Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from Corticobasal syndrome: a practical guide

Duncan Wilson ‍ ,1,2 Campbell Le Heron,1,2 Tim Anderson ‍ 1,2,3

1Neurology Department, Abstract We diagnosed corticobasal syndrome Christchurch Hospital, Corticobasal syndrome is a disorder of movement, referred her to physiotherapy and occupa- Christchurch, New Zealand 2New Zealand Brain Research cognition and behaviour with several possible tional therapy. An MR scan of brain showed Institute, Christchurch, New underlying pathologies, including corticobasal only mild involutional changes consistent Zealand 3 degeneration. It presents insidiously and is slowly with age but no perirolandic atrophy. Department of Medicine, Her condition progressed over the University of Otago, progressive. Clinicians should consider the diagnosis Christchurch, Christchurch, New in people presenting with any combination of next 4 years. She lost vertical eye move- Zealand extrapyramidal features (with poor response to ments and her alien limb became very pronounced. Her speech deteriorated to Correspondence to levodopa), apraxia or other parietal signs, aphasia Dr Tim Anderson, New Zealand and alien-limb­ phenomena. Neuroimaging showing ‘yes’ and ‘no’, although she could still Brain Research Institute, asymmetrical perirolandic cortical changes supports comprehend. She became more rigid Christchurch, New Zealand; ​tim.​ the diagnosis, while advanced neuroimaging with worsening dystonia particularly of anderson@otago.​ ​ac.nz​ may give insight into the underlying pathology. neck extension, and her postural reflexes Accepted 2 March 2021 Identifying corticobasal syndrome carries some became impaired. We gave an unsuccessful management implications (especially if protein-­ trial of levodopa and sought speech and based treatments arise in the future) and prognostic language involvement; botulinum injec- significance. Its treatment is largely symptomatic tions into the neck extensors gave some and is best undertaken within a multidisciplinary benefit. She continued to deteriorate and died 6 years from symptom onset. setting, including a neurologist, physiotherapist, occupational therapist, speech language therapist, psychiatrist and, ultimately, a palliative care clinician. Case vignette 2 Corticobasal syndrome can be a confusing entity A 79-year­ -old­ woman reported decreased for neurologists, not least because it has over time coordination, slowed movement and subtle http://pn.bmj.com/ evolved from being considered predominantly as right arm weakness that appeared to follow a movement disorder to a condition spanning a a fall. Over the next 9 months, her right arm wide range of cognitive and motor manifestations. became increasing difficult to use, causing In this practical review, we attempt to disentangle difficulty with tasks such as doing up a bra this syndrome and provide clarity around diagnosis, and cutting food. Her walking felt more

its underlying pathological substrates, key clinical uncertain and she had one significant fall. on July 26, 2021 at University of Otago. Protected by copyright. features and potential treatments. On examination, there was marked right arm rigidity with a grasp reflex, significant bradykinesia and ideomotor apraxia. Eye movements were normal and there were no Case vignette 1 (with video) pyramidal nor cerebellar signs. Our impres- A 68-­year-old­ woman had a 2-­year history sion was likely corticobasal syndrome. We of motor symptoms. Her first symptom arranged physiotherapy and occupational had been her left hand not doing what it therapy, requested brain imaging and gave was told to do when drying the dishes. She an empirical trial of levodopa. also developed difficulties getting her words Her right arm deficits progressed despite out. On examination, she had pseudobulbar levodopa, which we later stopped. Her right speech and made dysphasic errors, and there arm became of little use to her, and she © Author(s) (or their was apraxia and hypometria of saccades, held it in a dystonic posture, without pain, employer(s)) 2021. No particularly leftward (video 1). She showed though she still felt some agency over it. Her commercial re-­use. See rights and permissions. Published ideomotor apraxia and features of alien-limb­ balance deteriorated further with frequent by BMJ. syndrome in the left arm, and intermittent falls. She developed difficulty with speech, To cite: Wilson D, Le Heron C, dystonic posturing of the left arm and leg stumbling over longer words but her cogni- Anderson T. Pract Neurol but minimal limb rigidity. Her cognition was tion remained unaffected. MR scan of brain 2021;21:276–283. preserved. showed left perirolandic atrophy consistent

Wilson D, et al. Pract Neurol 2021;21:276–283. doi:10.1136/practneurol-2020-002835 1 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from

