REVIEW Diagnosis and management of Pract Neurol: first published as 10.1136/practneurol-2018-002096 on 2 May 2019. Downloaded from progressive ataxia in adults Rajith Nilantha de Silva,1 Julie Vallortigara,2 Julie Greenfield,2 Barry Hunt,2 Paola Giunti,3 Marios Hadjivassiliou4 1Department of Neurology, ABSTRACT diagnosis of many more cases with a Essex Centre for Neurological Progressive ataxia in adults can be difficult to genetic cause. Autoimmunity may also Sciences, Queen’s Hospital, Romford, UK diagnose, owing to its heterogeneity and the be important (but under-recognised) 2Ataxia UK, London, UK rarity of individual causes. Many patients remain in causing some progressive cerebellar 3 Department of Clinical and undiagnosed (‘idiopathic’ ataxia). This paper ataxias. There are no current treatments Movement Neurosciences, provides suggested diagnostic pathways for to halt the progression of most forms of Ataxia Centre, UCL Institute of Neurology, London, UK the general neurologist, based on Ataxia UK’s chronic ataxia (with a few notable excep- 4Academic Department of guidelines for professionals. MR brain scanning tions) but there have been recent advances Neurosciences, Sheffield can provide diagnostic clues, as well as identify in disease-modifying interventions. Ataxia Teaching Hospitals NHS Trust ‘structural’ causes such as tumours and multiple and University of Sheffield, management warrants a broad and multi- Sheffield, UK sclerosis. Advances in molecular genetics, disciplinary approach. including the wider and cheaper availability of In this review, we explore in detail the Correspondence to ‘next-generation sequencing’, have enabled progressive ataxias in adults, providing Dr Rajith Nilantha de Silva, Department of Neurology, clinicians to identify many more cases with a guidance on how to diagnose and to Essex Centre for Neurological genetic cause. Finally, autoimmunity is probably manage patients (and their families). Our Sciences, Queen’s Hospital, an under-recognised cause of progressive advice is based on Ataxia UK’s guide- Romford RM7 0AG, UK; ataxia: as well as patients with antigliadin desilva63@ aol. com lines on the management of the ataxias antibodies there are smaller numbers with (third edition July 2016), to which we Accepted 17 December 2018 various antibodies, including some associated have contributed (https://www. ataxia. Published Online First with cancer. There are a few treatable ataxias, 2 May 2019 org. uk/ Handlers/ Download. ashx? but also symptomatic treatments to help IDMF= 261e0aa4- 5ca0- 4b90- 9db0- people with the spectrum of complications 1ecb6ef8738a).1 Our emphasis is clinical, that might accompany progressive ataxias. guiding the busy general neurologist to Multidisciplinary team involvement and allied a precise diagnosis, identifying pitfalls http://pn.bmj.com/ health professionals’ input are critical to excellent to avoid and outlining best practice in patient care, including in the palliative phase. We managing patients. can no longer justify a nihilistic approach to the management of ataxia. Types of ataxia The ataxias may be broadly divided into those that are genetic (with or without on October 2, 2021 by guest. Protected copyright. INTRODUCTION a family history) and those that are Ataxia, or lack of coordination, is a acquired/degenerative. ‘Sporadic’ ataxia common manifestation of various neuro- implies there is no family history. Acquired logical conditions, including stroke, brain progressive ataxias can be immune medi- tumour, multiple sclerosis, traumatic ated (eg, paraneoplastic spinocerebellar brain injury, toxicity, infection (including degeneration, gluten ataxia), degenerative following varicella) and congenital cere- (eg, cerebellar variant of multiple systems bellar defects. Its evolution can be acute, atrophy (type C)), caused by deficiency subacute, episodic or chronic. Progressive states (eg, vitamin B12, vitamin E, and so ataxias frequently cause diagnostic uncer- on), toxicity (eg, alcohol-related ataxia, © Author(s) (or their tainty in general neurological practice, phenytoin), or associated with infections employer(s)) 2019. Re-use and many cases remain undiagnosed (or (HIV, sporadic Creutzfeldt-Jakob disease, permitted under CC BY. Published by BMJ. ‘idiopathic’). This review aims to provide progressive multifocal leucoencephalop- general neurologists with helpful path- athy, and so on). Inherited ataxias can have To cite: de Silva RN, Vallortigara J, Greenfield J, ways for diagnosing and managing adults autosomal dominant, autosomal recessive, et al. Pract Neurol with progressive ataxias. Recent advances X-linked or mitochondrial (maternal) 2019;19:196–207. in molecular genetics have enabled the inheritance. Metabolic disorders (eg, 196 