Corticobasal Syndrome

Abstract

Background and Objectives

Corticobasal syndrome (CBS) is a complex of symptoms and signs comprising limb rigidity, bradykinesia, dystonia, myoclonus, apraxia, cortical sensory loss, and a variety of cognitive and language impairments. CBS is commonly seen in tauopathies. Striking asymmetry in clinical and imaging findings in CBS raises questions about potential triggers initiating neurodegeneration. The objective of this study was to investigate potential central or peripheral triggers preceding CBS symptoms.

Methods

In this retrospective observational study, we reviewed medical records of patients with CBS at our Parkinson's Disease Center and Movement Disorders Clinic, focusing on evidence of possible central or peripheral “trigger” occurring within a year before the onset of CBS. We also reviewed records of patients with Parkinson disease (PD) for comparison.

Results

Of the 72 patients with CBS, 15 (20.8%) reported potential focal triggers before the onset of CBS-related neurologic symptoms. By contrast, only 1 of 72 patients with PD (1.4%) had a documented trigger before the onset of PD-related symptoms (p < 0.001). Of potential triggers, 13 were peripheral (related to hand or shoulder surgeries or trauma) and 2 were central (stroke and head trauma). Patients with CBS with triggers were younger, had earlier symptom onset, comprised a higher proportion of men, and had a higher likelihood of limb onset of symptoms than those without.

Discussion

Our finding of relatively high frequency of focal triggers in CBS compared with PD suggests potential central or peripheral triggers initiating neurodegeneration, possibly explaining asymmetric clinical and imaging features in CBS. Further research is necessary to validate and explore this observation's implications for CBS pathogenesis.

Introduction

Corticobasal degeneration (CBD) is a sporadic, progressive, neurodegenerative disorder. The neuropathologic hallmark of CBD is abnormal deposition of protein tau (4R isoform) in neurons and glial cells in both cortical and subcortical regions.¹ The term corticobasal syndrome (CBS) refers to the characteristic clinical syndrome associated with CBD pathology. The key clinical features include asymmetric apraxia, myoclonus, focal dystonia, cortical sensory deficits, and parkinsonism that is resistant to levodopa therapy.² Other features include pyramidal signs, alien limb phenomenon, cognitive impairment, and language difficulties. Several other neurologic, pathologically proven, conditions such as progressive supranuclear palsy, Alzheimer disease, frontotemporal dementia, and Creutzfeldt-Jakob disease may present as CBS.^3,4

One of the striking features of CBS is the marked asymmetry of clinical findings. Moreover, as the underlying disease progresses, a substantial majority of patients with CBS may develop asymmetric cortical atrophy that is most prominent in the parietal and frontal cortex (perirolandic pattern).^5,6 The side of focal or maximum brain atrophy is invariably contralateral to the side of the body with the classic clinical features. Such remarkable asymmetry in clinical, radiologic, and pathologic⁷ findings raises the question whether focal central or peripheral trigger initiates the cascade of the neurodegenerative process in CBS.

We postulate that discrete focal lesions, whether within the CNS (e.g., stroke, trauma, and surgery) or in the peripheral milieu (e.g., injury or surgery), engender localized pathologic perturbations. These aberrations may potentially facilitate the initiation of tau seeding, subsequently paving the way for a prion-like spread—a mechanism hitherto proposed for other proteinopathies such as Parkinson disease (PD).^8,9 Besides central triggers, there is growing body of literature supporting the notion of peripherally induced progressive movement disorders.¹⁰ In such instances, focal peripheral injury has been postulated to lead to central reorganization and alteration giving rise to asymmetric, and often progressive, motor disorder.¹⁰

In this study, we aimed to systematically review our patients with clinically diagnosed CBS and compare them with those with clinically diagnosed PD to determine the frequency and nature of potential central and peripheral triggers.

