After the introduction of levodopa to treat Parkinson disease (PD) in the late 1960s, the pathologies and clinical pictures of dopamine deficiency syndromes broadened dramatically. Clinicians identified patients who had signs of dopamine deficiency (masked facies, hypophonia, rigidity, slowness of movement and gait, loss of postural reflexes, and sometimes resting tremor and other features) but, unlike patients with PD, had minimal or no improvement with levodopa. As a group, these patients are said to have atypical parkinsonism. Today, the most common of these disorders are progressive supranuclear palsy (PSP), followed by multiple system atrophy (MSA) and corticobasal degeneration (CBD). The major problem, especially for PSP and CBD, is that patients with typical clinical signs and symptoms of the disease may have very different pathologies, and patients with the same pathology may have different clinical signs and symptoms. Unfortunately, no definitive diagnostic tests are easily available to distinguish these diseases from each other during life. The gold standard diagnostic test is autopsy, but autopsies are highly selected and may lead to conclusions that do not represent the entire population of a disease.
The history of MSA extends back at least to 1900. In 1900, Dejerine and Thomas described cases of late-onset ataxia and parkinsonism, later termed olivopontocerebellar atrophy. In 1960, Shy and Drager presented two cases of men aged 39 and 49 who developed impotence and urinary disturbance followed by multiple autonomic deficits, parkinsonism, ataxia, and, in one case, lower motor neuron disease, which was referred to as Shy-Drager syndrome. In 1960 and 1961, Adams, van Bogaert, and van der Eecken reported four cases of patients with gliosis of the striatum and degeneration of the substantia nigra who had rapidly progressive parkinsonism but also autonomic failure and cerebellar deficits, which they referred to as striatonigral degeneration. Similar cases had been reported before these three reports, but these reports were the first to identify each of these conditions as a syndrome. In 1969, Graham and Oppenheimer reviewed the published literature on patients with autonomic failure and either clinical symptoms or pathology indicating cerebellar and striatonigral involvement. They felt these syndromes overlapped so much that they should all be labeled MSA. In 1998, Lantos described α-synuclein deposits in glia (glial cytoplasmic inclusions) in all three conditions, making it even more likely they were all part of the same spectrum.
In 1964, Steele, Richardson, and Olszewski coined the term progressive supranuclear palsy (PSP) after reporting on patients with parkinsonism, loss of postural reflexes, supranuclear gaze palsy, axial rigidity, pseudobulbar state, and dementia who had midbrain and pontine degeneration as well as neuronal loss in the substantia nigra.
In 1968, Rebeiz and colleagues reported on three patients with asymmetric parkinsonism, apraxia, involuntary elevation of upper and lower extremities, and posturing, which would probably now be called dystonia, and a unique pathology involving the cortex as well as the basal ganglia and cerebellum and with neuronal achromasia. They referred to this as corticodentatonigral degeneration with neuronal achromasia, which was later shortened to corticobasal degeneration (CBD).
Although PSP, CBD, and MSA are difficult to accurately clinically diagnose at this time, this article presents the signs and symptoms of these conditions based primarily on clinical experience. Although relatively large series of patients with these conditions have been published based on autopsy, this article bases descriptions primarily on clinical experience. The reason for this choice is that autopsy series have two major shortcomings: (1) autopsies are rarely based on random or consecutive selection, leading to referral bias that is impossible to quantify and (2) the history and physical examinations in most autopsy series are not performed systematically by movement disorder specialists and sometimes not even by neurologists.
For more information on clinical features of autopsy-documented cases of PSP, CBD, and MSA, refer to Respondek and colleagues, Armstrong and colleagues, and Wenning and colleagues, respectively.
PROGRESSIVE SUPRANUCLEAR PALSY
Currently, the most commonly diagnosed of these three syndromes is PSP.
Clinical Symptoms and Signs
The signs and symptoms of PSP vary, probably because different parts of the brain may be affected first and to different degrees. Patients with the classic presentation, also called Richardson syndrome, develop a symmetric akinetic rigid syndrome with axial greater than limb rigidity, lack of resting tremor (although they may have an action tremor), early development of a supranuclear gaze palsy, and lack of response to levodopa. Supranuclear gaze palsy is the inability to look up or down on command, but upgaze is present when the neck is passively flexed, and downgaze is present when the neck is passively extended (ie, the doll’s eyes maneuver). Patients may have continuous square-wave jerks and other oculomotor disturbances, early loss of postural reflexes leading to falls, and progressive dementia. Square-wave jerks are involuntary horizontal saccades that go alternately to the right and then to the left with brief pauses before changing direction.
