Criteria for the diagnosis of corticobasal degeneration

Abstract

When first described, “corticodentatonigral degeneration with neuronal achromasia” was considered a distinct clinicopathologic entity,¹ eventually termed corticobasal degeneration (CBD).² Clinicopathologic studies have since revealed that the originally described clinical features of CBD, now called corticobasal syndrome (CBS), are often due to other pathologies. As a pathologic diagnosis, CBD is characterized by widespread deposition of hyperphosphorylated 4-repeat tau in neurons and glia, the latter as astrocytic plaques, in specific topographic areas.³ Despite various clinical diagnostic criteria (table e-1 on the Neurology® Web site at www.neurology.org),^4–10 the pathology of CBD is predicted antemortem in only 25% to 56% of cases.^11–17 Additionally, while these clinical criteria continue to be widely applied and cited, they reflect CBS alone and not the more recently recognized behavioral presentations of CBD.

Definition and standardization of clinical diagnostic criteria for CBD are critical, especially as potential neuroprotective therapies for tauopathies emerge. In light of advances in the understanding of CBD, we used specialist consensus, brain bank cases, and a critical literature review to develop new diagnostic criteria. During this process, however, it became clear that clinicopathologic heterogeneity of CBD confounds the development of specific criteria, unlike what has been accomplished for other neurodegenerative diseases. Thus, we propose 2 sets of criteria: a narrower, more specific one for probable CBD and a broader set for possible CBD that has less specificity for CBD pathology while still representing probable tau-based pathology.

METHODS

Previous CBD clinical diagnostic criteria were reviewed. Invited international specialists in behavioral neurology, neuropsychology, and movement disorders met on October 14–15, 2009, and based on participants' experience and literature reviews, clinical phenotypes were identified and CBD criteria were drafted.

Subsequently, a systematic literature search and later update using MEDLINE (1950 to April 2012) and EMBASE (1980 to April 2012) identified English-language pathologically proven CBD series. Search terms included “corticobasal,” “corticobasal degeneration,” and “CBD” text word searches paired with “pathology” as a MeSH search term and text word search. Inclusion criteria were 1) a minimum of 5 pathologically proven CBD cases (chosen a priori to avoid the bias toward atypical cases from case reports) and 2) extractable data for clinical phenotype, symptoms/features, or both. Only patients with pathologically proven CBD were included. Inclusion criteria were intentionally broad to enable a large sample size and decrease the impact of ascertainment bias and variations in CBD feature reporting. Information was entered into a database including commonly reported features and those deemed relevant by the panel. Publication authors and institutions were cross-checked to prevent case duplication. Additionally, 5 centers with CBD brain bank cases provided data on published and unpublished cases. When available, the original brain bank data were abstracted rather than using the less comprehensive information from brain bank–related publications. Two overlapping sets of cases were developed: cases for which features of CBD could be extracted and cases for which information was available regarding clinical diagnosis or phenotype.

Clinical features were recorded at 2 time parameters, at presentation and “ever” (during the disease course), variables for which the most consistent data could be abstracted. Presentation was a mean of 3.0 (SD 1.9) years after symptom onset in one series.¹⁸ When data were abstracted, features were considered as present or absent only if specifically described. While this approach carries the risk of overestimating the frequency of each feature, it was thought suitable due to the complexity of CBD and the varying degrees of detail in the retrospective data. Because of this approach, the denominator for calculating the frequency of any given clinical feature is less than the total number of cases identified, reflecting the number of cases for which that feature was reported. Finally, a literature search was conducted for clinicopathologic correlation articles including CBD subjects and cases with other proven pathologies to identify specific clinical features that might improve the accuracy of proposed CBD criteria vs other pathologic diagnoses. Results of the specialist panel, case reviews, and clinicopathologic studies were integrated into the proposed criteria. A glossary of terms is available in appendix e-1.