Methods

This retrospective study was conducted at the Parkinson's Disease Center and Movement Disorders Clinic (PDCMDC), Department of Neurology, Baylor College of Medicine, Houston, TX. The study cohort consisted of patients diagnosed with CBS by fellowship-trained movement disorder neurologists, identified through meticulous scrutiny of our regularly updated comprehensive video log. Comprehensive clinical insights were extracted from patient charts within the electronic medical record (EMR) at the PDCMDC. The search period spanned from 2009 to 2023, coinciding with the availability of patient data within the EMR since 2009. The patients identified as having CBS satisfied the Cambridge diagnostic criteria.¹¹ To investigate potential triggers, an exhaustive and detailed review was undertaken with focus on either central or peripheral potential precipitants within the year preceding the onset of CBS-related symptoms. The decision to include patients with a history of potential triggers within one year of symptom onset was based on the previously proposed diagnostic criteria for peripherally induced movement disorders.¹² Concurrently, for comparative purposes, the EMR was also thoroughly reviewed for an equivalent number of patients diagnosed with PD, chosen as controls because of their analogous asymmetric symptom presentation, akin to CBS. Patients with CBS having potential triggers before the onset of symptoms (CBS-T) were compared with those with no potential triggers (CBS-NT) for a number of demographic and clinical characteristics.

Continuous variables were compared using the Student t test, and categorical variables were compared using the χ² test. A p-value of <0.05 signified a statistically significant difference. We used GraphPad Prism (version 10.0.3) for the statistical analyses.

Standard Protocol Approvals, Registrations, and Patient Consents

Institutional Review Board (IRB) of Baylor College of Medicine, Houston, Texas, approved this study. Given the retrospective nature of the chart review, compliance with IRB policies obviated the requirement for written informed consent from the patients.

Data Availability

Anonymized data can be obtained by request from any qualified investigator for purposes of replicating procedures and results.

Results

We identified 72 patients with CBS in our EMR evaluated by movement disorders experts. All the patients had clear asymmetry in symptoms and signs. Among those, 15 patients (20.8%) reported having a potential peripheral or central trigger (CBS-T). By contrast, only 1 (1.4%) of 72 patients with PD had a potential peripheral or central trigger (Figure 1). The frequency of antecedent triggers was significantly greater in the CBS compared with the PD group (p < 0.001).

Figure 1. Comparison of the Proportion of Patients With Focal Peripheral or Central Trigger in CBS and PD.

Bar diagram displaying the percentage of patients in CBS and PD groups with potential peripheral/central triggers. Antecedent triggers were much more frequently present in the CBS compared with the PD group (p < 0.001). CBS = corticobasal syndrome; PD = Parkinson disease.

In the CBS-T group, 2 patients had a potential central trigger, one with stroke and one with head injury. Among 13 patients with CBS-T with potential peripheral triggers, 7 had surgeries for various focal problems (rotator cuff repair-2, carpal tunnel release-2, foot surgery-1, fixation of humerus fracture-1, tenosynovitis-1), 2 had cast immobilization of the limb after fracture, 2 had severe blunt trauma to the hand, 1 had stab injury, and 1 had extraction of 20 teeth as part of a certain dental procedure.

Patients with CBS-T were significantly younger and had a younger age at onset of CBS symptoms compared with the patients with CBS-NT (Table 1). A significantly higher proportion of patients with CBS-T were men compared with those with CBS-NT (66.7% vs 36.9%, p < 0.03). There was no significant difference in the scores of Montreal Cognitive Assessment (MoCA). A greater proportion of patients with CBS-T had a predilection for initial symptoms in the limbs (focal dystonia or apraxia) compared with those with CBS-NT (80% vs 49%, p = 0.03). Because we could not access the original magnetic resonance images in most of the patients, detailed analysis of the pattern of brain atrophy was not possible. However, we include MRI scans from 2 patients with CBS-T to illustrate marked focal brain atrophy (Figure 2).

Table 1.