de Silva RN, et al. Pract Neurol 2019;19:196–207. doi:10.1136/practneurol-2018-002096 REVIEW Niemann-Pick type C, Tay-Sachs disease), even though ► Rapid progression (within weeks to months) is character- Pract Neurol: first published as 10.1136/practneurol-2018-002096 on 2 May 2019. Downloaded from ‘inherited’, can present as late-onset ataxia with no istic of paraneoplastic spinocerebellar degeneration and family history, emphasising the need for careful clin- sporadic Creutzfeldt-Jakob disease. Multiple systems ical scrutiny and comprehensive and appropriate labo- atrophy type C can also advance faster than other ratory testing. progressive neurodegenerative ataxias (including inher- ited types), which generally progress over many years. There are validated measures (such as the ‘scale Clinical presentation for the assessment and rating of ataxia’, table 1) to Patients with ataxia report clumsiness, unsteadiness, 3 monitor the rate of progression serially. Therapeutic incoordination and slurred speech. Rarely, they expe- trials require researchers to use rating scales, which rience oscillopsia. When examined, there may be one 2 have as their endpoint the improvement or the halting or more of the following signs : of progression of ataxia. ► Gait ataxia and impaired sitting balance (usually late in the disease). Investigation ► Gaze-evoked nystagmus, jerky (saccadic) pursuit and Brain imaging with MRI (or CT, if MRI is contrain- hypo/hypermetropic saccades. dicated) is essential in almost everyone with ataxia. ► Dysarthria. While it is rarely diagnostic, it often provides helpful ► Intention tremor. diagnostic clues, as well as ruling out structural ► Dysmetria. pathology (table 2). The MR scan usually shows cere- ► Dysdiadochokinesis. bellar atrophy, in line with the clinical appraisal. The signs rarely indicate the cause of the patient’s ataxia but occasionally there are very helpful hints. Diagnostic tests ► Reflexes are usually reduced or absent in Friedreich’s Table 3 shows the investigations useful for patients ataxia, ataxia associated with vitamin E deficiency, presenting with ataxia, listed as first, second and third ataxia with oculomotor apraxia type 2 and spinocere- lines, based on the guidelines. bellar ataxia (SCA) type 2. Reflexes are present, even First-line studies, such as checking thyroid function, brisk, in patients with most of the dominant SCAs and serum B12 and folate (and homocysteine) and coeliac patients with multiple systems atrophy type C. serology, could be undertaken in primary care. Most ► Eye movements. Oculomotor apraxia can develop in people with ataxia require evaluation in secondary care, ataxia-telangiectasia and in ataxia with oculomotor preferably by a neurologist. At this point, in addition to apraxia type 1 (although rare in this condition) and type cranial (with/without spinal) imaging, patients may need 2. Slow saccades are typical of SCA type 2. (depending on clinical context) lumbar puncture, elec- ► Postural hypotension (often with impotence and urinary trophysiological testing, CT scan of thorax, abdomen urgency/incontinence) points towards multiple systems and pelvis, and muscle biopsy. Genetic testing (even if atrophy type C. there is no family history) may also be considered at http://pn.bmj.com/ ► Tendon xanthomas (and early-onset cataracts) suggest this stage, given how commonly genetic factors cause cerebrotendinous xanthomatosis. progressive ataxia. Rapid progression of ataxia (within ► Abnormal visually enhanced vestibulo-ocular reflexes months) should prompt a search for underlying malig- (and pathological head impulse test responses) are nancy, including with serological testing for parane- characteristic of cerebellar ataxia with neuropathy and oplastic antibodies.4 A fluorodeoxyglucose positron vestibular areflexia syndrome (CANVAS), which also has emission tomography study may be indicated, even if the on October 2, 2021 by guest. Protected copyright. a sensory neuropathy/neuronopathy.39 CT scan of thorax, abdomen and pelvis is normal. The The age of onset and the rate of ataxia progres- responsible malignancy may be occult and easily missed sion are perhaps the two most useful clinical features in the initial imaging. Its identification may enable earlier pointing to the cause. diagnosis of the cancer, and possibly cure. Some forms ► Age of onset. Ataxia may appear first in infancy (reflecting of Creutzfeldt-Jakob disease (including inherited forms, a congenital or developmental cause, often genetic) or such as Gerstmann-Straussler syndrome) can present develop before aged 20 years (early-onset ataxia). Most with progressive ataxia, when again the tempo of deteri- early-onset ataxias prove to be genetic (usually auto- oration may be relatively rapid.