RESULTS

Clinical features of CBD

Motor features

The motor features of CBD emerged from early case series with incomplete pathologic follow-up in which the CBS presentation predominated, manifesting with asymmetric onset of levodopa-resistant parkinsonism, dystonia, and myoclonus. Seventy-three percent (72/99) of reviewed patients with CBD with parkinsonism had documented asymmetry. Limb rigidity (85%) and bradykinesia (76%) were the most common motor findings (table 1); 57% had limb rigidity and 48% had bradykinesia at presentation (where described). Although often characterized as severe, the nature of limb rigidity was rarely described and may relate to parkinsonism, dystonia, or gegenhalten/paratonia. Axial rigidity was reported in 27% at presentation and 69% at some time during the disease course. CBD series emphasizing cognitive or behavioral presentations show low rates of early parkinsonism.^13,15,20

Table 1

Frequency of motor features in available brain banks and studies with ≥5 pathologically confirmed corticobasal degeneration cases^a

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Thirty-nine percent of CBD cases had tremor documented during the disease course (table 1), representing a mix of resting, postural and action, and undefined tremors. Tremor phenotype in CBD is poorly characterized, but a CBS series suggests that it differs from the typical rest tremor of Parkinson disease (PD).²⁵ Low-amplitude action myoclonus may resemble tremor.

Gait abnormalities (often poorly characterized) were described in 73% overall, but only in 33% at onset, with postural instability and falls occurring at similar frequencies (table 1). The timing of falls was rarely described.

Sustained levodopa responsiveness—related to parkinsonism—is an exclusion criterion in prior diagnostic schemes.^4,5,9,10,26 Patients with CBD may demonstrate transient mild to moderate improvement with levodopa therapy and rarely develop levodopa-induced dyskinesias,¹⁶ but a sustained response is rare. The presence or absence of a levodopa response was seldom described in compiled cases.

Dystonia is described in 59%–71% of patients in series mixing CBS and CBD^7,25,27; however, only 38% of compiled CBD cases ever had limb dystonia (table 1) and only 20% presented with limb dystonia.

Clinical series describe myoclonus in 55%–93% of patients with CBS,^7,25,27,28 but myoclonus occurred in only 27% of compiled CBD cases (table 1). Myoclonus in CBD may be superimposed on dystonia¹⁸ and is most commonly described in the upper extremities, but can also be present in the face.^13,18 Descriptions include “focal myoclonus,”¹⁸ “stimulus-sensitive myoclonus,”^13,16 and “action myoclonus.”¹⁶ Studies of myoclonus in CBS suggest that a very short latency may be characteristic,^29,30 but it is unclear if this is true in CBD.

Higher cortical features

Higher cortical features described in CBD include apraxia, alien limb phenomena, cortical sensory loss, cognitive impairment, behavioral changes, and aphasia.

Apraxia is core to all previous diagnostic criteria (table e-1). Limb apraxia was found in 57% of compiled CBD cases (table 2). Ideomotor apraxia is the most commonly described apraxia in CBD^15,16,18 with one series also describing limb-kinetic apraxia.²⁴ The presence of limb dystonia, bradykinesia, and rigidity can make assessing ideomotor apraxia challenging and diagnosing limb-kinetic apraxia impossible. Patients with CBD may also have orobuccal apraxia or “apraxia of eyelid opening,”^{13,15,16,18,21,24} though the latter is often a misnomer representing pretarsal blepharospasm rather than true apraxia.³¹

Table 2

Frequency of higher cortical features in available brain banks and studies with ≥5 pathologically confirmed corticobasal degeneration cases^a

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Alien limb phenomena are included in prior criteria (table e-1), yet what behaviors constitute alien limb phenomena remains a matter of debate.²⁶ Alien limb phenomena (including complex unintentional limb movements interfering with normal tasks¹⁸ and the sensation that a limb was foreign or had a will of its own¹⁶) were described in 30% of compiled CBD cases (table 2).

