Corticobasal Syndrome and Corticobasal Degeneration 

Updated: Dec 04, 2019
Author: Alexander Pantelyat, MD; Chief Editor: Selim R Benbadis, MD 

Overview

Background

Corticobasal degeneration (CBD), a sporadic neurodegenerative 4-repeat tauopathy, is a pathologically defined entity associated with several clinical phenotypes. The most common phenotype—corticobasal syndrome (CBS)—is defined by progressive dementia and typically asymmetric parkinsonism unresponsive to dopaminergic therapy, dystonia, limb apraxia, and myoclonus, but these may occur as a result of a number of other pathologic entities. The most characteristic are frontotemporal degeneration spectrum disorders, but Alzheimer disease and rare disorders such as Creutzfeldt–Jakob disease, CNS Whipple disease, and Niemann–Pick disease type C can be associated with corticobasal syndrome. CBD can also present clinically as progressve supranuclear palsy (there is significant clinical and some neuropathological overlap between these entities), a frontal behavioral-spatial syndrome, primary progressive aphasia[1] , or (rarely) as posterior cortical atrophy.[2]

The diagnosis of syndromes associated with CBD pathology is based on history and physical examination, while imaging, serum, and cerebrospinal fluid studies serve an ancillary role. As noted above, CBS is a heterogeneous disorder that can present as a primary tau-related neurodegeneration or could be secondary to other proteinopathies (including amyloid, TAR DNA-binding protein 43, alpha-synuclein (in Lewy bodies) or prion proteins).[3] In an attempt to sort out this heterogeneity of clinical and pathological presentations of CBD, Armstrong et al. proposed new diagnostic criteria for CBD in 2013 based on a review of 267 CBD cases from published reports (1950–2012) with pathological confirmation across five different brain banks.[1] They defined four clinical phenotypes associated with CBD pathology based on these data: (1) Corticobasal syndrome, (2) Frontal behavioral-spatial syndrome (FBS), (3) Nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and (4) Progressive supranuclear palsy syndrome (PSPS). Based on the above phenotypes, they suggested two separate criteria for Probable CBD (at least one CBS feature, however, the differential could include FBS or naPPA) and Possible CBD (more inclusive of other tau disorders including PSPS) intended to be applied during a patient's lifetime.[1]

However, in 2014 Alexander et al. disputed the utility of the above criteria after they applied them to their cohort of 33 patients followed longitudinally between 1990 and 2013.[4] While the Armstrong et al. criteria did help to identify patients with CBS, they were not specific enough to identify which of these patients had CBD pathology on post-mortem examination; that is, not all patients with a CBD diagnosis clinically were found to have CBD-related pathology (4R tau in a specific distribution in neurons and glia). They found 14 patients with possible or probable CBD according to the Armstrong criteria who were found to have non-CBD pathology (CBD mimics, which included 10 patients with AD pathology, 2 with FTLD, and 2 with mixed AD and Lewy body pathology).[4] In this study, no particular symptom was present more often in the 19 cases with CBD pathology vs. the 14 cases with non-CBD pathology to accurately make a diagnosis of CBD pathology on a clinical basis.[4] Thus, current diagnostic criteria lack specificity in identifying CBD pathology clinically (ante-mortem) and the main utility of the Armstrong et al. criteria lies in formally defining the clinical syndromes associated with CBD pathology. Future studies on biomarkers and imaging will likely be helpful in predicting CBD pathology more accurately.

There is no disease-modifying therapy for CBD to date, but a number of symptomatic treatments can be useful, particularly botulinum toxin injections for dystonia and several other indications. Lifelong rehabilitation of these patients with physical, occupational, speech, and swallow therapy focused on maximizing daily function is crucial to limit deconditioning and potentially slow decline.

Pathophysiology

Typical autopsy findings in corticobasal degeneration (CBD) include asymmetric frontoparietal cortical atrophy.[5] Both cortical and subcortical abnormalities are seen in CBD, as the name of the disorder suggests. The disorder is classified as a 4-repeat tauopathy, and although tau-immunoreactive neuronal and glial inclusions may be seen in progressive supranuclear palsy (PSP), Alzheimer disease, and Pick disease, these disorders may differ in the proportions of 4-repeat as compared with 3-repeat microtubule-associated tau protein isoforms, with CBD and PSP being the two predominantly 4-repeat tauopathies. The astrocytic plaque containing aberrantly hyperphosphorylated 4-repeat tau is the defining pathological feature of CBD, whereas PSP is characterized by the presence of tufted astrocytes.[2] Ballooned swollen neurons with loss of cytoplasmic staining (ie, achromasia) are a supportive feature when present in the cortex and basal ganglia, but are not a CBD-specific finding. CBD may be associated with both cortical and subcortical neuronal loss, neuronal and glial tau pathology (including astrocytic plaques); cortical loss predominantly affecting motor and premotor regions[6] may distinguish this disorder from PSP. The tau histopathology in CBD is found predominantly in the corpus callosum and parasagittal and paracentral gyri and correlates with areas of cortical atrophy.[5]  An autopsy study of multiple tau disorders that included 40 cases of CBD found a characteristic progression of CBD astrocytic plaque pathology: Stage 1 involving the frontal and parietal cortices; Stage 2 involving temporal and occipital cortices (stage 2); Stage 3 involving the striatum and amygdala; and Stage 4 involving the brainstem.[7]  

