Corticobasal Ganglionic Degeneration

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Pathogenesis and Pathophysiology. The characteristic pathological changes in CBGD include asymmetrical frontoparietal cortical atrophy with corresponding neuronal loss and gliosis, substantia nigra degeneration, and swollen achromatic neurons. Wi Variable degrees of degeneration in

other subcortical nuclei also occur. The achromatic neurons immunostain positively to neurofilaments (. Fig, 33-12 ). Some have regarded these neurons to be related to Pick cells, although immunohistochemical and ultrastructural analyses suggest that CBGD can be differentiated from Pick's disease, PSP, and AD. [101i CBGD is a diffuse cytoskeletal process characterized by the accumulation of pathologic tau proteins. [101] Impaired neurofilament phosphorylation, transportation, or degradation or distal axonal damage may be involved in the pathophysiology of neuronal achromasia. Neuronal achromasia may, therefore, represent the end result of one or more pathophysiological processes.

The profile of cognitive impairment reflects dysfunction predominantly of frontal and parietal cortices, including apraxia, psychomotor slowing, and visuoperceptual disturbances. Memory is also impaired. However, CBGD pathology has also been observed in occasional patients with FTD and progressive aphasia.

Epidemiology and Risk Factors. CBGD was originally described in 1967 by Rebeiz and colleagues W There are few data regarding epidemiology or risk factors, although clinical experience suggests that the prevalence may be similar to that of PSP or about 1 percent that of PD. There has been little evidence to date of a familial tendency.

Clinical Features and Associated Disorders. The vast majority of cases have exhibited a progressive perceptual-motor syndrome (see the section on ACDS, presented earlier), and the term progressive asymmetrical rigidity and apraxia syndrome has been proposed. Less common presentations with a similar histology include frontotemporal dementia and progressive aphasia. Asymmetrical hyperreflexia, postural instability, frontal release signs, oculomotor impairment, and hypokinetic dysarthria commonly occur. Dysphagia begins insidiously in the latter stages of the disease, and eventually aspiration pneumonia and death ensue.

Characteristic CBGD histological findings have been reported to co-exist with Pick's disease and AD, and alternate presentations with the same histology have included FTD and progressive aphasia, as noted earlier.

Differential Diagnosis. See the section on ACDS. The most common misdiagnoses are stroke, PD, and perhaps AD. CBGD falls within the spectrum of ACDS, and clinicopathological correlations are far from perfect, as previously discussed. Other degenerative histologies underlying a progressive apraxic or perceptual-motor syndrome include nonspecific degeneration, AD, Pick's disease, and PSP.

Evaluation. Neuroimaging is the single most important aspect in evaluating any focal-appearing cerebral syndrome, as discussed in the section on ACDS. A fairly consistent finding on CT and MRI is asymmetrical cortical atrophy, which is predominantly parietal with variable involvement of contiguous regions in patients with a progressive perceptual-motor syndrome. The laterality of atrophy correlates with the laterality of clinical impairment.

Asymmetrical cortical (and subcortical) hypoperfusion on SPECT is usually more extensive than the MRI appearance of atrophy. Asymmetrical fluorodeoxyglucose cortical hypometabolism and asymmetrical striatal fluorodopa hypometabolism on PET are also found in this disorder, but these tests should be regarded as ancillary.

The neurological and neuropsychological pattern of deficits is distinctive and should not be mistaken for an Alzheimer- or Parkinson-type pattern of dementia.

