Corticobasal Degeneration

From EyeWiki


Disease Entity

Disease

Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disease characterized by nerve cell loss and atrophy of multiple areas of the brain.[1] Specifically, CBD is a tauopathy classified by primarily 4-repeat (4R) tau deposition in different cell types and locations in the brain.[2][3] This disorder involves various combinations of motor features, cortical dysfunction, [1][4] and other features (e.g., movement abnormalities, changes in speech, and pyramidal dysfunction).[1][5] CBD can clinically manifest as several phenotypes, and other neurological disorders can be the underlying pathology for potential CBD phenotypes.[6]

Historical Perspective

CBD was first reported by Rebeiz et al. in 1968.[7] Rebeiz et al. described three patients in late adulthood who had a progressive neurologic disorder characterized by impairment in motor control and abnormal posture.[7] Rebeiz et al. called this “corticonigral degeneration with neuronal achromasia” based on pathological findings of brain atrophy.[7] This brain atrophy was characterized by asymmetrical frontoparietal and neuron loss of substantia nigra.[7] This disorder would not be mentioned for almost two decades until 1985, when 6 more patients were reported with similar findings.[8] CBD would then be coined as a term by Gibb et al. in 1989.[9]

Epidemiology

The typical age of onset of CBD is between the fifth and seventh decades of life.[4] However, the youngest pathologically confirmed case of CBD was at the age of 45,[10] and the youngest suspected, yet unconfirmed case was at the age of 28.[11] There have been claims that there is a predominance of CBD in women,[10] but other claims state there is no difference between sexes.[12]

Although cases of CBD are usually isolated occurrences, there have been rare, confirmed familial cases of CBD as well.[13] Moreover, the true incidence and prevalence of CBD are unknown because of the overlapping phenotypes of CBD and other neurological disorders.[14]

Etiology

The exact etiology of CBD is unknown but increased tau phosphorylation and vesicle trafficking dysfunction have been implicated while multiple susceptibility loci for these factors have been discovered.[15][16] These loci include myelin-associated oligodendrocyte basic protein (MOBP), a long non-coding RNA (lnc-KIF13B-1), son of sevenless homolog 1 (SOS1), C-X-C chemokine receptor type 4 (CXCR4), epidermal growth factor receptor (EGFR), glycine decarboxylase (GLDC), and in particular, microtubule-associated protein tau (MAPT). [15][16] It has been proposed that a seeding process induces the propagation of tau pathology in CBD.[1][17]

Ocular Manifestations.

Ocular manifestations may occur in CBD but they are not required for clinical diagnosis.[4] When ocular manifestations do occur, patients can experience abnormal eye movements (e.g., apraxia of gaze or vertical supranuclear gaze palsy).[5][18] Patients with CBD can experience apraxia of eyelid opening, which may cause dry eyes.[18] Visuospatial difficulties may also be present and can be the presenting complaint of CBD.[5][12]

Other Risk Factors

Currently, the only other known risk factor for CBD is advanced age, and there has been no evidence to suggest that environmental factors generate pathogenesis of CBD.[4][19] However, geographical mapping of tauopathies suggests that certain environments could play a role in CBD development.[20]

Pathophysiology

The pathophysiology of CBD is not entirely known. It is hypothesized that tau dysfunction is the main driving force for CBD pathogenesis.[1] Certain MAPT mutations, especially in the H1 haplotype, yield dysfunctional 4R-tau or increased 4R-tau.[1][3] Post-translational modifications of 4R-tau are thought to drive neurodegeneration; in particular, hyperphosphorylation is implicated.[1][21] Hyperphosphorylated 4R-tau accumulates, and this leads to tau filaments and deposits into various cell types, including neurons, microglia, and astroglia.[1] Greater microglial activation correlates with CBD confirmation, possibly due to increased tau burden in microglia.[22] However, the link between greater microglial activation and neurodegeneration in CBD cannot be established yet.[22]

This accumulation of tau is termed “tau seeding” and results in the recruitment of normal tau by pathological tau species, yielding tau aggregate formation.[23] Tau aggregation is believed to correspond with loss of physiologic function of tau, such as axonal transport.[24] Synaptic function thereby can be altered.[24]

Tau pathology spreads to other cells. “Prion-like” cell-to-cell spreading has been suggested as an explanation.[17][23] In this, tau is released and then taken up by other cells, in which new tau aggregates form by the aforementioned seeding process.[17][23] However, it is not completely understood how tau pathology spreads among cell types, but it is hypothesized that the accumulation of tau in astroglia precedes that in neurons.[25][26]

Neuropathological Findings

Post-mortem pathological examination of CBD reveals specific findings. There is cortical atrophy in mainly the frontal or parietal parasagittal regions.[1][19] The atrophy is asymmetric and focal, and the pre and post-central regions may be affected as well.[1][19] Moreover, basal ganglia degeneration is present and illustrated by caudate nucleus flattening or atrophy.[1] Frontotemporal lobar degeneration (FTLD) can be present.[1][19] The occipital lobe may also be atrophic with posterior cortical atrophy, but this is rare.[1][19]

Histologically, there are also distinct features. The most specific finding in CBD brains is astrocytic plaques in grey matter.[1][19] “Ballooned” achromatic neurons are also a hallmark of CBD.[1][19] However, these swollen neurons are seen in other neurologic disorders, such as Pick’s Disease (PiD).[1][19] Other classic findings include gliosis and neuronal loss in the atrophic cortical as well as subcortical regions.[1][19] This includes the substantia nigra when motor symptoms are present.[1][19]