Tau is a protein involved in axonal transport and stabilization of neuronal microtubules.[2] Abnormal phosphorylation of tau reduces its binding to microtubules and interferes with microtubule function, impairing axonal transport and leading to abnormal tau aggregation.[2, 8] Normal tau in the human brain contains six isoforms that are generated by alternative messenger RNA splicing of a single tau gene on chromosome 17.[2] Alternative splicing of exon 10 results in isoforms with either 3 or 4 repeats (3R or 4R) of the tau microtubule binding domain.[8] The normal ratio of 3R tau and 4R tau is approximately 1:1 and disruption of this ratio is thought to lead to neurodegeneration.[8] Isoforms common to both CBD and PSP are aggregates of the 4R-tau that occur because of splicing of exon 10.[8] The 3R-tau form dominates in the aggregates of some other tau disorders, such as Pick disease. The mechanism behind tau hyperphosphorylation in CBD is currently unknown, although some studies have implicated microglial signaling.[9, 10]  

A recent review of neurophysiological studies (quantitative electroencephalography and transcanial magnetic stimulation (TMS)) suggests that pathologic asymmetric hyperexcitability of the motor cortex is present in CBD and may be due to the loss of normal inhibitory inputs from the sensory cortex.[11]  Long latency reflexes in these patients are shorter than in cortical reflex myoclonus as seen in myoclonc epilepsies;[11] TMS studies have revealed revealed asymmetric intracortical disinhibition;[11]  and somatosensory evoked potential (SEP) studies show reduced N20–P25 amplitudes and absence of giant SEPs.[11]

Understanding of the genetic underpinnings of CBD is limited. Although CBD is thought to arise sporadically in the vast majority of cases, several rare mutations in the microtubule-associated protein tau (MAPT) have been implicated as causative for CBS and CBD.[12]  Also, both CBD and PSP are associated with a greater frequency of H1 tau haplotype homozygosity: in one study of 57 CBD cases, the odds ratio (95% CI) of H1/H1 haplotype in CBD versus controls was 3.61(1.85–7.05).[13]  A genome-wide association study of CBD identified several new CBD susceptibility loci and demonstrated that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).[14]

Epidemiology

Frequency

Data on incidence and prevalence of corticobasal degeneration (CBD) are still being collected. Clinical reports have multiplied geometrically in the last 20 years, suggesting either that clinical evaluation has become more sensitive (most likely) or that the syndrome is appearing more frequently. It is estimated to account for about 5% of cases of parkinsonism seen in clinics that specialize in movement disorders, or 0.62–0.92 per 100,000 per year, with an estimated prevalence of 4.9–7.3 per 100,000.[15] A study in Eastern European and Asian subjects reported an incidence of 0.02 case per 100,000 people.[16]

Demographics

No racial predilection is known.

In several studies, CBD was reported to be more common in women.[15, 17, 18]  However, more recent studies have not found this to be the case.[19]

Typically, CBD presents between the ages of 50 and 75 years. The CBD cases from multiple brain banks reviewed as part of the Armstrong et al. diagnostic criteria had mean age of onset of 63 years with a standard deviation of 7 years and range of 45–77 years.[1] No pathologically confirmed case of CBD has been published with onset before 45 years, but the previous author of this article personally reviewed medical records for a man who died with pathologically confirmed CBD whose first symptoms occurred at age 41 years, and a patient with the onset of corticobasal syndrome at age 28 years has been reported.[20]

Mortality/Morbidity

This is a progressive neurodegenerative disorder that causes increasing levels of disability and loss of independence. Individuals with CBD usually die within 10 years of symptom onset from complications of dysphagia (aspiration pneumonia), urinary incontinence (urinary tract infections complicated by urosepsis) and an immobile state (susceptibility to infections).

Prognosis

Prognosis is variable, with several studies indicating mean survival of 6–8 years from symptom onset; multiple cases with survival of >10 years have been reported.[2, 21]  One UK study found mean survival of 4.6 years from time of diagnosis.[1]  In the large number of CBD cases reviewed for the development of diagnostic criteria by Armstrong et al., mean (standard deviation) disease duration was 6.6(2.4) years with a range of 2.0 to 12.5 years.[1]  In their meta-analysis, Kansal et al. estimated the number of years of life lost based on mean survival from three studies at 11.33 years, with 95% confidence interval of 9.60 to 13.06.[22]  In a UK cohort comprised of 29 CBS, 35 PSP, 33 primary progressive aphasia, and 27 behavioral variant Frontotemporal degeneration patients, presence of apathy (as assessed from carer reports using the Apathy Evaluation Scale, Neuropsychiatric Inventory, and Cambridge Behavioral Inventory) predicted death at 2.5 years post-assessment and on average was highest for corticobasal syndrome (CBS).[23] Age at assessment, sex, and global cognitive impairment were not significant predictors of survival in this study.[23]