Patients with PSP often have an unusual facial expression, labeled dystonia, with deep nasolabial folds and furrowed brow, giving them an angry or puzzled expression. Patients may have hypophonia, often have growling speech, and frequently become aphonic. Patients with PSP develop dysphagia early in the course of the disease, and aspiration pneumonia is common. They often have a broad-based, slightly ataxic gait and often walk with their arms abducted and elbows flexed (a “gunslinger” gait). Gait freezing is common, and freezing of speech and manual movements may also occur.
Patients with Richardson syndrome (and other PSP subtypes) have a large variety of visual symptoms and signs. Patients with PSP often have limited downgaze and report difficulty reading, seeing the food on their plates, and looking at their feet while walking. They report diplopia, blurred vision, or more vague visual disturbances. They often have a severe reduction in blink rate and lid retraction, giving them a staring appearance. They have loss of vertical optokinetic nystagmus, and they may also develop blepharospasm. Occasionally, patients with PSP are unable to open their eyes, even without activation of the orbicularis oculi, which is referred to as apraxia of eyelid opening; even less commonly, patients are unable to close their eyes on command, referred to as apraxia of eyelid closing. It is now known that the apraxia of eyelid opening is not a true apraxia but a result of prolonged levator palpebrae inhibition following normal antagonist inhibition after a blink.
The dementia of Richardson syndrome usually involves bradyphrenia (ie, difficulty with attention and difficulty shifting tasks) and is considered a subcortical dementia, but the dementia of other PSP subtypes may differ, and mixed features of dementia are not uncommon. Bradyphrenia is when patients can answer questions and reason appropriately but take longer to do these tasks than would be reasonably expected. Patients usually have frontal release signs, such as glabellar, snout, and grasp reflexes. Depression is common, but apathy without depression is also common. Disinhibition leads to frequent falls in those with poor balance. Emotional incontinence can lead to emotionless crying or laughing (pseudobulbar palsy). A patient with Richardson syndrome is described in case 2-1.
Some patients with the pathology of PSP present with what looks like levodopa-responsive, asymmetric PD with resting tremor. These patients go on to lose levodopa responsiveness and develop imbalance, eye movement abnormalities, and the other signs and symptoms of classic PSP, which is referred to as PSP with predominant parkinsonism (PSP-P). Some patients’ symptoms begin with gait freezing, micrographia, and imbalance, which is referred to as pure akinesia or PSP with progressive gait freezing (PSP-PGF). Some patients present with nonfluent primary progressive aphasia or progressive apraxia of speech, referred to as PSP with predominant speech/language disorder (PSP-SL). Other patients have PSP with predominant corticobasal syndrome (PSP-CBS).
As the number of autopsies on patients with PSP grows, less common initial symptoms of PSP pathology have resulted in more categories, such as PSP with predominant ocular motor dysfunction (PSP-OM), which begins with oculomotor signs/symptoms; PSP with predominant postural instability (PSP-PI); PSP with predominant frontal presentation (PSP-F), which begins with a frontal syndrome including behavioral changes such as irritability and other personality changes, lack of insight, inappropriate behavior, impulsivity, and stereotyped behaviors; PSP with cerebellar ataxia (PSP-C), which begins with ataxia; and PSP with primary lateral sclerosis (PSP-PLS), which starts with a generalized spasticity syndrome similar to primary lateral sclerosis. In some patients with PSP pathology, symptoms may start with just dementia, although no abbreviation for the terminology currently exists,
To complicate matters even more, a variety of other pathologies may present clinically as PSP (sometimes called PSP syndrome). These include the pathologies of Whipple disease, Niemann-Pick disease type C, Gaucher disease, prion disease, Alzheimer disease, and others.
The course of PSP depends on the initial symptoms but the course can vary even with the same initial symptoms. Duration of disease ranges from 2 years to 28 years (mean of 8.7 years) depending on the subtype. The life-threatening symptoms of all forms of PSP are loss of balance leading to falls, aspiration, and infection due to pressure ulcers.