Table 1 Proposed criteria for corticobasal syndrome (the Cambridge criteria, modified Bak and Hodges)12 Mandatory criteria Insidious onset No sustained response to levodopa treatment* Major and minor criteria* Motor Akinetic rigid syndrome Focal or segmental myoclonus Asymmetric dystonia Cortical motor sensory features Limb apraxia Alien limb syndrome Video 1 Case Vignette 1. The video, taken five years after Cortical sensory loss or dyscalculia the onset of symptoms, shows (i) positive applause sign (motor perseveration), (ii) prominent dystonia and apraxia of the left Cognitive features Speech and language impairment hand and mirror movements and mild dystonia of the left hand, Frontal executive dysfunction and (iii) marked supranuclear gaze palsy (SNGP) overcome with Visuospatial deficits the vestibulo-­ocular reflex and, to a lesser extent, pursuit of A diagnosis of corticobasal syndrome requires all mandatory criteria, the examiner’s face. Note that saccadic apraxia with normal two major criteria (in italics) and two minor criteria. saccadic velocity (not seen in the video but see figure 3) had There are other proposed criteria, but the authors favour this as equal preceded the marked SNGP shown here. emphasis is attributed to the cognitive and motor aspects, furthermore the modified Cambridge criteria may pick up patients earlier in their 12 with corticobasal syndrome (figure 4). She remained at disease course when compared with the Mayo and Toronto criteria. *The response of the parkinsonism to levodopa therapy should be home with increasing support from physiotherapy and tested with at least 25/250 mg of carbidopa/levodopa administered occupational therapy. three times a day for at least 2 months. The response to levodopa is considered poor when the extrapyramidal features fail to show marked improvement, or the therapeutic effect is transient. Historical context In 1968, Rebeiz et al published three cases detailing the clinical and post mortem pathological findings of a Corticobasal degeneration ‘hitherto unrecognised disorder of the central nervous Corticobasal degeneration is a pathologically estab- system’.1 All three had an asymmetric movement disorder lished four-­repeat tauopathy.14 Its pathological features characterised by slowed and awkward voluntary move- are cortical and striatal tau-positive­ neuronal and glial ments with additional involuntary movements. Patholog- lesions of both white and grey matter, coupled with 14

ical assessment identified frontoparietal atrophy driven focal cortical and substantia nigra neuronal loss. http://pn.bmj.com/ by neuronal loss, gliosis and swelling of cell bodies, Importantly, there is not a 1:1 mapping between corti- resulting in resistance to histological staining methods. cobasal degeneration and corticobasal syndrome, and While the cortex was primarily involved, the substantia corticobasal degeneration pathology is associated with nigra was abnormal in all three, and the dentatorubroth- various clinical phenotypes (figure 1). There are four alamic system was abnormal in two. They coined the suggested broad clinical phenotypes:

term ‘corticodentatonigral degeneration with neuronal ►► Corticobasal syndrome. on July 26, 2021 at University of Otago. Protected by copyright. achromasia’. Three decades later Gibb et al reported three ►► Frontal behavioural-spatial­ syndrome. further patients with similar clinical and histopathological ►► Non-­fluent/agrammatic variant of primary progressive findings. They adopted the shorter name ‘corticobasal aphasia. 2 11 degeneration’, and the next decade saw many further ►► PSP syndrome. descriptions of this newly named disorder. The clinical Probable corticobasal degeneration criteria require phenotype expanded from primarily a movement disorder an insidious onset and gradual progression for at to include various cognitive and neurobehavioural defi- least 1 year, age at onset >50 years, no similar family cits3–5 while the underlying pathology of clinically diag- history or known tau mutations, and one of the clin- nosed cases also expanded to include Alzheimer’s disease, ical phenotypes outlined above. Features suggesting progressive supranuclear palsy (PSP), Pick’s disease and Parkinson’s disease (characteristic tremor, halluci- Creutzfeldt-­Jakob disease.6–9 Thus, the etymology has nations, response to levodopa), or multiple system slowly transitioned to ‘corticobasal syndrome’ as a clinical atrophy (prominent autonomic or cerebellar signs) are rather than a pathological diagnosis.10 Table 1 shows the exclusions. However, the criteria still lack antemortem current consensus diagnostic criteria for both the clinically specificity to separate pathologically proven cortico- defined corticobasal degeneration11 and the pathologi- basal degeneration from its mimics.15 cally defined corticobasal syndrome.12 13 Figure 1 shows the common clinical phenotypes of corticobasal degenera- Epidemiology of corticobasal syndrome tion and the common pathologies underlying corticobasal It is difficult to ascertain the true prevalence and incidence syndrome. of corticobasal syndrome, given the varied use of the term