Patient Education

Information for patients and families, guidelines for rehabilitation, virtual support groups specific to CBS/CBD can be found at https://www.psp.org/

Additional information from the Institute for Neurological Disorders and Stroke:  https://www.ninds.nih.gov/Disorders/All-Disorders/Corticobasal-Degeneration-Information-Page

 

Presentation

History

Armstrong et al. describe the following clinical symptoms as part of the phenotypic spectrum of corticobasal degeneration (CBD):[1]

  • Insidious onset and gradual progression

  • Minimum duration of symptoms of at least 1 year

  • If corticobasal syndrome (CBS), asymmetric presentation of at least 2 of the following: (i) limb rigidity or akinesia, (ii) limb dystonia, (iii) limb myoclonus; PLUS 2 of either (i) orobuccal/limb apraxia (ii) cortical sensory deficit or (iii) alien limb phenomena more than levitation or parietal drift

  • Other phenotypes of CBD may present with

    • Executive dysfunction, behavioral and personality changes and visuospatial deficits, termed frontal behavioral-spatial syndrome  (FBS)

    • Effortful, agrammatical speech with speech apraxia and/or relatively preserved single word comprehension and impaired sentence/grammar comprehension, termed nonfluent/agrammatical variant of primary progressive aphasia (naPPA)

    • Axial or symmetric limb rigidity or akinesia, supranuclear gaze palsy or decreased vertical saccade velocity, postural instability or falls, behavioral changes, and/or urinary incontinence, termed progressive supranuclear palsy syndrome (PSPS)

    • Outside of the Armstrong et al. criteria, posterior cortical atrophy (PCA; typically presenting as visual dysfunction due to cortical involvement, with intact retinal and ocular function) has been associated with CBD pathology and this association is formalized in the 2017 PCA consensus classification[24]

  • The presence of prominent delusions or hallucinations (not related to levodopa) is more characteristic of diffuse Lewy body disease and makes a primary tauopathy such as CBD less likely

Physical

Motor abnormalities

The “classic” corticobasal syndrome (CBS) presentation includes levodopa-unresponsive asymmetric parkinsonism (rigidity and/or bradykinesia), limb dystonia and limb myoclonus. Rigidity is such cases may be secondary to parkinsonism (cogwheel type), dystonia, paratonia, or their combination.

  • Dystonia: most often involves the limbs (upper extremities), however can present as cervical dystonia or blepharospasm

  • Myoclonus: of cortical origin, most often seen in the limbs, and is often action related and stimulus sensitive (can be elicited by tapping the limb or testing reflexes). Short latency of myoclonus is more commonly seen (this can be confused with tremor), in contrast with classic cortical reflex myoclonus.

  • Hyperreflexia

Gait abnormalities

These are typically parkinsonian (reduced stride length and gait/turn speed, reduced/absent arm swing on the more affected side), and can involve gait freezing and lead to falls.

Cortical abnormalities

See the list below:

  • Apraxia: can involve limbs and other body parts. Limb apraxia typically presents as ideomotor apraxia, but limb-kinetic variants are also seen. Leg apraxia may make walking impossible. Orobuccal apraxia is also reported. Eyelid opening apraxia is frequently described; this may in fact represent blepharospasm of the pretarsal muscles rather than true apraxia.

  • Cortical sensory loss: detected by abnormalities in graphesthesia and stereognosis

  • Alien limb phenomena: semi-purposeful/unintended movements (simple or complex) that appear to interfere with normal tasks; can include dissociation from one’s own limb, intermanual conflict, enabling synkinesis, grasping, impulsive hand groping, magnetic apraxia, and purposeless wandering of the limb; simple levitation or parietal drift alone are not sufficient to be characterized as alien limb phenomena[1]

Cognitive abnormalities

These can include the following:

  • frontal-executive dysfunction (distractibility, perseveration, loss of judgment, motor planning deficit)

  • memory impairment (typically recent memory)

  • language (reduced verbal fluency, syntax and apraxia of speech)

  • visuospatial deficits

  • when the presentation is of posterior cortical atrophy (visuospatial) or Gerstmann syndrome, the underlying pathology is most likely to be Alzheimer disease rather than CBD

  • calculation difficulties (i.e. arithmetic for double and single digits) are observed early on in some patients with autopsy proven CBD, although this was reported in a single-center study[25]

Eye movement abnormalities

Pursuit eye movements are slow and saccadic with the appearance of several steps to reach a target, ipsilateral to the side with apraxia;[26] can involve abnormal saccades, horizontal gaze or vertical gaze (in the latter case would represent PSP phenotype of CBD).