The pathology of PSP consists of widespread atrophy and neuronal loss with marked atrophy of the midbrain, subthalamic nucleus, dentate nucleus, and superior cerebellar peduncle but also of the frontal cortex and other basal ganglia structures. Accumulation occurs of mainly 4-repeat tau in neurofibrillary tangles in neurons in widespread areas including the subthalamic nucleus, globus pallidus, substantia nigra, locus coeruleus, periaqueductal gray matter, superior colliculi, inferior olive, red nucleus, oculomotor nuclei, and the prefrontal and precentral cortex. Tau also accumulates in astrocytes (called tufted astrocytes), distinct from the astrocytic plaques in CBD, and accumulations in oligodendroglia (called coiled bodies) and threadlike processes in the white matter. For a detailed description of the pathology of the subtypes of PSP, see the study by Dickson and colleages.
Treatment options for the symptoms of PSP are similar to the options in the other disorders discussed in the section below on the treatment of symptoms in PSP, MSA, and CBD. Attempts to treat the disease itself have not had success as of 2019. The most recent attempts to arrest or at least modify the course of PD and the syndromes discussed here depend on the hypothesis that diseases involving misfolded tau or α-synuclein depend on the prionlike properties of misfolded tau or α-synuclein. Clinical trials are underway of agents that might potentially reduce the spread of misfolded tau in PSP.
The classic presentation of CBD combines markedly asymmetric rigidity and bradykinesia with focal or hemidystonia and cortical deficits. Most patients develop symptoms in their fifties to seventies.
Clinical Symptoms and Signs
As with the other syndromes discussed in this article, the parkinsonism is usually without tremor, does not respond to dopamine replacement therapy, and loss of balance usually occurs early in the course. The dystonia, which may be painful, develops gradually but often becomes severe and fixed, leading to contractures. The patient’s dystonia may make it difficult to assess apraxia. Speech is hesitant and dysarthric, and aphasia and apraxia of speech occur. Other cortical signs may include apraxia (difficulty performing motor activities despite normal understanding and normal sensory/motor systems); cortical sensory loss (eg, two-point discrimination, agraphesthesia [difficulty recognizing letters/numbers written on the skin with eyes closed] and astereognosis [difficulty recognizing objects by touch alone]); cortical myoclonus (spontaneous or reflex, or both), which can be diagnosed accurately only with electrophysiology but usually consists of multifocal, very rapid shocklike jerks; alien limb phenomenon (involuntary movements of a limb together with the patient’s feeling that the limb does not belong to him or her); aphasia; apraxia of speech; and even hemiparesis. Dementia is common in patients with CBD.
Although some patients with CBD do make movements with a limb that seems foreign to them, they often have an overflow phenomenon in which movement in one limb triggers an involuntary movement in another, usually ipsilateral, limb. Resting tremor is very rare, but action tremor, often combined with myoclonus, is common. Supranuclear gaze palsies can occur late in the disease. case 2-2 describes a patient with classic CBD.
The pathology of CBD consists of asymmetric cortical atrophy usually in the frontoparietal region with relative sparing of the occipital lobes. Swollen vacuolated neurons are found in the atrophic cortical areas and to a lesser degree in the affected subcortical regions. These ballooned neurons contain phosphorylated neurofilaments and sometimes tau and ubiquitin. As with PSP, widespread neuronal loss and gliosis is seen, not just in the affected cortex but also in the globus pallidus, putamen, red nucleus, thalamus, subthalamic nucleus, substantia nigra, locus coeruleus, and, to a lesser degree, in the dentate nucleus. Remaining neurons in affected areas contain inclusions: globose tangles called corticobasal bodies and tau fibrils around nuclei of oligodendroglia called coiled bodies. Unlike the tufted astrocytes in PSP, the typical glial findings are tau-containing processes surrounding astrocytes called astrocytic plaques. As in PSP, 4-repeat tau predominates, but the insoluble tau fragments in CBD have a different ultrastructure from the insoluble fragments of tau in PSP.
