Details regarding the specific clinical features of the CBS can be found in several sources (3,5,10,12,15-17).
The core clinical features are progressive asymmetric rigidity and apraxia. Symptoms typically begin in one limb, with no apparent predilection for the right or left side. Patients describe their limb as "clumsy," "incoordinated," or "stiff." On examination the limb is mildly to severely rigid, and sometimes adopts a dystonic posture. Features of both rigidity (i.e., velocity-independent increased tone) and spasticity (i.e., velocity-dependent increased tone) can be present in the affected limbs. Alternating motion rates are markedly reduced. The affected limb often becomes profoundly apraxic. Initially, the clumsiness and breakdown of complex coordinated movements may represent limb-kinetic apraxia. However, this is difficult to completely distinguish from the effects of basal ganglia dysfunction including rigidity, bradykinesia, and dystonia. Later, clear features of ideomotor apraxia develop with the inability to correctly perform or imitate gestures and simple activities. When asked to perform these activities or gestures with an involved hand, patients often glare at the limb in question and visibly struggle. With time, the limb becomes completely useless, and other limbs become similarly affected. Typically, progressive asymmetric rigidity and apraxia is present in one of the upper limbs for at least 2 yr, then either the ipsilateral lower limb or contralateral upper limb becomes involved, eventually leading to severe generalized disability several years later. Less commonly, a lower limb is affected first, or progression occurs rapidly over many months.
Apraxia and rigidity have undegone further study. Leiguarda et al. evaluated buccofacial, ideomotor, and ideational praxis in 10 patients with the CBS (18). Their findings suggested that ideomotor apraxia was the most common type of apraxia in the CBS, and likely reflected dysfunction of the supplementary motor area. Those who had coexisting ideational apraxia correlated with global cognitive impairment, which suggested additional parietal or more diffuse cortical dysfunction (18). Caselli et al. compared detailed kinematic data in several patients with the CBS, including one case who had CBD at autopsy and another who had Alzheimer's disease (AD) (19). Severe abnormalities in temporal and spatial control, motor programming, and intermanual symmetry were present regardless of the presence or absence of dementia or specific histology (19). Boeve et al. studied two siblings with a familial neurodegenerative disorder associated with nonspecific histopathology, in which one brother exhibited the CBS during life whereas the other had classic frontotemporal dementia
(FTD) features (20). The case with the CBS features had no significant degenerative changes in the basal ganglia and substantia nigra, suggesting that extrapyramidal dysfunction can exist in the absence of appreciable pathology in the nigrostriatal system (20). Hence, additional clinical, radiologic, and pathologic studies are necessary to better define the anatomic substrates underlying apraxia and rigidity in the CBS.
The alien limb phenomenon is an intriguing feature in the CBS. Patients often describe their affected limb as "alien," "uncontrollable," or "having a mind of its own," and often label the limb as "it" when describing the limb's behavior. The movements are spontaneous and minimally affected by mental effort, sometimes requiring restraint by the contralateral limb. This phenomenon often lasts a few months to a few years before progressive rigidity or dystonia supercedes.
There has been debate as to what constitutes true alien behavior from pseudoathetosis owing to cortical sensory loss to simple levitation of a limb (21-25). This phenomenon likely relates to pathology in the supplementary motor area and the efferent/afferent connections.
Cortical sensory loss is often manifested symptomatically as "numbness" or "tingling." Impaired joint position sense, impaired two-point discrimination, agraphasthesia, and astereognosis in the setting of intact primary sensory modalities are all evidence of cortical sensory loss. This likely relates to pathology in somotosensory cortex ± thalamus.
Myoclonus, if present, usually begins distally in one upper limb and may spread proximally. The frequency and amplitude of myoclonic jerks typically increase with tactile stimulation (i.e., stimulussensitive myoclonus) and action (i.e., action myoclonus). Recent electrophysiologic studies suggest that the myoclonus in this disorder results from enhanced direct sensory input to cortical motor areas. Typically, a peripheral stimulus inducing myoclonic jerks is not associated with an enhanced soma-tosensory evoked potential (SSEP) and the latency from stimulus to jerk is brief, just sufficient to have reached the cortex and returned to the periphery (i.e., ~ 40 ms in the upper limb). These features are distinct from most other forms of cortical reflex myoclonus (which is associated with enlarged SSEPs and a longer stimulus-to-jerk latency) (26,27).
Mirror movements are present if the opposite limb involuntary performs the same activity as the one being examined. Mirror movements are often suppressible, but when the individual is distracted and rechallenged with the same maneuver several minutes later, they will recur. Patients also frequently demonstrate overflow movements on the same side of the body, whereby attempted movement in an arm or leg causes additional movement in the ipsilateral limb, including elevation, mirroring, etc. Mirror movements have been associated with the alien hand syndrome (28), although many patients have them without alien limb features. Mirror movements are often found on examination but are rarely symptomatic.