Other

See the list below:

  • Tremor: poorly characterized; can present as resting tremor (although not the typical 4–6 Hz frequency seen in Parkinson’s disease)

  • Autonomic dysfunction is generally not seen (however, may be a part of the PSP phenotype presenting as urinary incontinence)

Causes

The ultimate cause of corticobasal degeneration (CBD) is currently unknown, although symptoms are thought to be associated with progression of 4-repeat tau pathology and associated neuronal loss.

Case reports suggest that a familial predisposition may exist in some individuals with this disorder.

H1 tau haplotype homozygosity is associated with a predisposition to develop CBD and progressive supranuclear palsy (PSP).[13]

Rare mutations in the MAPT gene have been associated with CBD, as have C9orf72 repeat expansions and GRN (progranulin) mutations.[27, 12]

Physical Examination

A thorough neurological and cognitive assessment are required for a complete characterization of syndromes associated with CBD pathology (see Physical section above).  

Complications

Key complications in patients suffering from corticobasal degeneration (CBD) include:

  • Aspiration pneumonia in the setting of progressve dysphagia

  • Weight loss in the setting of progressive dysphagia (and potentially depression)

  • Sepsis due to complicated urinary tract infections in the setting of progressive neurogenic bladder dysfunction, or from wound infection in the setting of progressive loss of mobility

  • Loss of the ability to communicate due to progressive nonfluent aphasia coupled with motor and voice impairments limiting the choice of augmented/alternative communication devices

  • Loss of reading ability due to oculomotor difficulties and cortical visual impairment

  • Loss of the ability to socialize due to behavioral/personality changes

  • Injury due to falls in the setting of progressive imbalance (gait/limb apraxia may contribute to this)

  • Deconditioning due to reduced mobility and limited ability to exercise

  • Reactive depression with potential suicidality

 

DDx

Diagnostic Considerations

The key limiting factors for the diagnostic considerations include the lack of a reliable patient-level in vivobiomarker for corticobasal degeneration (CBD) and the significant heterogeneity of clinical CBD presentations (detailed in the Overview and Presentation sections). A careful historical review (including family history) aiming to determine the tempo of symptom progression is crucial (for example, patients with corticobasal syndrome (CBS) often look and sound like they have had a stroke, but there is no history of acute stroke and no imaging evidence of same), followed by a thorough examination targeting the wide range of motor and non-motor findings present in the phenotypes associated with CBD. Features that suggest a synucleinopathy (Parkinson disease, dementia with Lewy bodies, or multiple system atrophy) rather than a tauopathy like CBD include rapid eye movement sleep behavior disorder (confirmed with polysomnography) and loss of smell (which can be formally evaluated using tests such as the University of Pennsylvania Smell Identification Test). Rapid progression of symptoms in the course of < 2 years should trigger additional workup for rapidly progressive dementia, as patients with Creutzfeldt-Jakob disease can present with CBS. It is important to keep in mind that CBS can represent an atypical presentation of Alzheimer disease (AD), and that AD pathology is responsible for 20–30% of CBS cases.

Differential Diagnoses

 

Workup

Approach Considerations

All patients require brain MR imaging and a serum workup for reversible/effectively treatable etiologies (although CBS and other CBD presentations are not diagnoses of exclusion). FDG-PET may be useful in selected cases.[28]  Emerging tau PET ligands can image tau pathology in vivo and are currently available on a research basis.

Laboratory Studies

See the list below:

  • Serum copper and ceruloplasmin to evaluate for Wilson disease 

  • Workup for reversible systemic causes of cognitive deficits:

    • Serum vitamin B12 level

    • Thyroid function tests, and consider thyroid autoantibody screening

    • Consider rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test, which may be falsely negative in patients older than 65 years, to rule out neurosyphilis[29]

    • Electrolytes

    • CBC with differential and platelets

    • If appropriate or other evidence of systemic disease - Rheumatologic workup, including antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR), liver function tests, and ammonia level

    • Manual smear for acanthocytes or genetic testing for Huntington disease if the patient presents with chorea

Can consider CSF biomarkers of neurodegeneration:

  • 14-3-3 protein, neuron-specific enolase and RT-QuIC to test for prionopathies such as CJD in rapidly progressive cases

  • Amyloid beta-42, phosphorylated tau and total tau levels to assess for AD pathology

  • Neurofilament light chain (NFL) protein elevation, while not specific to CBD, can differentiate atypical parkinsonian disorders from Parkinson disease on a group level[30] ; this remains a research tool to date

Imaging Studies

MRI

Structural MR imaging has shown more asymmetric atrophy of frontal and parietal lobes in corticobasal degeneration (CBD). Recent MRI Quantitative Susceptibility mapping (QSM) of cerebral gyri has shown that CBD has a distinct three-layered pattern of signal density in the cerebral cortex: a higher susceptibility layer in superficial gray matter (layer 3), a lower susceptibility layer, and another higher susceptibility layer in corticomedullary junction. The areas of higher susceptibility were due to ferritin accumulation in microglia, confirmed by histopathology. This MRI finding was thought to be specific for CBD.[31]

MRI is helpful in evaluating the size and appearance of the midbrain if any disturbance of vertical eye movements is noted and progressive supranuclear palsy is being considered. Midbrain size should be relatively normal in typical CBD.