As with PSP, the pathology of CBD may also present as multiple other syndromes: a classic PSP syndrome, primary nonfluent aphasia, a frontal dementia with executive dysfunction and behavioral change, pure Alzheimerlike dementia or, rarely, idiopathic PD. Also, as in PSP, a variety of other pathologies can mimic the clinical features of CBD, known as corticobasal syndrome (CBS). These include the pathologies of PSP, Alzheimer disease, Pick disease, frontotemporal lobar degeneration with ubiquitin– and TDP-43–positive inclusions, dementia with Lewy bodies, frontotemporal lobar degeneration with fused-in-sarcoma–positive inclusions, and Creutzfeldt-Jakob disease. Consensus criteria have been proposed for the clinical diagnosis of CBD, but the criteria have proven neither sensitive nor specific (sensitivity was 68.4%, specificity was described as low but percentage was not given).video 2-1 (links.lww.com/CONT/A56) and video 2-2 (links.lww.com/CONT/A204) contain examples of patients with CBS and CBD, respectively.
As with PSP, the current attempts at treating CBD itself as opposed to treating the symptoms are focused on detoxifying misfolded tau.
MULTIPLE SYSTEM ATROPHY
PSP and CBD have overlapping symptoms with PD despite having a pathology that includes misfolded tau and not–misfolded α-synuclein. MSA also shares symptoms with PD, and its pathology includes misfolded α-synuclein, not–misfolded tau, but MSA also can have a variety of complex presentations.
Clinical Symptoms and Signs
When middle-aged patients have sporadic disease with parkinsonism (usually including bradykinesia and rigidity), autonomic insufficiency (usually including urinary incontinence or retention, orthostatic hypotension sometimes alternating with hypertension, anhidrosis, and impotence in men), and cerebellar abnormalities (including ataxia, dysmetria, and nystagmus), MSA is the most likely diagnosis. However, patients diagnosed with MSA (either clinically or pathologically) often initially have symptoms in just one of these categories, although they eventually develop additional symptoms. Patients starting with bradykinesia and rigidity (called MSA with predominant parkinsonism [MSA-P]) usually do not have resting tremor and do not improve with levodopa. However, a significant minority of patients may have resting tremor and respond well to levodopa, at least for some time. Most symptoms are bilateral and symmetric but some may resemble idiopathic asymmetric PD. Patients starting with ataxia and other cerebellar features (eg, scanning speech, hypometric saccades, square-wave jerks) would be consistent with MSA with predominant cerebellar ataxia (MSA-C). There is not currently a category of MSA with predominant autonomic symptoms (MSA-A) even for patients that begin with autonomic symptoms. Nonetheless, there are patients with pure autonomic failure that eventually develop an MSA syndrome and have the pathology of MSA.
Any of these subtypes may also develop some other characteristic (although not pathognomonic) features. Axial dystonia (including anterocollis) is common. A variety of gastric motility problems may evolve. Laryngeal stridor, which often occurs at night but sometimes during the day as well, can be life-threatening. Stridor is the choking sound made when the vocal cords involuntarily adduct during breathing. In patients with MSA, this happens during inspiration.
Since MSA is a synucleinopathy, sleep disturbances such as rapid eye movement (REM) sleep behavior disorder are common. Other sleep symptoms such as dysrhythmic breathing and central apnea can also occur.
Cases of pathologic MSA that combined amyotrophy mimicking amyotrophic lateral sclerosis (ALS) with parkinsonism have been reported. Dementia in MSA was usually reported to be mild, but recently, cases with the pathology of MSA were reported to have a frontotemporal-type dementia called frontotemporal lobar degeneration–synuclein. Patients with this variant can have CBS, progressive nonfluent aphasia, or behavioral-variant frontotemporal dementia.
Most forms of the disease progress rapidly, and more than 40% of people diagnosed with probable MSA were severely disabled or used a wheelchair by 5 years after onset, although patients with cerebellar deficit predominance seem to progress more slowly. As with the other disorders discussed in this article, patients can die of pulmonary, urinary tract, and pressure ulcer infections and complications of falls. Unlike PSP and CBD, patients with MSA are also at risk for anoxic damage from stridor and cardiopulmonary arrest due to autonomic dysfunction. Consensus criteria for the clinical diagnosis of MSA were proposed in 2008.video 2-3 (links.lww.com/CONT/A283) includes an example of a patient with MSA, and case 2-3 describes a typical patient with MSA-P.