Management. Pharmacotherapy generally provides minimal if any improvement in most symptoms, but an empirical trial of levodopa is nonetheless reasonable and will occasionally result in modest symptomatic amelioration of rigidity. Clonazepam may yield modest improvement in myoclonus, but it may cause sedation with worsening of balance and cognitive function. Botulinum toxin injection can permit a clenched dystonic hand to be opened for hygiene maintenance. Pharmacotherapy should be supplemented

Figure 12-12 Corticobasal ganglionic degeneration, Note the circumscribed perirolandic cortical atrophy. A ballooned achromatic neuron typical of corticobasal ganglionic degeneration is shown in the center of the photomicrogi(Hematoxylin andeosin; 50courtesy J. E. Parisi, Mayo Clinic, Rochester, Minnesota.)

with physical, occupational, and speech therapies. Passive range of motion exercises may retard the development of contractures. Ambulation becomes impaired in all individuals at some point, hence the need for gait assistance devices. Apraxia is often the most debilitating feature of the disorder. A home assessment by an occupational therapist can aid in determining which changes could be made to facilitate functional independence, although experience to date has been disappointing. Speech therapy and communication devices can optimize communication when dysarthria, apraxia of speech, or aphasia is present, although they are generally of minimal benefit. Therapists also counsel patients and families on swallowing maneuvers and food additives to minimize aspiration when dysphagia evolves. Decisions regarding placement of feeding gastrostomy tubes should be discussed before dysphagia becomes problematic.

Prognosis and Future Perspectives. Most patients succumb to the disease in 7 to 10 years. Death usually results from aspiration pneumonia or urosepsis. The main focus of a recent symposium on CBGD and other ACDS[103] regarded nosological status and terminology. Diffuse Lewy Body Disease (Lewy Body Dementia)

Pathogenesis and Pathophysiology. Between 20 and 30 percent of brains of patients with a degenerative dementia have concomitant AD and PD changes, therefore making Lewy body-related pathology the second most common histopathology behind AD. A much smaller percentage have diffuse Lewy bodies without AD changes. Therefore, the dementing disorders associated with Lewy bodies can be categorized into three groups: PD without cortical Lewy bodies or AD changes, PD with cortical Lewy bodies but not concomitant AD changes (DLBD), and PD with cortical Lewy bodies and AD changes (the Lewy body variant of AD or LBV). Numerous data indicate that PD and AD have distinctly separate clinical, pathological, pathophysiological, and genetic correlates. However, there is a significant proportion of patients with combinations of the classic features of PD and AD, which suggests that there is a pathophysiological relationship between them. We will therefore take a middle stance and discuss LBV and DLBD separately when sufficient data indicates distinctions can be made, and we will discuss them together when these distinctions are not apparent.

Pathologically, the gross appearance of the brain is normal to slightly atrophic. The substantia nigra is pale. In the LBV of AD, there are sufficient numbers of NPs to apply the neuropathological diagnosis of AD. NFT counts are more variable. Lewy bodies, if present in the cortex, are invariably also present in the brain stem. The Lewy bodies in the brain stem are easily seen on sections stained with hematoxylin-eosin, where they tend to reside in the substantia nigra, locus caeruleus, and raphe nuclei. Cortical Lewy bodies often lack the surrounding halo that is typical of those in the brain stem, and are more difficult to visualize unless immunostains for ubiquitin are used ( .Fig 33-13 ). The locations of maximal numbers of cortical Lewy bodies include the cingulate gyrus, insular cortex, and parahippocampal gyrus.

Ubiquitin-positive neuritic changes are also present in the CA2/CA3 region of the hippocampus, whereas Lewy bodies are rarely found in the hippocampus. The degree of neuronal loss in the hippocampal CA subfields is variable in LBV and DLBD. These findings suggest that the type of ubiquitin-positive changes may be site specific. The cholinergic neurons in the nucleus basalis are markedly depleted.

As noted earlier, a subgroup of AD cases with primarily plaque-only changes were found to have numerous extranigral Lewy bodies. y In those cases with more typical NPs

Figure 12-13 Photomicrograph of cortical Lewy bodies using an antiubiquitin immunostain. The core is composed of 7 to 8 nm f\\am((Hematoxylin and eosin; 400*; courtesy J. E. Parisi, Mayo Clinic, Rochester, MN.)

and NFTs, the number of NFTs tends to be less in AD- plus-PD brains than in AD-only brains. All of these cases had sufficient numbers of NPs to apply the neuropathological diagnosis of AD. However, because frequent NPs have also been observed in cognitively normal individuals, debate has surrounded the issue of whether these cases represent a variant of AD (thus the name LBV of AD) or a distinct entity (thus the name DLBD) with co-existing AD changes.