2 of 10 Wilson D, et al. Pract Neurol 2021;21:276–283. doi:10.1136/practneurol-2020-002835 Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from

Figure 1 Unpicking corticobasal syndrome and corticobasal degeneration. From phenotype to underlying pathophysiology. This is a simplified view and includes only the common phenotypes of corticobasal degeneration and common pathological substrates underlying corticobasal syndrome. CBS, corticobasal syndrome; CBD, corticobasal disease; AD, Alzheimer’s disease; FTLD-TDP43,­ frontotemporal lobe degeneration TDP43; PSP, progressive supranuclear palsy; FTD Tau, frontotemporal dementia; FBSS, frontal behavioural-­spatial syndrome; PPA, primary progressive aphasia. and its interchangeability in early reviews with cortico- haplotype of the MAPT gene may predispose to sporadic basal degeneration. Estimates are therefore at best a guide corticobasal syndrome.28 and even then, remain crude. The estimated prevalence of corticobasal degeneration is 4.9–7.3 cases per 100 000 Clinical signs and symptoms in population.16 The annual incidence calculated from the corticobasal syndrome prevalence and life expectancy would be between 0.5 and Corticobasal syndrome has an insidious onset and is 1 per 100 000 per year, though this is higher than the rate slowly progressive.12 29 Patients with dramatic presen- observed in a population based study.17 The typical age of tations and/or rapidly progressive disease courses presentation is 50s–70s and average lifespan from diag- should be considered mimics (see below).

nosis to death is 7 years. There does not appear to be any http://pn.bmj.com/ sex bias.18 Motor features Extrapyramidal motor features are common with no 12 Genetics of corticobasal syndrome dramatic or sustained response to levodopa therapy. 29 A single pathogenic mutation is unlikely to contribute Rigidity is the most frequent extrapyramidal motor greatly to the pathogenesis of corticobasal syndrome. sign, present in 73%–100% of cases, mostly presenting 13 29 30

However, familial clustering can occur with up to 31% as an asymmetric akinetic–rigid syndrome. on July 26, 2021 at University of Otago. Protected by copyright. have a family history of parkinsonism or dementia19 Dystonia is much less common than rigidity and tends The most common monogenic mutations associated to affect a single limb, often the upper and usually 12 13 with familial corticobasal syndrome are in microtubule-­ early in the disease course. Other extrapyramidal associated protein tau (MAPT) resulting in frontotem- features such as bradykinesia and postural instability 12 poral lobar degeneration (FTLD)-tau­ pathology strongly may also occur. A tremor can develop but is an resembling corticobasal degeneration,20 although action or postural jerky movement that subsides with genome-wide­ association studies have identified other rest, and is quite unlike a resting Parkinson’s disease 12 13 29 single nucleotide polymorphisms.21 More recently corti- tremor. It can overlap with another common cobasal syndrome has been associated with FTLD with motor feature—myoclonus—which occurs in roughly 12 13 29 ubiquitin-immunoreactive­ inclusions (FTLD)22 or TAR 40% of cases. Electrophysiology studies suggest 31–33 DNA-binding­ protein 43 (TDP-43) leading to frontal the myoclonus is cortical or subcortical in origin. temporal lobe degeneration (FTLD-­TDP)23 both of which are most often caused by progranulin mutations24 but not Alien limb syndrome always.25 Pathogenic GGGCC expansion with mutations The alien limb syndrome comprises involuntary limb in C9orf72 (chromosome 9 open reading frame 72) and movements combined with an altered sense of limb mutations in LRRK2 (previously limited to Parkinson’s belonging or ownership. It usually involves the hand but disease)26 are also associated with corticobasal syndrome.27 may uncommonly occur only in the leg, or both arm and Outside of familial monogenic mutations, a case–control leg, and rarely is bilateral.34 35 A detailed account of the study suggests single-nucleotide­ polymorphisms in the H1 underlying neurobiological processes causing alien limb is