Classically, the pathology of MSA consists of widespread neuronal loss and atrophy including striatonigral, cerebellar, autonomic, and corticospinal pathways. These can involve the substantia nigra, globus pallidus, parts of the cerebellum, middle cerebellar peduncle, inferior olives, intermediolateral cell columns, corticospinal tracts, anterior horn cells, and other structures. Unlike in PSP, the subthalamic nucleus, dentate nucleus, and superior cerebellar peduncle are relatively uninvolved.
The characteristic microscopic finding is the glial cytoplasmic inclusion consisting mainly of α-synuclein. These inclusions occur throughout the brain, but mostly in the basal ganglia. There are also neuronal nuclear and cytoplasmic inclusions and dystrophic neurites in striatonigral and cerebellar structures but also in some cortical structures. The neuronal cytoplasmic inclusions take various forms including Picklike bodies, ring-shaped, and neurofibrillary tangle–like inclusions. The predominant symptoms in MSA roughly correlate with the regions most affected pathologically. In a small minority of patients with MSA, synuclein pathology results in the presence of Lewy bodies.
As with PSP and CBD, other pathologies can produce signs and symptoms that can be confused with MSA; spinocerebellar ataxias (especially types 1, 2, 3, 6, and 7), fragile X tremor-ataxia syndrome, and inflammatory diseases such as paraneoplastic conditions can rarely be misdiagnosed as MSA.
Attempts to treat MSA rather than just the symptoms of MSA have so far been unsuccessful. As with PD, new attempts at treating MSA have focused on detoxifying misfolded α-synuclein, which remains a promising approach.
table 2-1 summarizes the distinguishing clinical features of PSP, MSA, and CBD. table 2-2 summarizes the pathologic features of these diseases.
EPIDEMIOLOGY AND GENETICS OF PSP, CBD, and MSA
The reported prevalence of each syndrome is probably underestimated in clinical studies and overestimated in pathologic studies since unusual cases are more likely to come to autopsy. Among the three disorders discussed here, PSP is most commonly reported in clinical studies. A recent study reported estimates of the prevalence of clinically defined PSP as about 1.4/100,000 to 6.4/100,000 and the prevalence of clinically defined MSA as about 1.9/100,000 to 4.4/100,000 in people older than 50 years of age. The prevalence of CBS based on clinical criteria was about 2/100,000 in a population initially defined by all physicians, including primary care doctors, and then refined.
Citing a large community-based autopsy study of 233 cases, a recent report estimated the prevalence of PSP as 15.8% of the prevalence of PD, the prevalence of MSA as 4.7% of the prevalence of PD, and the prevalence of CBD as 2.1% of the prevalence of PD. That study followed all 1920 people living in two districts of Vienna for up to 13 years, of which 233 had autopsies after dying in one target hospital. The study does not report how many people died in other hospitals, perhaps producing bias. Also, it is extremely likely that people with non-PD diagnoses died more often during that period than people with PD, which would increase their relative prevalence. However, the relative prevalence of PSP versus MSA versus CBD should be more accurate.
In the past, PSP, CBD, MSA, and their syndromes were thought to be sporadic, but recently a small number of rare genetic conditions have been identified that may be clinically diagnosed as PSP, MSA or CBD, including mutations in the genes MAPT and PGRN (for tau and progranulin) as well as mutations in C9orf72 (commonly causing familial ALS and frontotemporal dementia), TARDBP, CHMP2B, and other rare genetic disorders. Multiple genetic susceptibility variants have been proposed for PSP and CBD (in the microtubule-associated protein tau or MAPT gene and other genes that can affect the tau protein) and for MSA (in the gene COQ2) but the significance of these findings is not clear.
DISTIGUISHING THESE DISORDERS FROM PARKINSON DISEASE AND FROM EACH OTHER
The clinical diagnosis of PSP is primarily based on the history, signs, and symptoms, as mentioned above. There are auxiliary tests that may occasionally be helpful, but none are definitive except for autopsy. Midbrain atrophy in PSP may give a characteristic sign on brain MRI (sometimes called the hummingbird sign on sagittal MRI or morning glory sign on axial MRI) (figure 2-1), and these may be specific but are not sensitive. Supranuclear vertical ophthalmoparesis early in the course of disease suggests PSP–Richardson syndrome, but this can also develop in CBD, usually later in the course. The ophthalmoparesis is usually horizontal in MSA. Demonstration of a dopamine deficiency state by fludeoxyglucose positron emission tomography (FDG-PET) or dopamine transporter imaging is sensitive for many forms of PSP but does not distinguish PSP from PD, CBD, or MSA and may not be sensitive for all subtypes.