When reported (less than half of compiled CBD cases), cortical sensory loss was present in approximately a quarter of cases (table 2). Visual neglect occurs in CBD,^15,18,20 but also in Alzheimer disease (AD).²⁰

Language impairments are now recognized as a common and frequently presenting feature of CBD. Aphasia occurred in 40% of compiled CBD cases at presentation and in 52% over the disease course (table 2). Reports most commonly categorized the aphasia as primary progressive aphasia (PPA), progressive aphasia, or progressive nonfluent aphasia (PNFA),^{15,20,32–34} though these terms overlap and reflect older terminology that has recently been revised.³⁵ Aphasic patients with CBD may progress to mutism.^13,15,36 Apraxia of speech (AOS) has also been described in CBD on its own and coexisting with aphasia,^20,32 though challenges in diagnosing AOS limit efforts to estimate its frequency. Some consider AOS a speech disorder rather than language dysfunction³⁷; consensus has been elusive. Speech abnormalities in general were described in 53% of cases (23% at presentation) (table 3). Some patients had dysarthria,¹⁸ but for others, few details were provided.^13,15,21

Table 3

Frequency of other features in available brain banks and studies with ≥5 pathologically confirmed corticobasal degeneration cases^a

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Over half of compiled CBD cases had cognitive impairment at onset and 70% during the disease course (table 2). While this represented patients' subjective memory concerns in some series, memory complaints may relate to amnestic or nonamnestic (e.g., executive, language) cognitive disturbances. Neuropsychological testing in one study revealed that patients with CBD had difficulties with learning tasks, word fluency, verbal comprehension, perceptual organization, and cognitive flexibility.³⁸ Another study showed impairments in executive, language, and visuospatial domains with relatively preserved episodic memory.¹⁵ In contrast, prominent memory loss was a presenting symptom in one series without neuropsychological testing.¹³ The presence of memory impairment in CBD is underscored by numerous series in which the clinical diagnoses of AD or atypical AD proved to be CBD.^{12,13,15,16,21,23,39} Acalculia and visuospatial difficulties (with limited details) are rarely described in CBD.¹⁵ Behavioral changes and executive dysfunction are common in CBD, underscored by many patients presenting with a behavioral variant frontotemporal dementia (FTD) syndrome.^{13,15,16,20,33,39–41} Symptoms include apathy, bizarre or antisocial behavior, personality changes, irritability, disinhibition, and hypersexuality.^13,15,16,39 Fifty-five percent of reviewed CBD cases had behavioral changes, often at presentation (table 2). Clinical depression (rather than formal diagnosis) was described in 51% of patients where mood was recorded (table 2), but this information was provided in less than half of cases. Only a single published patient had hallucinations, coincident with levodopa treatment,¹⁶ but hallucinations not associated with levodopa were also rarely described in brain bank subjects (S.E. Lee and D.W. Dickson, personal communications, 2011).

Other features

Eye movement abnormalities may be present in CBD, but details are rarely provided and terminology is often ambiguous. Sixty percent of compiled cases had eye movement abnormalities. At onset, 33% showed such abnormalities (table 3). Studies of patients with CBS describe increased saccadic latency,^42–45 but this was not confirmed in a publication including oculographic measurements in 4 subjects with CBD, where 3 had visually guided saccades that were indistinguishable from normal controls. Antisaccade performance was abnormal in all cases.⁴⁶ Upper motor neuron signs are another feature described in CBD cases (table 3), but since they also occur in other atypical parkinsonisms, they are unlikely to be a helpful distinguishing sign.

CBD diagnostic criteria

Given the complex clinicopathologic correlations and varying phenotypes over time,^34,36 it is not surprising that developing CBD diagnostic criteria has proven challenging. Five potential phenotypes were identified above, but while AD was a common clinical misdiagnosis of CBD in compiled cases, few details are available regarding how these diagnoses were made and what features prompted this diagnosis. Given the relative frequencies of AD and CBD, the false-positive diagnosis rate of an AD phenotype for CBD would be high if this phenotype was included; it was thus excluded. The 4 clinical phenotypes thought to be most representative of CBD were CBS, frontal behavioral-spatial syndrome, nonfluent/agrammatic variant of primary progressive aphasia, and PSPS (table 4).

Table 4

Proposed clinical phenotypes (syndromes) associated with the pathology of corticobasal degeneration^a

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While these 4 phenotypes are frequent clinical presentations of CBD, it was difficult to identify specific features that would consistently predict a CBD diagnosis vs other pathologic diagnoses such as FTLD or PSP (supplemental text). Our deliberations led us to propose 2 diagnostic classifications for CBD (table 5): 1) clinical research criteria for probable CBD (cr-CBD), which attempt to maximize the chance of diagnosing classic CBD without contamination from other pathologies; and 2) possible CBD criteria (p-CBD), which are less restrictive but still emphasize presentations consistent with underlying tau pathology. The p-CBD criteria will catch more CBD cases but will also yield more false-positives, including patients who also meet criteria for other neurodegenerative conditions such as PSP. This approach could be acceptable if research studies, including experimental therapies, were directed at the broader issue of tau-based pathology.