Diagnosis

Unfortunately, a definitive diagnosis of CBD can only be done postmortem by pathological exam.[27] CBD can present with various phenotypes comprising a diverse array of symptoms.[1][4] Thus, CBD diagnosis can be difficult and misdiagnoses occur frequently.[4]

History/Signs/Symptoms

CBD may be a likely diagnosis if a patient presents with the following symptoms:

Main Features:

Motor:[1][5]

● Limb rigidity

● Bradykinesia or clumsy limb

● Postural instability


Cortical:[1][5]

● General cognitive impairment

● Changes in behavior

● Limb apraxia

● Aphasia


Less Common Features:


Motor:[1][5]

● Abnormal gait

● Axial rigidity

● Myoclonus

● Limb dystonia

● Tremor

● Falls


Cortical:[1][5]

● Depression

● Cortical sensory loss

● Alien limb phenomenon


Other Features:[1][5]

● Speech changes

● Abnormal eye movements

● Hyperreflexia and other pyramidal signs

Imaging and Biomarkers

Several neuroimaging modalities have been used to aid in CBD diagnosis.[27] These include magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), computed tomography scan (CT), direct tensor imaging (DTI), positron emission tomography (PET), and more.[1][27] It should be noted that neuroimaging mostly focuses on the location of pathology; thus, neuroimaging cannot provide much information about the exact pathophysiology of many neurodegenerative diseases.[1]

Neuroimaging has been able to somewhat aid in CBD diagnosis by dissuading other diagnoses based on structural features.[1] For example, imaging that shows larger patterns of brain atrophy suggests Alzheimer disease (AD) or FTLD, while more focal atrophy in the premotor cortex suggests CBD or progressive supranuclear palsy (PSP).[28] However, neuroimaging cannot make a certain diagnosis of CBD.[27]

There are no proven biomarkers that have been proposed in CBD.[27] [18F]flortaucipir can help illuminate tau uptake in the brain in PET scans.[29][30] Although this can suggest a CBD pathology, uptake of [18F]flortaucipir is variable and not present in all CBD patients.[29][30] Thus, neuroimaging and biomarkers, though helpful, cannot definitively make a CBD diagnosis.[27]

Differential Diagnosis

While CBD is a specific disorder, it is not a single clinicopathological entity.[5] CBD has a very heterogeneous clinical spectrum, and it can manifest as multiple phenotypes.[5] These phenotypes have been delineated and include probable and possible corticobasal syndrome (CBS), progressive supranuclear palsy syndrome (PSPS), frontal-behavioral-spatial (FBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfPPA).[5] These phenotypes are based on different combinations of potential CBD symptoms.[5]

These phenotypes broaden CBD criteria and aid in diagnosis; however, several other disorders can mimic these CBD phenotypes.[1][4] In fact, CBD accounts for less than 50% of the CBS phenotype.[18] Coupled with the lack of antemortem confirmation, CBD is commonly misdiagnosed and underdiagnosed.[1][4]

Common disorders that overlap with CBD clinical phenotypes include Lewy Body Disease, vascular disorders, PSP, AD, FTLD, PiD, Creutzfeldt–Jakob disease (CJD), frontotemporal dementia and parkinsonism (FTDP), and more.[1]

While attempts have been made to update diagnostic criteria, CBD mimics can still be mistaken as CBD.[6] Thus, CBD diagnosis remains difficult, and diagnostic specificity and sensitivity must be refined.[6]

Management

There are currently no effective disease-altering treatments for CBD.[1][4] Thus, the management of CBD focuses on symptomatic management and supportive treatment.[1][4] For symptomatic management, these symptoms can be the target of possible pharmacologic management:

● Parkinsonism - Levodopa has been observed to offer limited improvement for some patients.[18]

● Myoclonus - Valproic acid, clonazepam, piracetam, leveiritcam, and gabapentin have shown to provide effective improvement of myoclonus.[1][31][32]

● Limb dystonia - Chemodenervation with botulinum toxin may improve pain and abnormal posture.[32][33]

● Eyelid opening apraxia and dry eyes - botulinum toxin injections into pretarsal orbicularis occuli have been shown to alleviate apraxia of the eyelid. Artificial tears, acetylcysteine, carbomers, and 0.9% sodium chloride ophthalmic drops are effective for dry eyes due to eyelid dysmotility.[34][35]


There have been anecdotal reports of various medications used that have improved symptoms, such as benzodiazepines for dystonia, but these have not been corroborated.[35]

In addition to symptomatic management, supportive treatment should be initiated at the time of diagnosis.[1][4] Physical and occupational therapy may help patients retain some mobility; speech therapy aids with potential swallowing difficulty to prevent possible aspiration; dietary guidance can help maintain sufficient nutrition.[1][4]

Clinical trials of potential tau-lowering therapies are being conducted, and it is expected that these treatments can apply to CBD to at least slow the progression of the disease.[1][4] However, more research must be done in diagnosis and treatment for this to have appropriate benefit.[1][4]

Prognosis

The prognosis of CBD is poor.[1] Disease duration of CBD is typically around 6-7 years, with a range of 2-12.5 years.[10][18][36] There is shorter survival in patients also presenting with dementia.[4] The most common causes of death are sepsis and aspiration pneumonia.[1][10]

Summary

CBD is a rare disorder characterized by progressive atrophy of multiple areas of the brain. Common features involve impaired motor function, cortical dysfunction, and other miscellaneous features. This disorder is difficult to diagnose since it can present with highly variable clinical phenotypes. However, it is important that ophthalmologists are aware of CBD because ocular manifestations are not uncommon in CBD. There are currently no curative treatments for CBD; thus, management should focus on supportive treatment and symptomatic management.

References

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