The most important clinical clues to the diagnosis of CBD/CBS are focal cortical deficits such as myoclonus, apraxia, and aphasia. However, these can occur in a minority of patients with PSP and other conditions.
It is currently very difficult to identify MSA in patients whose MSA begins with isolated cerebellar signs or autonomic failure. Fluorodopa PET can accurately identify patients with unsuspected dopaminergic deficiency, but the test is currently not easily available. Brain MRI in patients with MSA may show hyperintensity in the dorsolateral margin of the putamen (putaminal slit sign) (figure 2-2) and cruciform increased signal in the pons (hot cross bun sign) (figure 2-3), but the sensitivity of these tests, while unknown, is probably low. If orthostasis is an early feature in a patient with parkinsonism, the diagnosis may be either MSA or diffuse Lewy body disease. In MSA, the central preganglionic sympathetic neurons are mostly affected (plasma epinephrine is normal when the patient is supine but fails to rise when the patient stands), and this may differentiate it from diffuse Lewy body disease, where the autonomic impairment affects mostly peripheral postganglionic neurons.
Moderate to marked cognitive impairment is common is PSP and CBD but uncommon in MSA. Visual hallucinations and levodopa-induced dyskinesias are more likely to be present in PD than in PSP-P or the other syndromes. Frontotemporal lobar degeneration–parkinsonism can mimic any of these conditions, especially if the dementia lags behind the motor symptoms.
The use of biomarkers for PSP, CBD, and MSA is being studied. The hope is that treatment strategies for these diseases are more likely to be successful if used early in the course and that specific biomarkers would allow identification of the disease before symptoms develop or when symptoms are very mild. However, currently tested biomarkers lack sufficient specificity and sensitivity for clinical use.
TREATMENT OF SYMPTOMS IN PSP, MSA, and CBD
Since none of these diseases are curable, treatment is directed to specific symptoms, many of which can occur in any of the conditions. Medications are usually ineffective for parkinsonian symptoms in these conditions, but occasionally provide benefit, at least temporarily, especially in PSP-P and MSA.
Treating patients with MSA with dopaminergic agents often worsens orthostasis, which may be difficult to manage since blood pressure support agents such as supplemental salt, fludrocortisone, midodrine, desmopressin, and other agents may produce hypertension. Botulinum toxin injections can treat apraxia of eyelid opening, blepharospasm, painful dystonia or rigidity, and sialorrhea. Botulinum toxin type B is more potent at reducing sialorrhea but is more painful to inject than botulinum toxin type A. However, patients with these syndromes are at higher risk for developing dysphagia, and it is prudent to start with lower doses than are used for PD. A pseudobulbar state can be treated with tricyclic antidepressants or dextromethorphan/quinidine.
Depression can be treated as it is for PD (it is not known if some antidepressants are better than others for these syndromes). Patients with all forms of parkinsonism do not tolerate dopamine receptor–blocking agents that are sometimes used as adjunctive antidepressive medications. Desmopressin at bedtime may help avoid nocturnal incontinence (and also help orthostasis). Constipation is managed similarly to idiopathic PD but may be less responsive to treatment. Mild constipation may be successfully managed with high-fiber diets or laxatives such as bisacodyl or senna. Liquifying stool with agents such as polyethylene glycol or lactulose may help more severe cases. Newer laxatives such as lubiprostone or linaclotide have also been used in PD. Feeding tubes can be used for patients with dysphagia who are at risk of aspiration, but not all patients and families choose this option.