Wilson D, et al. Pract Neurol 2021;21:276–283. doi:10.1136/practneurol-2020-002835 3 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from non-dominant­ parietal lobe.35 It is characterised by a Table 2 Alien limb differential diagnosis sense that the affected limb does not belong to the person. Disorder Definition/distinguishing feature There are usually other parietal cortical deficits including Grasp reflex Simple frontal release sign. sensory hemineglect, and astereognosis. The typical motor Utilisation behaviour Involuntary (and inappropriate) use of a features are not as intrusive as in the frontal variant but presented object for its usual purpose. may take the form of levitation and other non-­purposeful Hemineglect Loss of awareness of limb as belonging to actions, abnormal posturing and ataxia. the person. Corticobasal syndrome is easily the most common Mirror movements One hand involuntarily mimics the cause of an alien limb (two-thirds­ of cases).35 By the movement of the other. same token the alien limb syndrome develops in about Pseudoathetosis Involuntary movement of extremities due a half of people with corticobasal syndrome.35 37 While to proprioceptive loss. the asymmetry of corticobasal syndrome involves the left Task specific limb Provoked task specific abnormal limb dystonia posturing (eg, writer’s cramp). and right hemispheres equally, alien limb in this condition usually develops in the non-dominant­ limb, for unclear Focal dystonia Abnormal limb posturing that may increase 36 with distraction or as overflow from reasons. In patients presenting with alien limb, the movement of other limbs. timing of onset during the disease may help to suggest Hemiballismus Unilateral large amplitude ballistic the cause; for example, it can be the presenting symptom movements of limbs -exaggeration of of Creutzfeldt-Jakob­ disease but occurs a median of chorea. 1 year after disease onset in corticobasal syndrome.35 Clonic perseveration Rhythmic, stereotyped and repetitive The associated neurology can also help in the differen- movements. tial diagnosis. Thus, mirror movements develop in 40% Hemiataxia Clumsy ataxic limb with no involuntary of corticobasal syndrome patients with the alien limb but movements. are uncommon in other causes, while intermanual conflict Neurological phenomena that should be distinguished from alien limb. is very uncommon in corticobasal syndrome.36 Myoc- Note that for the motor phenomena in this table there is preserved sense of limb ownership and no sense of the affected limb(s) being lonus is usual in patients with Creutzfeldt-Jakob­ disease ‘foreign’. Adapted with permission from: Hassan and Josephs.72 but common in corticobasal syndrome, and uncommon in other causes of alien limb.35 beyond this review but proposed mechanisms have been There are no proven treatments for alien limb syndrome suggested.36 The alien limb is easily confused with other and management approaches are based on anecdotal expe- neurological signs (table 2). There are three recognised rience and the type of alien limb. The frontal variant may variants: frontal, callosal (together termed ‘anterior’) and respond to sensory tricks (eg, wearing a glove), distracting posterior (figure 2). tasks (eg, holding a ball in the hand), verbal cues that

The posterior variant is the most often encountered enhance voluntary action and cognitive–behavioural http://pn.bmj.com/ type in corticobasal syndrome and usually affects the therapy for anxiety reduction. For the posterior variant non-dominant­ upper limb, with lesions involving the (common in corticobasal syndrome), treatments used have on July 26, 2021 at University of Otago. Protected by copyright.

Figure 2 Classification algorithm of the alien limb syndrome. Modified from Hassan and Josephs.72 CBS, corticobasal syndrome; CJD, Creutzfeldt-Jakob­ disease.

4 of 10 Wilson D, et al. Pract Neurol 2021;21:276–283. doi:10.1136/practneurol-2020-002835 Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from included clonazepam, botulinum toxin injections into the most active proximal muscles, visualisation strategies (eg, putting the affected hand into a mirror box) and spatial recognition tasks, but these approaches are not always well tolerated or maintained and there is scant informa- tion on their long-term­ benefits.38

Apraxia Limb apraxia is among the most commonly identified signs that suggests cortical dysfunction in the cortico- basal syndrome, occurring in 70%–80%.39–41 Apraxia is defined as a disorder of higher level motor control, manifesting as impaired skilled and learnt motor acts, despite intact primary sensory and motor pathways39 Apraxia generally affects both sides of the body. Because corticobasal syndrome is usually asymmet- rical, finding apraxia on the less affected side (as is common) adds weight to the conclusion that abnor- Figure 3 Schematic of typical saccade abnormalities in mality of movements are not simply due to extrapyra- CBS, compared with PD and PSP. In this schematic of eye 40 midal features such as rigidity and bradykinesia. movement recordings, patients were asked to make a leftward When screening patients for the presence of apraxia, saccade of 20° towards a target as quickly as possible. Y axis it can help to test different types of complex move- is displacement amplitude, the X axis is time. Mild undershoot ments—thought to correspond to different underlying followed by a small secondary saccade is normal. Patients with PD commonly show mild hypometria (undershooting) neurobiological processes that can be disrupted by 39 requiring two or more corrective saccades to reach target. In brain pathology. These include: CBS the degree of saccadic hypometria is often greater than in ►► Performing a gesture, miming the use of tools and PD with the key feature being delayed launching of saccades copying meaningless gestures. Deficits in these move- (saccadic apraxia). In PSP the hallmark is early saccadic slowing ments, usually referred to as ideomotor apraxia, are (especially vertically) with considerable hypometria developing common in corticobasal syndrome and can be readily over time. CBS, corticobasal syndrome; PD, Parkinson’s disease; assessed in the clinic. PSP, progressive supranuclear palsy. Figure by Bronstein & Anderson (2021), distributed at https://doi.org/10.6084/ ► Performing complex, multistep tasks. Deficits in these ► m9.figshare.14390951 under an open CC-­BY 4.0 license. processes are often referred to as conceptual, or idea-