Cortical atrophy usually occurs, and this can be more localized to the central sulci/supplementary motor area (SMA) and superior frontal gyrus than to the temporal/parietal cortex (the latter pattern is classically seen in AD).[6]

Abnormal signal in basal ganglia can occur with metal deposition in Wilson disease or the spectrum of neurodegeneration with brain iron accumulation.

Functional brain imaging is not generally needed, but it can be helpful in some patients to document that cognitive changes are neurological and not psychological in origin.

PET and SPECT

Position emission tomography (PET) and single-photon emission computed tomography (SPECT) reveal asymmetric activity in both cortical (frontal-parietal) and subcortical (basal ganglia) regions. Recent FDG-PET studies in CBD presenting as CBS have shown marked asymmetric hypometabolism of the contralateral frontoparietal cortex (including the superior, middle and inferior frontal gyri, pre- and post-central gyri, superior parietal lobule and supramarginal gyrus), as well as the thalamus and caudate nuclei. In the ipsilateral hemisphere, a smaller cluster of hypometabolism involving the precentral gyrus, superior frontal gyrus and caudate have been demonstrated.[28]  

Dopamine transporter (DAT SPECT) imaging can confirm presence of a neurodegenerative parkinsonian disorder, but does not differentiate between parkinsonian syndromes and can be normal early in the course of CBS (as many as 39% of cases in one longitudinal study of CBS without autopsy confirmation).[32]

Tau PET is currently available on a research basis only; the tau ligands studied thus far lack the ability to accurately discriminate between neurodegenerative syndromes on a single patient level, partly due to off-target binding in the basal ganglia (eg, to monoamine oxidase-B). Longitudinal 18F-AV-1451 (the tracer used in the largest patient cohorts thus far) tau imaging in individual patients with CBS has shown an increase in tracer binding with disease progression.[33] Newer ligands that lack off target binding issues are under investigation.[34]

Other Tests

Neuropsychological testing and/or evaluation of cognition and cortical signs by a cognitive neurologist with advanced training and experience with neurodegenerative disorders is recommended. This can be useful to differentiate the more common patients with concomitant parkinsonism and Alzheimer disease, who also can be apraxic but should not have as severe a motor coordination deficit or alien limb phenomena.

Electroencephalography (EEG) can be considered in cases of rapid decline

Somatosensory evoked potentials are not generally a part of the clinical workup. 

Procedures

In patients with prominent segmental myoclonus (especially if involving the face); eye movement disorder; and history of celiac sprue, chronic diarrhea, or unexplained arthritis, consider further workup to rule out the diagnosis of CNS Whipple disease.

  • Lumbar puncture (LP) may be done to examine cerebrospinal fluid (CSF) for cells and elevated protein as well as markers of neurodegeneration: amyloid beta-42, total tau, phosphorylated tau (evaluation for AD); neurofilament light chain; and prionopathy testing in rapidly progressive cases < 2 years' duration: RT-QuIC or neuron-specific enolase or 14-3-3); the polymerase chain reaction (PCR) test for the organism Tropheryma whipplei should be considered in select cases (eg, presence of oculomasticatory myorthythmia).

  • Consider jejunal biopsy; it can show changes characteristic of Whipple disease in the gut.

  • In cases with atypical features (eg, rapid course but negative CSF prionopathy testing), consider brain biopsy.

Histologic Findings

(See Overview.) Cortical findings include frontoparietal atrophy and astrogliosis, chracteristic astrocytic plaques containing hyperphosphorylated 4-repeat tau, neuropil threads, and occasionally neurofibrillary tangles and presence of swollen achromatic neurons (ballooned neurons or pale bodies). Argyrophilic tau-immunoreactive inclusion bodies can be found subcortically in the substantia nigra, where neuronal loss can also occur, as well as the basal ganglia and dentato-rubro-thalamic tracts. Although this description is different from that of progressive supranuclear palsy, tau-positive inclusions of CBD may be coiled and thus they can be confused with tau-positive neurofibrillary tangles. Some cases of CBD may thus be difficult to distinguish pathologically from progressive supranuclear palsy.

Staging

An autopsy study of multiple tau disorders that included 40 cases of corticobasal degeneration (CBD) found a characteristic progression of CBD astrocytic plaque pathology: Stage 1 involving the frontal and parietal cortices; Stage 2 involving temporal and occipital cortices (stage 2); Stage 3 involving the striatum and amygdala; and Stage 4 involving the brainstem.[7]

 

Treatment

Approach Considerations

The approach is centered on maximizing the patient's quality of life through rehabilitative interventions (physical, occupational, and speech/swallow therapy) and judicious use of symptomatic therapies.

Medical Care

See the list below:

  • Discontinue anticholinergics or other medications that impair attention and memory.

  • Discontinue any medications that may cause or worsen parkinsonism (dopamine blocking medications: all antipsychotics as well as metoclopramide and prochlorperazine).