Katzman and colleagues^ have provided several lines of evidence supporting the LBV of AD concept: (1) the clinical features of AD and LBV are similar, (2) the LBV has been observed in several familial AD1 cases, (3) the LBV has also been observed in rare Down's cases, and (4) the LBV is frequently observed in ApoE epsilon-4/epsilon-3 cases. Other investigators have observed an association between ApoE epsilon-4 dosage and PD-related changes, but interestingly, the severity of ubiquitin-positive neuritic changes in the hippocampus correlated with ApoE epsilon-4 dosage, whereas the frequency of cortical Lewy bodies did not. [105] It has been suggested that the LBV of AD may represent the result of a co-existent gene that promotes LB rather than NFT in degenerating neocortical neurons. [104]

The cardinal features of LBV and DLBD involve dementia and mild to moderate parkinsonism. The extrapyramidal symptoms reflect basal ganglia and nigral degeneration. The nature of cognitive impairment in LBV and DLBD is likely multifactorial. In both conditions, the degree of neurofibrillary degeneration is less than in pure AD. Although supportive data are lacking, the presence and frequency of cortical LB may be a contributor, and the effects of LB and AD changes may be additive in LBV. Subcortical degenerative changes underlie the psychomotor slowing. Prominent hallucinations, delusions, illusions, and behavioral dyscontrol are also characteristic clinical features. It is unclear whether the neuropsychiatric features reflect unique qualities of cortical Lewy bodies themselves; the topographic distribution of LB or cortical degeneration, or both; or neurochemical abnormalities.

The nucleus basalis atrophy and marked cholinergic deficiency in brains affected by LBV mirror that noted in brains affected by AD only, although findings in pure DLBD are less clear. Choline acetyltransferase activity has been found to be lower in patients with LBV than in those with AD only. Reportedly, some patients with LBV with very low levels of this enzyme have improved while on tacrine therapy, but parkinsonism can worsen with tacrine. The brains of patients with AD plus PD changes have also been found to have reduced levels of dopamine and homovanillic acid compared with normal brains and those affected by AD only.

Epidemiology and Risk Factors. The relationship among DLBD, AD, and PD is debated because there is evidence to support all points of view, that is, that DLBD is related to AD and to PD and that can be a distinct entity unrelated to either. Hence, it is unclear whether epidemiological data that relate to AD and PD are relevant for DLBD. There are no large epidemiological studies, but autopsy series suggest that the mean age of onset of DLBD is 57 years, that it affects men more often than women (male to female ratio 1.7:1), and that death ensues after roughly 10 to 15 years. ^ In this series, there were 20 patients who died with PD and 8 who died with DLBD, suggesting that the prevalence of DLBD is, very roughly, 30 percent that of PD [107] (although personal clinical experience suggests that it is less common than that). Extrapyramidal findings occur with increasing frequency as AD progresses (in close to 30 percent of patients ^ ), but how often this reflects Lewy body-related pathology is uncertain. In an autopsy series of AD, 15 percent of patients had some type of Lewy body-related pathology. W The relationship of ApoE to DLBD depends on how closely DLBD is related to AD, and although ApoE genotype appears relevant, the relationship is weaker than for AD. [110I

Clinical Features and Associated Disorders. AD and PD are both part of the nosological spectrum of DLBD, which seems to bridge the cortical and subcortical degenerative dementias. The literature is divided on whether parkinsonian or cognitive symptoms present first, but all investigators agree that both are important components.^ , [111] In general, the clinical picture of a mild parkinsonian syndrome with a more severe dementia and prominent visual hallucinations and paranoid delusions should prompt consideration of DLBD. Although the parkinsonism can be levodopa responsive, levodopa may exacerbate the psychosis, and in the early to middle stages, the neuropsychiatric disturbance is generally the more disabling feature. As the disease progresses, however, both components worsen, and the patient may eventually develop severe parkinsonian symptoms and become wheelchair bound. Rest tremor is less frequent (about 29 percent of patients [107] ) than in PD, but bradykinesia is a predictable feature. The quality of the dementia resembles the subcortical pattern with pronounced psychomotor slowing, absence of severe aphasia, agnosia, or apraxia, and concurrent parkinsonism. Atypical features, including impaired vertical gaze and progressive spasticity, have been described further, highlighting the clinicopathological overlap that occurs among many of the degenerative dementias.