tional apraxias, capturing the idea that it is loss of http://pn.bmj.com/ knowledge about objects and their associated actions use of an assisting simultaneous or preceding head that underlies the patient’s difficulties. This is harder to movement, and in the laboratory as a substantial screen for in a routine clinic appointment but may be increase in saccade latency.44 45 Typically, the saccadic inferred from the history, or from a formal occupational apraxia is greatest towards the side with the greatest therapy assessment. Ideational apraxia can be extremely limb apraxia.42 43 In contrast to PSP, saccade velocities 46 disabling for a person’s day-to-­ ­day functioning. in patients with corticobasal syndrome are normal on July 26, 2021 at University of Otago. Protected by copyright. ►► Performing repetitive distal limb movements such as 47 (figure 3). Smooth pursuit can also be moderately tapping the thumb with each finger in turn. Deficits such impaired but not as severely as in patients with PSP. as clumsy or inaccurate movements, are referred to as The neuropathological substrate of saccadic apraxia in limb-­kinetic apraxia—a somewhat controversial classifi- corticobasal syndrome awaits further clarification but cation that can be difficult to distinguish from the effects it remains a distinctly useful clinical diagnostic feature. of weakness or bradykinesia. Other sorts of higher order cortical dysfunction are often Aphasia termed apraxias—for example, gait apraxia, construc- The typical language disturbance in corticobasal tional apraxia, dressing apraxia, orobuccal apraxia and syndrome is non-­fluent variant primary progressive apraxia of speech (to name a few). When present, these aphasia, with slowed, effortful and/or groping (apraxia of point towards cortical dysfunction signs that can provide speech) speech and grammatical errors being common.48 evidence for the presence of a corticobasal syndrome. However, patients can also develop a logopenic aphasia, characterised by prominent difficulty in word retrieval 48 Apraxia of saccades and other eye movements in and sentence repetition. The latter is commonly associ- corticobasal syndrome ated with underlying Alzheimer’s disease pathology, while The traditional oculomotor hallmark of clinically non-fluent­ variant primary progressive aphasia, including diagnosed corticobasal syndrome is saccade apraxia,42 apraxia of speech, may suggest tau pathology. Therefore, 43 which manifests clinically as difficulty and delay in aside from providing evidence of ‘cortical’ involvement, initiating saccades towards a target, usually with the the pattern of aphasia may help to identify the pathology

Wilson D, et al. Pract Neurol 2021;21:276–283. doi:10.1136/practneurol-2020-002835 5 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from underlying corticobasal syndrome, but further research is required.

