Pathological heterogeneity of clinically diagnosed corticobasal degeneration

Abstract

Two patients fulfilling suggested clinical diagnostic criteria for corticobasal degeneration (CBD) are presented, who were found at postmortem to have alternative pathological diagnoses not suspected during life, namely, Alzheimer's disease and Pick's disease, respectively. The nosological position of these cases is considered in light of a literature review of previous reports of clinically diagnosed corticobasal degeneration with atypical (not corticobasal degeneration) pathology. Since such phenocopies may be common, we suggest that all clinically diagnosed cases of corticobasal degeneration should initially be labelled as “corticobasal degeneration syndrome” (CBDS) to emphasize that this is a diagnosis based on clinical phenotype, with the term corticobasal degeneration being reserved for the specific neuropathological phenotype, which itself may have a variety of clinical presentations.

Introduction

In the late 1960s, Rebeiz et al. described a disorder which they called “corticodentatonigral degeneration with neuronal achromasia” [1], [2] Subsequent authors have designated this condition as “corticobasal degeneration” (CBD) or “corticobasal ganglionic degeneration,” (CBGD) [3], [4], [5], [6]. The “classical” clinical picture is of a chronic progressive akinetic–rigid syndrome with asymmetric onset in middle to late life, accompanied by higher cortical dysfunction in the form of an apraxic limb, sometimes displaying an alien limb syndrome, and cortical sensory dysfunction. Movement disorders such as dystonia and myoclonus (action-induced, stimulus-sensitive) may also occur. Supranuclear gaze palsy, dysarthria, ataxia, chorea, blepharospasm, and corticospinal tract signs have also been described [1], [2], [3], [4], [5], [6], [7], [8]. Neuropsychological studies have shown deficits of sustained attention and verbal fluency, as in Alzheimer's disease (AD), along with deficits of praxis, finger tapping, and motor programming, unlike AD. These changes were thought to reflect basal ganglia and posterior frontal lobe involvement in CBD [9], [10]. Although the first reports [1], [2] and early reviews [6], [7], [8] of CBD suggested that dementia was an unusual and late feature, more recent studies with less bias suggest that dementia may be common [11], and indeed may be the first [12], [13] and most frequent presenting feature [14]. Cases presenting with features of frontotemporal dementia (FTD) without a motor disorder have also been reported [11], [15], [16], [17], as have patients with parieto-occipital (Balint-like) cortical dysfunction [18] and a combination of dementia, parkinsonism, and motor neurone disease [19].

Typical pathological findings in CBD comprise cortical atrophy, especially in the frontal and anterior parietal lobes, with degeneration of the substantia nigra. Nerve cell loss and gliosis is seen in the cortex, underlying white matter, thalamus, lentiform nucleus, subthalamic nucleus, red nucleus, midbrain tegmentum, substantia nigra, and locus ceruleus. Many residual nerve cells are swollen and chromatolysed with eccentric nuclei (achromasia [1], [2]), resembling the central chromatolysis of axonal reaction [3], [4], [5], [6]. Neuronal inclusions resembling the globose neurofibrillary tangles (NFTs) of progressive supranuclear palsy (PSP) are present in the substantia nigra, but no cortical NFTs, Pick bodies or Pick cells, senile plaques, Lewy bodies, granulovacuolar change or amyloid deposits are seen; hence, the pathological picture is distinctive [3], [4], [5], [6]. The condition is of unknown aetiology; most cases are sporadic, but occasional familial cases have been reported [13]. No effective treatment is currently known, the syndrome being unresponsive to levodopa.

Hence, CBD is a clinicopathological entity of variable clinical phenotype, for which clinical diagnostic criteria have been suggested [6]. The best predictors for the antemortem clinical diagnosis of CBD are reported to be limb dystonia, asymmetric parkinsonism at onset, and ideomotor apraxia which becomes more severe throughout the illness [20]. Clinical and pathological overlap of CBD with PSP is recognised in some cases [21], [22], [23], and the two conditions may share a common genetic background [24]. Occasional cases with the typical clinical phenotype of CBD but lacking the typical neuropathological features have been reported. We present two further cases which fall into this category and consider their nosological position in the light of a review of the literature describing similar cases.