symptoms, although not
in everyone (and the exact form and dose of CoQ10
remains uncertain).17 18 Patients with mutations in
APTX (AOA1) and ANO10 can develop secondary
CoQ10 deficiency, and supplementation may also help
them.19
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Figure 9 Infographic 2: Symptom Management, including Multidisciplinary Team Input
Patients with cerebrotendinous xanthomatosis may
develop chronic diarrhoea in infancy, and cataracts
in the first decade. There may be visible deposits
of cholestenol in tendons. If confirmed (usually
biochemically), then chenodeoxycholic acid treat-
ment can stabilise or partially reverse the symptoms,
or (if given very early) may even help the neurolog-
ical complications.20 21
Niemann-Pick type C is a multisystem disorder caused
by the accumulation of cholesterol and glycosphin-
golipids in the brain and other organs. Consequently,
patients may develop splenomegaly and hepatomegaly
as well as ataxia. There may be a vertical supranu-
clear gaze palsy, sometimes with dystonia, myoclonus,
epilepsy and cognitive decline. The diagnosis can be
challenging, especially in (atypical) cases that present
later in life, and biopsy (of bone marrow and skin) does
not always give a definitive answer.22 Genetic testing for
the two causative genes (NPC1 implicated in 95% and
NPC2 implicated in 5%) may be more reliable. Plasma
oxysterols and bile acid measurements may prove to be
useful and inexpensive screening tools.23–25 Miglustat is
an approved disease-modifying therapy for patients with
Niemann-Pick type C.26 27
There are other treatable causes of ataxia, but these
typically present in children and are usually managed
in paediatric practice. These include CoQ10 (or
ubiquinone) deficiency, hypobetalipoproteinaemia,
Hartnup disease, biotinidase deficiency and pyruvate
dehydrogenase deficiency. Glucose transporter 1
deficiency often presents with paroxysmal movement
disorders, spasticity and ataxia, and its onset can be
delayed. A ketogenic diet is effective in treating the
associated epilepsy but perhaps is less effective in
helping the gait difficulties.28
Symptomatic treatments
The infographic summarises the potential symptoms
that neurologists may need to address (figure 9). The
treatment ‘strategies’ are frequently derived from
other neurological conditions with similar symp-
toms, and generally work equally well. The approach
to treating spasticity and bladder symptoms, for
example, is the same as for people with multiple scle-
rosis.29 30 The assessment and management of these
complications are best done by involving therapy
specialists, and multidisciplinary team working can
greatly enhance patient care. Speech and language
therapy input is essential throughout the patient
journey, from monitoring swallowing function in the
early stages and providing helpful hints on avoiding
complications, to planning percutaneous gastrostomy
feeding.31 Note that almost all these interventions to
manage patients with ataxia are non-evidence based,
and will probably never be studied in high-quality
randomised controlled trials.
The impact of cerebellar disease on cognition
is not widely known but can significantly impact
on morbidity. Such ‘remote’ effects of cerebellar
dysfunction can include subcortical frontal impair-
ments, affecting personality, behaviour and judge-
ment.32 Mental health complications (anxiety,
depression) may exacerbate people’s sense of isola-
tion and fear of the future. These symptoms often
accompany sleep disorders and fatigue but are
poorly recognised (according to Ataxia UK’s survey).
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The management of cardiac complications is espe-
cially important in Friedreich’s ataxia; patients need
regular ECGs and (ideally) echocardiograms to
detect cardiomyopathy developing.33–35 Echocardi-
ography may show concentric left ventricular hyper-
trophy (possibly in over half of cases, especially in
those of early onset). With disease progression, the
hypertrophy regresses, resulting in a thin and dilated
left ventricle. Serum troponin may be asymptomat-
ically elevated (in the absence of arrhythmia or an
acute coronary syndrome), and it may help to have
baseline values for future comparison. It is essential
to involve an interested and knowledgeable cardi-
ologist with experience of the care of Friedreich’s
ataxia, initially to advise on medication to treat the
cardiomyopathy and heart failure, and later for the
management of arrhythmias.
Episodic ataxia type 2 is characterised by periods
of cerebellar dysfunction lasting for hours or days,
sometimes with migraine, and rarely epilepsy. Later
in life, the ataxia becomes progressive, and MRI may
show cerebellar atrophy.36 Attacks can be precipitated
by stress, exertion, caffeine and alcohol, and patients
should be counselled appropriately. Acetazolamide
remains the mainstay of treatment but carries a risk of
renal calculi and (more commonly) of paraesthesia.
As well as good hydration, we recommend annual
ultrasound scans of the urinary tract. Flunarizine
and 4-aminopyridine, a potassium channel blocker,
can also help but (like acetazolamide) they are not
licensed in the UK to use in episodic ataxia type
2.37 Dichlorphenamide is extremely effective and
well tolerated but is currently too expensive to use
routinely. Having seizures is a contraindication to
using 4-aminopyridine.