  • Consider cholinesterase inhibitors such as rivastigmine or donepezil if memory loss is present.

  • Consider empiric treatment of depression

  • Initiate a trial of carbidopa/levodopa (Sinemet IR) if rigidity and movement disorder are disabling. Institute a plan for titration of this medication to an appropriate level (at least 900–1000mg levodopa per day for at least 1 month) before declaring the patient to be levodopa-unresponsive.

  • Consider botulinum toxin injections if the patient has bothersome or painful limb dystonia (with EMG +/- ultrasound guidance for localization), blepharospasm/eyelid opening apraxia, and/or sialorrhea.

  • Consider treating bothersome myoclonus with levetiracetam and/or clonazepam.

  • Refer early and continuously to occupational therapy (for upper extremity functional evaluation and management), physical therapy (gait and safety evaluation and training), and speech-language pathology (speech evaluation/cognitive training, swallow evaluation using modified barium with video), consider assistive devices for ambulation, ADLs and comunication, and an exercise program to maintain endurance and strength. 

  • Refer to Social Work to discuss long term care planning and state-specific as well as federal resources for patients, most of whom are Medicare-eligible

  • CurePSP has developed a free Allied Health (PT/OT/SLP/Social Work) guide to signs, symptoms, and management strategies for CBD, PSP, and MSA:  https://www.psp.org/wp-content/uploads/2016/08/ALLIED-HEALTH-BROCHURE_web.pdf

Consultations

See the list below:

  • Physical and occupational therapists: Physical and occupational therapy can be helpful to maintain endurance in patients with impaired gait and to teach patients with visual agnosia different strategies for performing activities of daily living.

  • Speech-language pathologist: These professionals can train patients with primary progressive aphasia or buccofacial apraxia to use an assistive communication device, similar to those used by patients with amyotrophic lateral sclerosis and other neuromuscular diseases. This training must be instituted early when patients are still capable of learning procedural/motor skills. If the diagnosis is in doubt, speech therapists with graduate training also can assess apraxia with quantitative standardized tests.

  • Nutrition: dietary modifications, protein supplementation, PEG management (along with Gastroenterology) if elected by patient

  • A social worker and/or geriatric case manager can be very helpful in counseling patients and their families on issues relating to increasing disability and, ultimately, end-of-life care.

  • A neuropsychological or experienced cognitive care provider (eg, behavioral neurologist, geriatric nurse) may be helpful in adapting the usual procedure for determining competence, communicating wishes and concerns, presenting hypothetical scenarios, and other tasks, since the cognitive problems of CBD can specifically interfere with a person’s ability to speculate about the future and make complex contingent decisions.

  • Early referral to Movement Disorders and/or Behavioral Neurology for confirmation of the diagnosis and advanced management. A growing number of tertiary referral centers have established advanced multidisciplinary (with PT/OT/SLP/Social Work, for example) care for patients with CBS and other parkinsonian disorders (see CurePSP Centers of Care: https://www.psp.org/ineedsupport/centers-of-care/). Clinical trials for neurodegenerative tauopathies are underway. Additionally, some patients find taking part in research studies, especially brain banking or genetics research, extremely gratifying, as they may derive meaning and a sense of purpose from contributing to the understanding and future treatment of others.

  • Referral to Psychiatry in cases of psychiatric comorbidity, frontal-behavioral presentation, or notable reactive depression.

Diet

See the list below:

  • Dysphagia may occur in many patients as a late symptom.

  • Speech therapy consultation for video barium swallow evaluation is recommended.

  • Thickened liquids or soft foods (depending upon degree of impairment) may be necessary under the guidance of a speech-language pathologist.

  • Constipation is common and is treated with conservative measures such increased fluid intake, high-fiber diets, encouragement of physical activity, stool softeners, and laxatives as necessary.

  • Referral to a Nutritionist: Liquid protein supplementation may be necessary to mitigate weight loss; Appetite stimulants can be considered

  • Discussion of patient wishes regarding gastrostomy tube placement (most elect not to pursue this) should be carried out and documented as early as possible

Activity

Activity is not restricted and is in fact encouraged using a positive risk-taking approach, but increasing motor assistance is required as the disease progresses. Many corticobasal syndrome (CBS) patients lose ambulation in advanced disease stages and may require wheelchair, electric stair glide, and/or patient lift devices.

Surgical Care

Deep brain stimulation surgery is not recommended for corticobasal syndrome (CBS) or other phenotypes associated with corticobasal degeneration (CBD) pathology. There is a lack of studies evaluating this modality for patients with CBS.