Comparison of Key Demographic and Clinical Characteristics of CBS Patients With and Without Potential Peripheral/Central Triggers

Parameters	CBS-T (n = 15)	CBS-NT (n = 57)	Significance
Age at first evaluation	66.5 ± 9	71.7 ± 8.3	p = 0.03
Age at onset of symptoms	63.2 ± 9.1	68.2 ± 8.3	p = 0.04
Men	66.7%	36.9%	p = 0.03
MoCA	22 ± 4.2 (n = 9)	20.8 ± 6.2 (n = 41)	p = 0.59
Onset with limb symptoms	80% (n = 12)	49% (n = 28)	p = 0.03

Abbreviations: CBS = corticobasal syndrome; CBS-T = CBS with a potential trigger (central or peripheral); CBS-NT = CBS with no potential trigger (peripheral/central); MoCA = Montreal Cognitive Assessment (the score was available for 9 patients with CBS-T and 41 patients with CBS-NT); PSP = progressive supranuclear palsy.

Figure 2. Demonstration of Asymmetric Cortical Atrophy in Patients With Corticobasal Syndrome.

(A and B) T2 FLAIR axial and T1 coronal slices showing left-sided frontoparietal atrophy in a patient with CBS with antecedent painful hyperextension of the contralateral elbow. (C and D) T2 FLAIR axial and T2 coronal slices slowing right-sided frontoparietal atrophy in a patient with CBS with antecedent fracture and cast immobilization of the contralateral wrist.

Discussion

Our retrospective analysis showed that a significantly higher proportion of patients with CBS had potential central or peripheral precipitating factors in comparison with those diagnosed with PD (21% vs 1.4%, p < 0.001). The mean age at symptom onset for the entire CBS group was 67.1 ± 8.1 years, a range consistent with the literature's reported values of 50–70 years.^13,14 The CBS-T cohort had a younger age at symptom onset, a greater predilection for male sex, and a greater propensity for limb onset of symptoms compared with the CBS-NT group (Table 1).

We explored whether the subgroups of CBS differ regarding the initial presentation. A significantly greater proportion of patients with CBS-T had a predilection for onset of symptoms in the limb (focal dystonia and/or apraxia) affected by the peripheral trigger than those in the CBS-NT group (80% vs 49%, p = 0.03). On the contrary, presenting symptoms in CBS-NT were predominantly axial or generalized, which include difficulty in walking, balance impairment, difficulty in speaking, and slowness of activities of daily living. This observation lends credence to the notion that the CBS-T group indeed experienced a phenomenon that could be attributed to peripherally induced factors, originating in the limb that had been affected by trauma or surgery and thus leading to prominent asymmetry in clinical presentation.

While both CBS and PD are characterized by an asymmetric onset of symptoms, CBS presents with a much more pronounced and persistent asymmetry, particularly evident in symptoms such as dystonia, rigidity, and apraxia.¹⁵ Various triggers were identified within the CBS-T subgroup of patients in our study, with the majority being of peripheral origin. This observation aligns with growing body of evidence that peripheral insult can lead to a progressive movement disorder that may be centrally mediated.¹⁰

The pathogenesis of peripherally induced movement disorders remains enigmatic; however, insights from animal studies have provided valuable contributions. There is growing support for the hypothesis of central neuronal reorganization in response to peripheral trauma (injury, surgery, or immobilization).^16,17 For example, in a study on cats, experimental deafferentiation of the spinal cord (by dorsal rhizotomy) resulted in spontaneous hyperactivity and abnormal firing of second-order neurons,¹⁸ which could be manifested by segmental myoclonus. Indeed, ours and other studies^12,19-22 identified immobilization, such as casting, as a major risk factor of the development of peripherally induced movement disorders. In the context of CBS, a study conducted at the Mayo Clinic found that 10 (23%) of 44 patients with CBS exhibited a history of immobilization or trauma affecting their most afflicted limb, preceding the onset or exacerbation of symptoms.²³ In our own series, we encountered 2 such patients who developed apraxia and dystonia in limbs that had previously been subjected to immobilization through casting after sustaining limb fractures. Another piece of evidence comes from the association of peripherally induced movement disorders with complex regional pain syndrome (CPRS), which by definition is focal and asymmetric.^10,22,24 There are 2 case reports that highlight the association of CBS and CPRS, and in both reports, the motor features of CBS and the pain, vasomotor, and sudomotor changes related to CPRS were in the same extremity.^25,26

Additional important evidence of peripheral triggers leading to movement disorders comes from recent studies on mouse models of DYT1 (Tor1A)-associated dystonia wherein experimental crush injuries of peripheral nerves resulted in dystonic posturing of lesioned hind limbs of mutant and wild-type mice.^27,28 These findings underscore the potential for peripheral injury acting as a “second hit” in individuals already predisposed to vulnerability, such as those harboring Tor1A variations.^27,28 Extrapolating the animal findings to our patients with CBS-T, it is plausible that peripheral injury, coupled with some underlying susceptibility, leads to alteration of central organization with local seeding and subsequent misfolding and spread of tau, resulting in an asymmetric progressive neurodegeneration.