Allied health professional interventions
The multidisciplinary team is clearly important
in evaluating and managing patients with ataxia.
Speech and language therapy (for both communi-
cation and swallowing), occupational therapy and
physiotherapy can each make important contribu-
tions at different stages of the patient journey. It
can be difficult to access interested and knowledge-
able therapists in the community, and this type of
expertise is rare outside of specialist ataxia clinics.
The guidelines have sections in each of these fields,
giving comprehensive advice on the types of assess-
ments and interventions that need to be done, and
may serve as an educational resource to accom-
pany referrals to community therapy teams. In our
experience, the nurturing of local ‘champions’ in
ataxia management (frequently a therapy colleague
working in a district general hospital) can generate
enthusiasm and help develop local expertise; in time
these therapists frequently become effective access
points for services for patients and their carers.
Reviews and monitoring
Patients with progressive ataxias should be offered
6–12 monthly reviews, ideally by a general neurolo-
gist or (where available) an ataxia specialist (neurolo-
gist or nurse). There are also services specifically for
adults and children with ataxia-telangiectasia, where
specialist input (again by multiprofessional teams)
can tackle the complications associated with this
condition, including cancer predisposition, immuno-
deficiency and lung disease. Patients require regular
review to identify any new symptoms early that may
need treatment, and for patients to take advantage of
advances in diagnostics and any new available treat-
ments. In addition, those with no established cause
for their ataxia can undergo thorough and repeated
review of the clinical features and investigation
results, which sometimes leads to a clearer diagnosis.
Patient support groups
Patients and their families should be encouraged
to contact patient support groups, such as Ataxia
UK. When a family first receives the diagnosis of
progressive ataxia, patients are usually not heard of
the condition or come across other people with it.
Support from patient organisations can therefore be
particularly important at this stage. The possibility
of meeting others in the same situation, receiving
emotional support and information, and the oppor-
tunity to learn of research developments (as well as
taking part in research projects) can all help.
Palliative care
Given that most progressive ataxias are incurable,
there are strikingly few published studies on their
palliation and end-of-life care. Many patients with
progressive ataxia have a normal life expectancy but
some forms (eg, multiple systems atrophy type C) can
progress rapidly, with a shortened life. The recom-
mendations in these guidelines are drawn from the
wider field of progressive neurological conditions.
We suggest that patients discuss advanced care
planning at the appropriate time. Patients with
intractable and/or distressing physical symptoms
may benefit from referral for specialist palliative
care, which might also help those with complex
social, psychological or spiritual needs. The time
for planning end-of-life care is when the clinician
answers ‘No’ to the ‘surprise question’—‘Would
you be surprised if this patient died in the next 12
months?’—as well there being generic and specific
(for ataxia) indicators that the patients have reached
the terminal phase of their illness. Management in
this phase should be geared towards enabling a ‘good
death’: being treated as an individual, with dignity
and respect, without pain or other distressing symp-
toms, in familiar surroundings, and in the company
of close friends and family.38
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REVIEW
Key points
►Progressive ataxia in adults is heterogeneous and can
be difficult to diagnose.
►Brain imaging, ideally with MRI, is essential.
►Rapidly progressive ataxia warrants urgent
investigation (particularly to exclude underlying
malignancy).
►Next-generation sequencing is enabling many more
‘idiopathic’ ataxias to be given a genetic cause.
►Immunity may be an under-recognised (and potentially
reversible) cause of progressive ataxia.
►The complications accompanying certain ataxias (eg,
Friedreich’s ataxia with cardiomyopathy and diabetes)
require active monitoring and management.
Acknowledgements The authors thank Andrea Nemeth for
detailed and informative discussion on genetics testing; Sanjiv
Chawda for guidance on the interpretation and presentation
of imaging data; and Grant Lipszyc for compilation and
presentation of references. The authors are grateful to the
specialist contributors to the Guidelines, for their expertise,
time and effort, and their indefatigable support to Ataxia UK.
Contributors RNdS conceived the idea of producing a clinically
relevant review article, based on the Ataxia UK guidelines,
and wrote the first draft. JV designed the infographics and
produced the final versions. All authors made substantial
contributions to the text, and revised the paper for important
intellectual content. All authors have given final approval of
the version submitted for review.
Funding The authors have not declared a specific grant for this
research from any funding agency in the public, commercial or
not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally
peer reviewed by Bart van de Warrenburg, Nijmegen, The
Netherlands.
Open access This is an open access article distributed in
accordance with the Creative Commons Attribution 4.0
Unported (CC BY 4.0) license, which permits others to copy,
redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link
to the licence is given, and indication of whether changes were
made. See: https:// creativecommons. org/ licenses/ by/ 4. 0/.
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