Complications

Key complications in patients suffering from corticobasal degeneration (CBD) include:

  • Aspiration pneumonia in the setting of progressve dysphagia

  • Weight loss in the setting of progressive dysphagia (and potentially depression)

  • Sepsis due to complicated urinary tract infections in the setting of progressive neurogenic bladder dysfunction, or from wound infection in the setting of progressive loss of mobility

  • Loss of the ability to communicate due to progressive nonfluent aphasia coupled with motor and voice impairments limiting the choice of augmented/alternative communication devices

  • Loss of reading ability due to oculomotor difficulties and cortical visual impairment

  • Loss of the ability to socialize due to behavioral/personality changes

  • Injury due to falls in the setting of progressive imbalance (gait/limb apraxia may contribute to this)

  • Deconditioning due to reduced mobility and limited ability to exercise

  • Reactive depression with potential suicidality

Prevention

No effective preventive strategies exist for corticobasal degeneration (CBD). Since CBD is commonly associated with dementia, general strategies aiming to develop cognitive reserve and mitigate effects of progressive neurodegeneration are advisable: pursuing education beyond a 4-year college degree, learning a musical instrument/singing, learning a new language, regular aerobic exercise, adhering to a Mediterranean diet, and maintaining social engagement. 

Long-Term Monitoring

Regular follow-up with a movement and/or cognitive neurologist is indicated to monitor for symptom changes and emergent complications. For patients receiving botulinum toxin injections, follow up at 2–3 month intervals is necessary to parallel the timing of the toxin wearing off. Patients require long-term physical, occupational, and speech/swallow therapy, even if only on a weekly basis, in order to maintain residual function and quality of life.Annual (or more frequent if there is decompensation) video barium swallow assessments should be considered. 

 

Medication

Medication Summary

Unfortunately, no regimen is reported to be highly effective in reversing or slowing the motor or cognitive symptoms of corticobasal syndrome (CBS) or other clinical corticobasal degeneration (CBD) phenotypes.[35]  Cholinesterase inhibitors can be tried; these have been reported to benefit patients with other tauopathies.[36] Medications for Parkinson disease, particularly levodopa at doses of 900–1,500 mg/day, may improve symptoms such as tremor to some extent in some patients and should be tried in everyone presenting with a component of parkinsonism.[17, 37]  Botulinum toxin injections may improve dystonia, blepharospasm/eyelid opening apraxia and sialorrhea. Clonazepam may improve myoclonus and tremor (in 23% per one study), but its use is limited by sedation and levetiracetam may be of benefit for myoclonus as well.[17, 38] Antidepressants such as sertraline, escitalopram, and venlafaxine should be considered for all patients with depression and anxiety in the context of CBD. When initiating antidepressants, patients should be monitored for clinical worsening of symptoms, behavior changes, and suicidality.[39] They should never be stopped abruptly, but gradually tapered off – during this time patients should be monitored for withdrawal symptoms, including agitation, emotional lability, nervousness or irritability. Sleep quality may be improved with melatonin up to 15mg used nightly; trazodone may be considered as well if melatonin is ineffective.

Benzodiazepines

Class Summary

Useful for the management of myoclonus. By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Clonazepam (Klonopin)

Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission. Can suppress myoclonus and also improve tremor.

Neuromuscular Blocking Agents, Toxins

Class Summary

These may be useful for the management of dystonia, especially painful dystonia. Botulinum toxin can inhibit transmission of impulses in neuromuscular tissue.

OnabotulinumtoxinA (Botox)

Useful in reducing excessive, abnormal muscular contractions. Binds to receptor sites on motor nerve terminals and after uptake inhibits release of acetylcholine, blocking transmission of impulses in neuromuscular tissue. Thought to also exert pain-relieving effects through centrally acting mechanisms (uptake into CNS).

Strongly advise having patients monitor and document their response to injections weekly (using a diary or spreadsheet) to assess for satisfactory response and side effects.

Increase doses 1.5 to 2 times over previously administered dose for patients who experience incomplete paralysis of target muscle. Doses of 100-800 units are administered, depending on the number of target symptoms/sites and patient tolerance of higher doses.

Cholinesterase Inhibitors

Class Summary

Galantamine may reduce symptoms of primary progressive aphasia in cortical basal ganglionic degeneration. Other cholinesterase inhibitors may also be effective, although supportive data are preliminary and only available for galatamine at this time.

Galantamine (Razadyne, Razadyne ER)

Galantamine is a competitive and reversible inhibitor of acetylcholinesterase. While the mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of acetylcholinesterase available for synaptic transmission in the CNS and enhance cholinergic function. There is no evidence that acetylcholinesterase inhibitors alter the course of underlying dementia.

Rivastigmine (Exelon)

Rivastigmine is a competitive and reversible acetylcholinesterase inhibitor. Although its mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the CNS and thereby enhance cholinergic function. Rivastigmine’s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. May improve recent memory and (less likely) overall cognition.

Donepezil (Aricept)

Noncompetitively inhibits centrally active acetylcholinesterase, which may increase concentrations of ACh available for synaptic transmission in CNS. May improve recent memory.

Antidepressants

Class Summary

Selective serotonin reuptake inhibitors (SSRIs) are greatly preferred over the other classes of antidepressants. Because the adverse-effect profile of SSRIs is less prominent than the profiles of other drugs, improved compliance is promoted. SSRIs do not have the cardiac arrhythmia risk associated with tricyclic antidepressants. Arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered when one treats a child or adolescent with a mood disorder.