Besides peripheral factors, central triggers may also play a role in the asymmetric onset and development of CBS. This concept is well illustrated by focal traumatic brain injury (TBI) leading to “chronic traumatic encephalopathy,” a slowly progressive neurodegenerative condition caused by a single or repetitive blows to the head.²⁹ It has been postulated that TBI triggers local acute neuroinflammation associated with microglia activation and release of toxic levels of cytokines, chemokines, glutamate, and other excitotoxins that inhibit phosphatases, resulting in hyperphosphorylated tau and formation and deposition of neurofibrillary tangles. These pathologic abnormalities initially occur focally in the area of the TBI and then spread through prion-like mechanisms to other parts of the brain leading to a progressive neurodegeneration (tauopathy).^30,31 This notion is supported by experimental animal data. In one recent study, patient-derived tau aggregates injected in the supranigral region of macaque brains were found to induce motor and behavioral impairments through prion-like seeding and spreading resulting in generalized tauopathy.³² Among various central triggers, stroke-induced occurrences in brain regions beyond the cortex or basal ganglia, such as those within the pons, have been documented as trigger for CBS in patients who have received postmortem diagnosis of CBD.³³ This suggests that focal brain lesions induced by injury, stroke, or other insults may initiate a cascade of pathologic events resulting in progressive, generalized, asymmetric neurodegeneration manifested clinically as CBS.

The mechanism of asymmetric onset of motor symptoms in patients with PD is not well understood but has been attributed to “a complex interplay of hereditary and environmental factors.”³⁴ The asymmetry in PD seems to be more prominent in the tremor-dominant form of PD, where the neuronal cell loss is more severe contralateral to the side of motor symptom onset.³⁴ Indeed, the substantia nigra asymmetry index, determined by examining hyperechogenicity, was linked to motor asymmetry in the tremor-dominant group but not in the patients with PD without tremor.³⁵ The reason for the difference in the pattern of asymmetry between PD and CBS is not known, but using various neurophysiologic and imaging techniques, one study showed that while patients with PD exhibited an asymmetric pattern of brainstem excitability, patients with CBS showed an asymmetric pattern of cortical atrophy. This suggests that PD neurodegenerative process may initially start in the brainstem while CBS initially involves primarily cortical and subcortical brain structures.¹⁵

Our study has several limitations, primarily because of the retrospective design and lack of confirmation of diagnosis by autopsy. It is possible that not every patient with CBS or PD was asked comprehensively about the history of peripheral or central injury during the clinical encounter, thus underestimating the actual number of patients who had a potential trigger. Moreover, there exists the possibility of recall bias influencing the results, particularly among patients with cognitive impairments, which could affect the accuracy of reported data. Furthermore, establishing a direct causal link between the emergence of symptoms in the CBS-T group and the antecedent triggers poses a significant challenge. Notwithstanding these limitations, our study, although preliminary in nature, lays the foundation for further exploration into the potential association between peripheral or central triggers and the onset of CBS. Our findings also offer potential insights, at least in a subgroup of patients, into the notable asymmetry observed in clinical characteristics in CBS. In the future, well-designed prospective studies may provide better insights into this intriguing hypothesis.

This retrospective study provides preliminary evidence that peripheral or central triggers may initiate local neurodegenerative process, clinically manifested by asymmetric motor features of CBS, at least in a subset of patients. Further studies are needed to validate our observations by prospective clinical and experimental studies.

Appendix. Authors

Name	Location	Contribution
Abhishek Lenka, MD, PhD	Parkinson Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Joseph Jankovic, MD	Parkinson Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.