Dystonic posturing of a limb is a common early manifestation, usually affecting one upper limb. Frequently, the posturing of the hand takes on a "fisted" appearance, although hyperextension of one or more fingers may occur. Initially, dystonia may only be evident during walking or reaching. In those with symptoms beginning in a lower limb, the foot is often tonically inverted, and ambulation is severely limited. Pain often but not always accompanies dystonia. The "fisted hand sign" may represent one of the most specific clinical features for underlying CBD in the CBS (Rippon et al., unpublished data).
Tremor is another common presenting feature, and patients typically describe the affected extremity as "jerky." A postural and action tremor often evolves to a more jerky tremor and then to myoclonus. Unlike the tremor of Parkinson's disease (PD), which is most prominent at rest and dampens with action, the tremor is amplified with activity and minimal at rest. A classical 4- to 6-Hz parkinso-nian rest tremor is rarely, if ever, evident in this disorder.
There are no published cases in which a significant and sustained clinical improvement has occurred with levodopa therapy (29). Many regard the lack of objective improvement during therapy with at least 750 mg of daily levodopa (divided doses, on an empty stomach) as a diagnostic feature of the disorder (realizing that other akinetic-rigid syndromes fail to respond to levodopa as well).
Clinically significant dementia is not a typical early finding in patients with the CBS, but impairment in one or more cognitive domains is often present. However, it should be emphasized that the absence of early clinically significant dementia relates largely to the application of diagnostic criteria that have attempted to exclude other disorders such as AD and Lewy body dementia. In fact, as discussed below, although the pathology of CBD may be the most common cause of the CBS, some studies have found that it presents more commonly as a dementia syndrome (30).
A very intriguing feature in the CBS (as well as other disorders) is the tendency for patients to shake their head and respond "yes" when they actually mean "no," and vice versa (31). Whereas some patients and relatives describe this phenomenon spontaneously, this often requires specific questioning by the clinician. Relatives and friends of affected patients tend to repeat their questions, or ask "do you really mean yes or no?" and thus this issue can significantly affect communication in some patients. This phenomenon is likely due to frontosubcortical dysfunction, in which mental flexibility and inhibitory control is impaired (31).
Aphasia (which is typically nonfluent) (32), ideomotor apraxia, hemineglect, etc., are lateralized cognitive features that are as frequent as the motor features. Apraxia of speech and/or nonverbal oral apraxia are quite common; in fact, one published case presented with speech apraxia and did not develop other "typical" features until at least 5 yr later (33). Although rarely symptomatic, patients often demonstrate constructional dyspraxia on drawing tasks, particularly if the parietal lobe of the nondominant hemisphere is sufficiently affected. Other nondominant parietal lobe findings such as hemineglect and poor spatial orientation can also occur, which often are symptomatic in activities of daily living. Apraxic agraphia may result if the homologous region of the dominant hemisphere is dysfunctional. The lack of these findings being noted in the CBD literature probably stems from clinicians not including assessment of visuospatial/visuoperceptual functioning and neglect (11,16).
Depression, obsessive-compulsive symptomatology, and "frontal" behavioral disturbances can occur in the CBS syndrome (34,35). Visual hallucinations and delusions are very rare. The presence of visual hallucinations in the setting of cognitive impairment and/or parkinsonism may therefore favor a diagnosis of Lewy body disease rather than CBD (36,37).
Ocular motor apraxia occurs to some degree in almost every patient (17). This includes difficulty initiating saccades and voluntary gaze, but pursuit and optokinetic nystagmus are typically preserved. In contrast to patients with progressive supranuclear palsy (PSP), those with the CBS have normal speed and amplitude of the saccades. On the other hand, eventually patients may develop supra-nuclear gaze paresis that can be indistinguishable from that seen in PSP. Eyelid opening/closing apraxia is also frequent.
Several other less specific findings may also occur. Frontal release signs, hypokinetic dysarthria, asymmetric hyperreflexia, and/or extensor toe responses also occur with some frequency. Postural instability is very common later in the disease and may be related to gait apraxia, bilateral lowerlimb parkinsonian, dystonia, or less frequently vestibular involvement. If balance problems are present at an early stage, they are usually secondary to lower-limb involvement at onset. Appendicular ataxia, chorea, and blepharospasm are infrequent manifestations. Dysphagia begins insidiously in the later stages of the disease in contrast to what usually occurs in PSP, and as in that disorder eventually leads to aspiration pneumonia and death in most instances.
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