Escitalopram (Lexapro)

Selective serotonin reuptake inhibitor (SSRI) and S-enantiomer of citalopram. Used for the treatment of depression. Mechanism of action is thought to be potentiation of serotonergic activity in central nervous system resulting from inhibition of CNS neuronal reuptake of serotonin. Onset of depression relief may be obtained after 1-2 wk, which is sooner than other antidepressants. Use at standard recommended doses.

Sertraline (Zoloft)

Is an SSRI used to treat impulse-control problems or underlying illness. It selectively inhibits presynaptic serotonin reuptake with minimal or no effect in reuptake of norepinephrine or dopamine. Use at standard recommended doses.

Trazodone (Desyrel, Desyrel Dividose, Oleptro)

Trazodone can be tried, with starting doses of 25 to 50 mg BID-TID (up to 150 mg total per day as a starting dose). This can be increased by 25-50 mg/day every 3–4 days to a maximum dose of 400 mg daily. Side effects include dizziness, somnolence, fatigue, constipation, diarrhea, nervousness, dream disorders, blurred vision, and hypotension.

Venlafaxine (Effexor, Effexor XR)

Venlafaxine is structurally unrelated to other available antidepressants. It inhibits serotonin reuptake at select receptors, as well as the reuptake of norepinephrine.

NMDA Antagonists

Class Summary

Glutamate release inhibition and glutamate receptor blockade are alternatives to potentiating D2 receptors in the indirect pallidal outflow pathway by reducing the glutamate-related excitatory circuit in this outflow pathway.

Memantine (Namenda)

This agent, approved for the treatment of Alzheimer disease in the US, may be of benefit for CBS since 20-30% of patient will have AD pathology.

Antiparkinson Agents, Dopamine Agonists

Class Summary

A dopamine agonist must stimulate D2 receptors if it is to offer clinical benefit. D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system or more directly by neuroleptic agents

Amantadine (Gocovri, Osmolex ER)

Amantadine inhibits N-methyl-D-aspartic acid (NMDA) receptor-mediated stimulation of acetylcholine release in the striatum. This agent may enhance dopamine release, inhibit dopamine reuptake, stimulate postsynaptic dopamine receptors, or enhance dopamine receptor sensitivity.

Decarboxylase Inhibitors

Class Summary

Dopamine agonists directly stimulate postsynaptic dopamine receptors to provide benefit against symptoms of of the diseae. In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine receptor subtypes is currently unclear.

Levodopa/carbidopa (Sinemet, Ritary, Duopa)

Lack of robust response to this medication in the context of CBS supports the diagnosis of CBD, although the same is generally true of PSP; an empiric trial, titrated to relatively high dose (minimum of 900- up to 1,500 mg daily for at least 1 month), is recommended in every patient.

Anticonvulsants

Class Summary

Many anticonvulsants are used to alleviate painful dysesthesias, which frequently accompany peripheral neuropathies. Although they have many different mechanisms of action, their use for alleviating neuropathic pain probably depends on their general tendency to reduce neuronal excitability.

Levetiracetam (Keppra, Keppra XR, Roweepra XR, Spritam)

Has been used successfully for myoclonus in CBS. Use limited by irritability, particularly in patients with a history of psychiatric disorders.

 

Follow-up

Further Outpatient Care

Periodic follow-up is appropriate to adjust dopaminergic medications, levetiracetam or clonazepam for myoclonus, inject botulinu toxin for dystonia or sialorrhea, treat depression/anxiety or other conditions. It may also help the caregiver to make plans for future care as the patient becomes more disabled.

Further Inpatient Care

Inpatient admission can facilitate a more rapid diagnostic workup as outlined in the Overview; if deterioration has been rapid with a high degree of suspicion, a brain biopsy may be advisable. 

Complications

Patients with significanat cerebral atrophy can develop subdural hematoma after a lumbar puncture, a fall, or spontaneously. See list of complications in the Overview section.

Prognosis

Corticobasal degeneration (CBD) is a progressive disorder, leading to increased cognitive and motor disability. Average course of the disease is about 7 years from symptom onset to death and about 4.6 years from diagnosis to death, although survival beyond 12 years has been reported.

Aspiration pneumonia, urosepsis, traumatic falls with head injury or other complications are the most frequent causes of death.[18]

Patient Education

A  Social Worker or geriatric case manager can be very helpful in counseling the patient and family about community resources, need for supervision, etc. CurePSP has a free guide for Social Workers and rehabilitation specialists conerning CBD, PSP, and MSA: https://www.psp.org/wp-content/uploads/2016/08/ALLIED-HEALTH-BROCHURE_web.pdf

Information for patients and families, guidelines for rehabilitation, and virtual support groups specific to CBS/CBD can be found at https://www.psp.org/

Additional information from the Institute for Neurological Disorders and Stroke:  https://www.ninds.nih.gov/Disorders/All-Disorders/Corticobasal-Degeneration-Information-Page