Differential Diagnosis. The differential diagnosis of DLBD is particularly broad because of its overlap with cortical and subcortical degenerative dementias, as well as the clinical similarities with nondegenerative dementing illnesses. Dementia and mild parkinsonism is perhaps the most common presenting symptom complex of small vessel-type multi-infarct dementia (another, and perhaps the most common, cause of subcortical dementia). Prominent visual hallucinations can be an important clinical feature of certain reversible chronic progressive encephalopathies, including chronic inflammatory meningoencephalitis, chronic meningitides occurring on infectious or neoplastic bases, and many toxic-metabolic encephalopathies. Although they do occur in other degenerative dementias, including AD and PD, they are less frequent and should not be considered typical early features.

Evaluation. In addition to the usual tests for dementia evaluation (MRI, neuropsychological testing, and laboratory studies, as described in the section on AD), the EEG is particularly useful. Many reversible chronic progressive encephalopathies produce severe dysrhythmic slowing, whereas most degenerative diseases, at least in early stages, produce mild or no dysrhythmic slowing. A severely abnormal EEG should prompt strong consideration of more exhaustive laboratory studies looking for unusual autoimmune

causes and other systemic medical causes of encephalopathy, as well as a CSF examination. CSF tests should include microbiological, cytological, and immunological studies (including IgG index, IgG synthesis rate, and oligoclonal bands). These immunological studies may provide evidence of an intrathecal immunological response that, although nonspecific, may be more sensitive than fungal cultures or cytology and therefore may be the only sign of an autoimmune process. If the patient has a so-called psychotic delirium with minimal parkinsonian features, a severely dysrhythmic EEG, and a CSF profile that suggests an inflammatory mediated process, in the absence of another obvious cause, meningeal and brain biopsy should be considered, observing for CIME, CNS vasculitis, CNS infection, and meningeal carcinomatosis. Because CIME is very steroid responsive, an empirical trial of corticosteroid therapy could be considered, especially if there is reticence to perform a brain biopsy.

Management. As noted earlier, treatment of the parkinsonian syndrome may exacerbate the neuropsychiatric disorder, and treatment of the neuropsychiatric disorder may exacerbate the parkinsonian syndrome. A decision, therefore, must first be made regarding whether treatment is necessary at all, and if so, what symptoms warrant treatment. Generally, the neuropsychiatric syndrome is the most disabling aspect in mild to moderate stages, and selective neuroleptic therapy with risperadone should be considered as a first choice. Very low dose therapy should be tried initially because risperadone, despite its selectivity, can exacerbate parkinsonism. More selective, but more hazardous because of potential blood dyscrasias, is clozapine. Treatment of the parkinsonian syndrome is similar to that of PD, generally beginning with Sinemet at a very low dose and gradually titrating the dose to symptoms and side effects. Other nonpharmacological aspects of caregiving are similar to those described for AD except that physical and occupational therapies are of greater importance at an earlier stage due to the extrapyramidal syndrome. Benefits, however, are generally modest.

Prognosis and Future Perspectives. As noted earlier, the mean age of onset of DLBD is 57 years, and death ensues after roughly 10 to 15 years. [107] Treatment is difficult, often inadequate, and caregiving is especially difficult usually because of the psychosis.

DLBD is an important nosological entity because it appears to occupy an intermediate position between AD and PD, two common degenerative diseases that are generally thought to have little in common. Therefore, understanding the genetics and disease mechanisms of DLBD may provide important insights into its more frequent cousins as well. Also, this group of patients will be an important testing ground for newer antipsychotic agents with greater selectivity.

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