Neuropsychiatric aspects of corticobasal syndrome Corticobasal syndrome has a range of neuropsychiatric comorbidities. However, the lack of large scale studies means that while we commonly see features such as depression, apathy, anxiety and agitation (among others) in the clinic, we do not have accurate estimates of their prevalence at different stages of corticobasal syndrome— or know whether these features associate with particular underlying pathologies.49 A study of 15 patients with what we would now refer to as corticobasal syndrome found particularly high rates of depression and apathy and also an absence of hallucinations.50 This latter point suggests that the presence of visual hallucinations in a patient with Figure 4 Example of an MR scan of a brain in a patient with parkinsonism and cognitive deficits should raise concerns corticobasal syndrome A. Small arrows show moderate focal they may in fact have an alpha-synucleinopathy­ such as asymmetric left perirolandic atrophy on T2-­weighted imaging. dementia with Lewy bodies. We advocate for screening all patients presenting may include Parkinson’s disease or other parkinsonian with corticobasal syndrome for neuropsychiatric syndromes. symptoms, particularly as these features have a major Striatal dopamine transporter (DAT) density can be impact on quality of life for patients and their fami- imaged and measured using single-­photon emission lies. Screening can be performed formally (eg, using 51 CT or positron-­emission tomography (PET). Most, the neuropsychiatric inventory, or by questioning but not all, patients with corticobasal syndrome have both the patient and an informant for presence of a positive DAT scan.54 One follow-­up study suggests mood disturbance (dysphoria, anhedonia, anxiety), that in time all such patients will have a positive behavioural change (apathy, obsessive or compulsive result.55 For the clinician, the DAT scan’s limitation behaviours, agitation, irritability, impulsivity, loss of is that it does not differentiate corticobasal syndrome empathy) and psychotic features (hallucinations, delu- from other parkinsonian disorders. sions). Education of caregivers about the possibility of emergence of these complications can be helpful. Imaging to predict the underlying pathology http://pn.bmj.com/ Neuroimaging in corticobasal syndrome There has been a recent emphasis on developing measures Brain imaging has three roles in the assessment of to identify reliably the underlying pathology in cortico- 53 patients with corticobasal syndrome—ruling out basal syndrome. Such measures will be increasingly rele- mimics/structural causes (see below), providing support vant as protein-­specific treatments hopefully emerge over 33 for the clinical diagnosis of a corticobasal syndrome, the coming years. Ultimately their utility will depend on 33 their ability to distinguish between pathologies at indi- and providing clues to the underlying pathology. on July 26, 2021 at University of Otago. Protected by copyright. vidual rather than at group level. Imaging correlates These strategies can be split into techniques that iden- Corticobasal syndrome is associated with asymmetrical tify the presence of abnormal protein (such as imaging to cortical changes in markers of neuronal loss or dysfunction detect increased concentrations of brain amyloid protein), (grey matter atrophy, hypometabolism or hypoperfusion). and techniques that identify patterns—either in neuronal This particularly affects frontal-parietal­ regions encom- loss/metabolism or brain connectivity—closely associ- passing premotor, motor and sensory association cortex, ated with the underlying pathology. The use of amyloid and typically develop contralateral to the more affected PET imaging to identify corticobasal syndrome caused side of the body33 52 53 (figure 4). Notably, such ‘periro- by Alzheimer’s pathology is the clearest example of the landic’ patterns of change do not appear specific to any former approach. In turn, researchers are now examining underlying pathology but instead associate directly with clinical and standard imaging correlates of amyloid posi- the clinical features of corticobasal syndrome, consistent tive and negative groups to further refine understanding with the importance of these regions for processing higher of how corticobasal syndrome may differ between pathol- order sensory information and translating this into motor ogies.56 Given that there is often an associated underlying actions. Therefore, finding asymmetrical perirolandic tauopathy, emerging tau-based­ PET techniques—which atrophy or hypometabolism on clinical imaging supports are still troubled by some technical issues such as off-target­ a clinical diagnosis of corticobasal syndrome, though binding—are also generating strong interest for their its absence does not exclude it. This can be particularly potential to identify underlying corticobasal degeneration helpful early in the disease course, when the differential or progressive supranuclear pathology.33 57