Table 5

Diagnostic criteria for corticobasal degeneration^a

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Both sets of criteria require insidious onset and gradual progression with symptom duration of at least 1 year to exclude rapidly progressive conditions more likely to represent other pathologies (e.g., CJD). Age at onset ≥50 years is required for cr-CBD given that this will identify 98% of patients with CBD and exclude pathologies with younger age at onset (e.g., FTLD). No age minimum is set for p-CBD, allowing for young-onset familial cases of CBD related to tau mutations. In addition, a family history (>1 relative) of a similar neurodegenerative disease is an exclusion criterion for cr-CBD but not p-CBD.

Accepted phenotypes are slightly different for the 2 sets of criteria. While PSPS is a CBD phenotype, it is much more likely to represent PSP than CBD.⁵⁸ Thus, PSPS is an acceptable phenotype only in the p-CBD criteria. Features suggestive of idiopathic PD (classic 4- to 6-Hz resting tremor, excellent and sustained levodopa response) are exclusion criteria for both diagnostic criteria, as are hallucinations, which are much more suggestive of PD or DLB than CBD. Prominent dysautonomia and cerebellar signs are thought to be more suggestive of multiple system atrophy than CBD and thus are exclusion criteria based on consensus; CBD series do not routinely describe these signs. Because of their association with non-tau pathology (supplemental text), the presence of coincident upper and lower motor neuron signs or semantic- or logopenic-variant PPA are exclusion criteria for both cr-CBD and p-CBD.

While tau mutations are allowed for p-CBD, GRN, TDP-43, or FUS mutations are exclusions for both sets of criteria. Because emerging research suggests that amyloid imaging and CSF Aβ42/tau ratio may be useful in diagnosing AD and these biomarkers have been incorporated into the 2011 AD diagnostic criteria,⁵⁹ results suggestive of AD on these studies are exclusion criteria for CBD, acknowledging that we lack confirmation of the ability of these tests to distinguish AD from CBD. Mutations known to be associated with AD are also exclusion criteria. Similarly, imaging studies suggestive of other pathologies (e.g., CJD) are exclusions for CBD diagnoses, but CBD-supportive imaging is not included as a criterion given the need for further validation.

DISCUSSION

Development of the proposed criteria relied on expert consensus among behavioral neurology, neuropsychology, and movement disorders specialists and a critical review of brain bank and published clinical–pathologic series. Limitations to the use of published and brain bank series include their retrospective nature, often relying on incomplete records, and subspecialty biases in reporting centers. We attempted to minimize these biases by strategically searching for cases, seeking brain bank data where available, and maximizing the sample size of the compiled cohort. Our decision to only consider features as present or absent if specifically described may result in overestimation of the frequency of CBD features. Given the reliance on often incomplete retrospective data from a wide variety of sources, this was thought to incur less bias than marking undescribed features as absent. Our results should be interpreted with this limitation in mind. Furthermore, the lower end of feature frequency can be calculated from the provided tables and the total sample size of 209 cases.

Identifying clinical phenotypes and features specific for CBD is an ongoing struggle limiting the ability to create definitive clinical criteria. This is addressed by proposing 2 sets of CBD criteria. Ultimately, a clear diagnosis of CBD may only be possible once biomarkers and associated genetic mutations are identified. In the meantime, the broader criteria may be useful, since potential disease-modifying agents are likely to deal with tauopathies as a class rather than considering tau-based diagnoses separately.

Our understanding of CBD has grown tremendously since its initial description but challenges with clinical diagnosis remain. We propose new CBD diagnostic criteria based on recent advances and a review of a large number of pathologically proven cases. We expect that these criteria will need continued revisions as our understanding of CBD improves and as imaging studies and biomarkers advance and are validated for distinguishing different phenotypes and diagnoses.

Supplementary Material

ACKNOWLEDGMENT

GLOSSARY

Footnotes

REFERENCES