Corticobasal Degeneration

A 73-year-old woman was brought in by her daughter for functional decline. The patient didn’t notice anything wrong. Per her daughter, memory problems were prominent, but there was also trouble with her movements. Her daughter noted that she didn’t have control of the left hand or foot; they had “a mind of their own.” She reported that these difficulties came out when her mother dressed and undressed, and when she ate using utensils; she was unable to cut up anything. On exam a paucity of spontaneous speech was evident. She had almost continuous myoclonus and asterixis evident in both upper extremities, which her family described as “shaking” and another clinician described as “tremor.” She veered off to the left when walking and sometimes bumped into the hallway wall. She did not use the left hand spontaneously. She attempted to untie her shoes with her right hand only—the left hand stayed gripping the arm of the chair. She demonstrated multiple apraxias, all worse with the left hand, including an inability to pantomime use of objects such as a comb or a knife, which improved markedly when imitating the examiner or using the actual object. She was unable to identify coins placed in either hand or identify any number (except 1) drawn in either hand.

Quick Start

Definition	• Corticobasal degeneration is a neurodegenerative disease of the brain caused by the accumulation of hyperphosphorylated tau isoforms and characterized by asymmetric cortical dysfunction. • Clinically there are difficulties with motor control of a limb (apraxia), cognitive dysfunction, rigidity, a jerky postural tremor, myoclonus, dystonia, and a gait disorder.
Prevalence	• It is a relatively rare disorder, with the prevalence being about 2 per 100,000. • The age of onset ranges from 45 to 77 (mean 64) years, with a disease duration of 2–12.5 (mean 6.6) years.
Genetic risk	• There are no known genetic or other risk factors.
Cognitive, behavioral, and motor signs and symptoms	• Focal and asymmetric signs and symptoms are the cardinal features of corticobasal degeneration, including asymmetric apraxia, myoclonus, dystonia, cortical sensory loss, and unilateral visual or sensory neglect. • An “alien limb”—a limb with “a mind of its own”—is a pathognomonic but uncommon sign. A “useless limb” not able to participate in functional activities is common. • Speech may be disrupted owing to apraxia or non-fluent aphasia. • Cognitive testing demonstrates frontal and parietal cognitive dysfunction with relative preservation of recognition memory.
Summary of diagnostic clinical research criteria for probable sporadic corticobasal degeneration (see text for details)	• Insidious onset and gradual progression of at least one year. • Clinical phenotypes of one of the following: • Probable corticobasal syndrome: • Asymmetric presentation of two of: a) limb rigidity or akinesia b) limb dystonia c) limb myoclonus • plus two of: d) orobuccal or limb apraxia e) cortical sensory deficit f) alien limb phenomena • Frontal behavioral-spatial syndrome: • Two of: a) executive dysfunction b) behavioral or personality changes c) visuospatial deficits • plus at least one corticobasal feature (a–f, above) • Non-fluent/agrammatic variant of primary progressive aphasia • Effortful, agrammatic speech plus at least one of: a) impaired grammar/sentence comprehension with relatively preserved single-word comprehension b) groping, distorted speech production (apraxia of speech) • plus at least one corticobasal feature (a–f, above) • Exclusion criteria: evidence of other neurological disorder that could explain signs and symptoms.
Treatment	• There are no US Food and Drug Administration–approved medications to treat corticobasal degeneration; treatment is supportive. • Antidepressants should be used to treat depression, which is often present. • Dystonia may be relieved with botulinum toxin. • Clonazepam may be helpful for myoclonus.
Top differential diagnoses	• Frontotemporal dementia, primary progressive aphasia or apraxia of speech, progressive supranuclear palsy, dementia with Lewy bodies, Alzheimer’s disease, vascular dementia.

Prevalence, Prognosis, and Definition

Corticobasal degeneration is a neurodegenerative disease of the brain characterized by asymmetric cortical dysfunction, often affecting motor control of a limb, along with executive dysfunction, rigidity, a jerky postural tremor, myoclonus, dystonia, and a gait disorder. Speech may be disrupted owing to apraxia or non-fluent aphasia. It is caused by the accumulation of hyperphosphorylated four-repeat tau isoforms. It is a relatively rare disorder with a prevalence of about 2 per 100,000. From one literature review, the mean age of onset was 64 years, ranging from 45 to 77 years, with an average prognosis from diagnosis to death of about 6.6 years, ranging from 2 to 12.5 years ( ).

Criteria

Based on the clinical phenotypes of 129 autopsy-proven cases, a 2013 paper presented two sets of criteria for corticobasal degeneration: more specific clinical research criteria for sporadic probable corticobasal degeneration and broader, more inclusive criteria for possible corticobasal degeneration that may overlap with other tau-based pathologies ( Table 10-1 ) ( ). Both criteria are based on five clinical phenotypes that have been proven to be associated with the pathology of corticobasal degeneration ( Table 10-2 ). See also the Quick Start, above, for a succinct summary of the criteria. Definitions and explanations for many of the terms used in these criteria can be found below in the “Common signs, symptoms, and stages” section.

TABLE 10-1

Diagnostic Criteria for Corticobasal Degneration

	Clinical Research Criteria for Probable Sporadic Corticobasal Degeneration	Clinical Criteria for Possible Corticobasal Degeneration
Presentation	Insidious onset and gradual progression	Insidious onset and gradual progression
Minimum duration of symptoms	1 year	1 year
Age at onset	> or = 50 years	No minimum
Family history (2 or more relatives)	Exclusion	Permitted
Permitted phenotypes (see Table 10-2 )	1. Probable corticobasal syndrome or 2. Frontal behavioral-spatial syndrome plus at least one corticobasal feature (a–f in Table 10-2 ) or 3. Non-fluent/agrammatic variant of primary progressive aphasia plus at least one corticobasal feature (a–f in Table 10-2 )	1. Possible corticobasal syndrome or 2. Frontal behavioral-spatial syndrome or 3. Non-fluent/agrammatic variant of primary progressive aphasia or 4. Progressive supranuclear palsy syndrome plus at least one corticobasal feature (b–f in Table 10-2 )
Genetic mutation affecting tau (e.g., MAPT)	Exclusion	Permitted
Exclusion criteria (same for both)	1. Evidence of Lewy body disease: classic 4-Hz Parkinson’s disease resting tremor, excellent and sustained levodopa response, or hallucinations. 2. Evidence of multiple system atrophy: dysautonomia or prominent cerebellar signs. 3. Evidence of amyotrophic lateral sclerosis: presence of both upper and lower motor neuron signs. 4. Semantic- or logopenic-variant primary progressive aphasia. 5. Structural lesion suggestive of focal cause. 6. Granulin mutation or reduced plasma progranulin levels; TDP-43 mutations; FUS mutations. 7. Evidence of Alzheimer’s disease (this will exclude approximately 14% of cases of corticobasal degeneration with coexisting amyloid): laboratory findings strongly suggestive of AD such as low CSF Aβ42 to tau ratio or positive amyloid PET; or genetic mutation suggesting AD (e.g., presenilin, amyloid precursor protein).