6 of 10 Wilson D, et al. Pract Neurol 2021;21:276–283. doi:10.1136/practneurol-2020-002835 Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from Finally, the distribution of neuronal loss or brain reasonable.37 Physiotherapy input is also important in hypometabolism in patients with corticobasal optimising mobility following botulinum toxin injections. syndrome predicts the underlying pathology, at Specific options to consider for the alien limb least at a group level. In particular, corticobasal syndrome are summarised above. Management to syndrome caused by Alzheimer’s pathology often mitigate the effects of apraxia is best coordinated has a posterior pattern of hypometabolism, while by an occupational therapist with knowledge of the corticobasal degeneration may show more subcor- condition. Speech therapists can teach patients tech- tical hypometabolism, and PSP pathology shows niques to overcome some of their language deficits more frontal hypometabolism.52 58 More compli- and it is worth seeking their input when speech cated techniques assessing brain structural (white difficulties are a prominent feature—they can also matter) or functional connectivity are also showing provide patients with practical advice if swallowing promise for distinguishing between pathologies but difficulties develop. We often refer patients for phys- are not yet clinically useful.59 iotherapy aimed at strength and balance training as In summary, a corticobasal syndrome diagnosis can well as gait assessment—the addition of gait aids can be supported—but not refuted—by imaging features, allow some people to maintain relative physical inde- while emerging techniques may direct the neurolo- pendence. Although there are no proven treatments gist to the underlying pathological cause of a patient’s for cognitive deficits such as memory and attentional syndrome—information that over time will have prac- impairment in corticobasal syndrome, many clinicians tical relevance. consider trialling cholinesterase inhibitors if there is a strong suggestion from the history (memory impair- ment), examination (predominate cortical signs) and Treatment of corticobasal syndrome cognitive assessment (visuospatial or memory defi- There are currently no proven treatments for cortico- cits) to suggest an underlying Alzheimer’s disease basal syndrome. Recent advances in the treatment of pathology. tauopathies with immunotherapies and gene expression There are several available pharmacological options for show promise,60 61 but for the moment we emphasise neuropsychiatric manifestations.62 Many mild behavioural the importance of making a diagnosis that can explain a issues may be better managed non-pharmacologically­ puzzling array of problems for a patient and their family. (caregiver education, environment changes, etc) but It provides a valid explanation for their symptoms and undoubtedly medications can help with more severe allows a reframing of priorities from obtaining a diagnosis disruptions. Seeking psychiatric guidance is useful and to coping with the problem. Ideally, treatment should be building a strong relationship with an interested psychia- provided within a multidisciplinary setting with expertise trist can help patient management and improve job satis-

provided by a neurologist, physiotherapist, occupational faction. Selective serotonin reuptake inhibitors are useful http://pn.bmj.com/ therapist, speech language therapist, psychiatrist and, ulti- for treating common problems such as anxiety, depression mately, palliative care services. and obsessive-compulsive­ disorder. Apathy, or reduced Although parkinsonism in corticobasal syndrome does motivated behaviour, is common, debilitating and diffi- not generally respond well to levodopa, most patients will cult to treat. Informing caregivers that it is part of the try it as part of their initial assessments (often when the disease process can help. Agents targeting dopaminergic,

diagnosis is less clear), and it is reasonable to push the dose cholinergic and serotonergic neuromodulatory networks on July 26, 2021 at University of Otago. Protected by copyright. up towards at least 1000 mg/day before classifying a patient may help apathy in other degenerative disorders, but there as a ‘non-responder­ ’.62 In our experience, other dopami- is no good evidence to guide use of these treatments in nergic therapies (dopamine agonists, monoamine oxidase corticobasal syndrome. Finally, some patients will develop inhibitors) also have very limited efficacy in treating motor marked behavioural disturbances, including irritability/ symptoms of corticobasal syndrome, but a dopamine aggression and psychosis. Management can be difficult agonist may be worth considering in those with promi- but can include atypical antipsychotics, for example, nent apathy. Options for treating troublesome myoclonus quetiapine or clozapine with appropriate blood count include levetiracetam and clonazepam. Dystonia can be monitoring. functionally disabling and at times painful. Anticholiner- Other practical issues to address include driving safety gics, benzodiazepines and amantadine provide modest help and checking whether driving licensing agencies need to at best, and adverse effects—especially cognitive impair- be informed, the importance of updating a person’s will, ment, hallucinations and confusion—often outweigh any and establishing an enduring power of attorney early in benefit, particularly in older patients, while amantadine the disease course, as these can be problematic later if can also cause insomnia and leg oedema.63 Botulinum significant cognitive impairment develops. Lastly, putting toxin injections can help, depending on the dystonic patients in touch with local charities can greatly help pattern. Particularly when treating upper limb dystonia, patients and families. If specific charities are not avail- the disabling effects of symptoms must be weighed against able (eg, the PSP association in the UK and curePSP in the potential limb weakness resulting from injections—but the USA) exploring Parkinson’s and dementia charities is a as with other interventions a pragmatic trial is certainly reasonable first step.

Wilson D, et al. Pract Neurol 2021;21:276–283. doi:10.1136/practneurol-2020-002835 7 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002835 on 23 July 2021. Downloaded from Corticobasal syndrome mimics should have a low threshold for genetic testing especially Conditions that may initially be diagnosed as corticobasal in younger patients with atypical features. syndrome but turn out to be something else tend to be those with subacute or chronic onset, and those that have some, Prognosis but not all, symptoms and signs resembling true neurode- The prognosis for a patient diagnosed with corticobasal generative corticobasal syndrome. Most of these mimics syndrome depends mainly on the underlying neuropa- feature alien limb syndrome with or without myoclonus, thology (i.e. cause), the difficulty being that that cause is not and/or one of the rapidly progressive dementias, often easily determined during life. Consequently, there is little with aphasia. Thus, many of the non-­neurodegenerative available information to assist counselling of the patient and causes of the alien limb syndrome may mimic corticobasal family. In a study of 10 Japanese patients with corticobasal syndrome, including stiff-­person syndrome,64 Hashimo- syndrome coming to post mortem (three each with cortico- to’s encephalitis,65 66 thalamic cavernoma,67 as well as basal degeneration, PSP and Alzheimer’s disease pathology, Creutzfeldt-­Jakob disease68 and other rapidly progressive and one with atypical tauopathy) median survival was 7 dementias.69 Mimics can usually be distinguished from true years with a range of 4–15 years. Survival was similar across corticobasal syndrome by the careful neurological exam- pathologies.70 An earlier study of 14 patients with patho- ination to identify peripheral (such as areflexia, proprio- logically confirmed corticobasal degeneration reported a ceptive loss) or central (eg, pyramidal) nervous system median survival time after onset of symptoms of 7.9 years signs, combined with appropriate investigations such as with a considerable range of 2.5–12.5 years. Survival was MR scan of brain, electroencephalogram, serum antineu- shorter in those with early and widespread parkinsonism ronal and other autoantibody assays, which together may or frontal lobe syndrome.71 In summary, on present knowl- indicate an alternative diagnosis. It is critical to identify edge, average survival in corticobasal syndrome is 7–8 years these mimics as early as possible as many are treatable or but with a considerable range of some 3–15 years. have a better prognosis than true corticobasal syndrome. A careful family history is also important, and clinicians Conclusion Corticobasal syndrome is a disorder of movement, cogni- tion and behaviour, caused by several underlying pathol- Key points ogies including corticobasal degeneration. Clinicians should consider the diagnosis in patients presenting with ►► Corticobasal syndrome is a clinical entity with many any combination of extrapyramidal features, apraxia or different underlying pathologies, including corticobasal other parietal signs, aphasia and alien limb phenomena. degeneration. Neuroimaging showing asymmetrical perirolandic cortical ►► Corticobasal degeneration is a pathological diagnosis changes supports the diagnosis and advanced neuroim- associated with several clinical syndromes, one of aging may give insight into the underlying pathology. http://pn.bmj.com/ which is corticobasal syndrome. We suggest neuropsychological screening in all patients ►► Corticobasal syndrome has a varied presentation: presenting with corticobasal syndrome. Identifying corti- distinguishing clinical features include asymmetric cobasal syndrome carries some prognostic significance, parkinsonism, myoclonus, alien limb, cortical sensory management implications and in the future if protein-­ loss, eye and limb apraxia, and imaging may show based treatments arise—may direct further investigations asymmetric perirolandic atrophy. as to underlying pathology. on July 26, 2021 at University of Otago. Protected by copyright. ►► Corticobasal syndrome has several important mimics (eg, Creutzfeldt-­Jakob disease, Hashimoto’s Contributors DW, CLH and TA all contributed equally to encephalitis), some of which are treatable. the manuscript. All were involved in manuscript conception, drafting and critical revisions. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or Further reading not-­for-­profit sectors. Competing interests None declared. 1. Armstrong MJ, Litvan I, Lang AE, et al. Criteria Patient consent for publication Not required. for the diagnosis of corticobasal degeneration. Provenance and peer review Commissioned. Externally peer Neurology 2013;80(5):496–503. doi: 10.1212/ reviewed by Negin Holland, Cambridge, UK and Oliver WNL.0b013e31827f0fd1 Bandmann, Sheffield, UK. 2. Mathew R, Bak TH, Hodges JR. Diagnostic criteria for ORCID iDs corticobasal syndrome: a comparative study. J Neurol Duncan Wilson http://​orcid.​org/​0000-​0002-​4479-​6974 Neurosurg Psych 2012;83(4):405–10. doi: 10.1136/ Tim Anderson http://​orcid.​org/​0000-​0002-​1116-​3839 jnnp-2011-300875 3. Pardini M, Huey ED, Spina S, et al. FDG-­PET patterns References associated with underlying pathology in corticobasal 1 Rebeiz JJ, Kolodny EH, Richardson EP. Corticodentatonigral syndrome. Neurology 2019;92(10):e1121–35. doi: degeneration with neuronal achromasia. Arch Neurol 10.1212/WNL.0000000000007038 1968;18:20–33.

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