PSP, CBD, and MSA were first identified by pathology that involved the substantia nigra but, unlike PD, also involve other cortical and subcortical structures. Once levodopa was introduced for the treatment of PD, these diseases could be suspected when people with dopamine deficiency symptoms (soft voice, facial masking, rigidity, bradykinesia, postural change, generalized slowing, including gait) did not improve with levodopa, had relatively early development of dysphagia and imbalance compared to patients with PD, and had other neurologic signs not seen in patients with PD. Initially, it appeared that the three conditions were easily separated. In addition to parkinsonian features, people with PSP develop multiple visual abnormalities including a supranuclear gaze palsy, have early dysphagia leading to aspiration pneumonia, have a growling voice, tend to have marked axial rigidity, and start falling in the first few years of disease. People with CBD have marked limb dystonia (often unilateral and painful), cortical signs such as multifocal myoclonus, apraxia, agnosia, agraphesthesia, and falls in the first years of disease. People with MSA have some combination of autonomic failure (eg, orthostasis, urinary frequency/urgency or urinary retention, constipation, impotence in men) and cerebellar deficits (eg, gait and limb ataxia, scanning speech). Inspiratory stridor, although uncommon in MSA, is not seen in the other conditions.
As more autopsies were conducted, it became clear that the signs and symptoms of PSP and CBD could be identical in some patients. In addition, some other disease pathologies could look like PSP or CBD, and PSP or CBD pathology could look like other diseases as well. Although some signs and symptoms are characteristic of each of these diseases, it has been difficult to devise clinical guidelines for these conditions that are both highly sensitive and highly specific.
Most recently, there has been a hypothesis that misfolded tau (in PSP and CBD) and misfolded α-synuclein (in MSA) may act like prions and drive the progression of these conditions. Studies are now underway to slow or stop the spread of these proteins inside the brain.
- Patients with parkinsonian features who do not improve with levodopa usually do not have idiopathic Parkinson disease and often have either progressive supranuclear palsy, multiple system atrophy, or corticobasal degeneration.
- Progressive supranuclear palsy is a likely diagnosis in patients with parkinsonian features and early development of a supranuclear gaze palsy.
- Some patients with progressive supranuclear palsy do not develop a supranuclear gaze palsy until later in the course of the disease. Early features that suggest progressive supranuclear palsy are an angry or puzzled look, growling speech, early development of dysphagia, and a broad-based gait with abducted arms.
- A minority of patients with the pathology of progressive supranuclear palsy may have signs and symptoms suggesting a variety of conditions, including corticobasal degeneration and, rarely, idiopathic Parkinson disease, primary progressive aphasia, cerebellar ataxia, frontotemporal dementia, and primary lateral sclerosis.
- Other pathologies may produce signs and symptoms suggestive of progressive supranuclear palsy, including Alzheimer disease, some frontotemporal dementias, Whipple disease, Niemann-Pick disease type C, and Gaucher disease.
- The pathology of progressive supranuclear palsy is characterized by deposits of 4-repeat tau in astrocytes and oligodendroglia in multiple regions of the basal ganglia and cortex of the brain.
- Preliminary studies of agents that interfere with the formation or spread of misfolded tau are being conducted with the hope of stopping or slowing the progression of progressive supranuclear palsy.
- The clinical hallmarks of classic corticobasal degeneration are parkinsonism combined with unilateral dystonia, myoclonus, and cortical deficits such as apraxia, cortical sensory loss, and alien limb phenomenon.
- As in progressive supranuclear palsy, the pathology of corticobasal degeneration also involves widespread deposition of 4-repeat tau but also includes asymmetric cortical atrophy and neuronal, oligodendroglial, and astrocytic deposits distinct from the deposits in progressive supranuclear palsy.
- As with progressive supranuclear palsy, multiple pathologies may mimic the signs and symptoms of corticobasal degeneration, including progressive supranuclear palsy, Alzheimer disease, Pick disease, and Creutzfeldt-Jakob disease. When this happens, it is known as corticobasal syndrome. Similarly, the pathology of corticobasal degeneration may present as progressive supranuclear palsy, primary nonfluent aphasia, Alzheimer disease, and other conditions.
- Middle-aged patients presenting with parkinsonism, autonomic insufficiency, and ataxia usually have multiple system atrophy. However, many patients with multiple system atrophy may initially only have symptoms in one or two of these categories, making the correct diagnosis more difficult. The development of laryngeal stridor is a strong clue that the diagnosis is multiple system atrophy.
- Unlike progressive supranuclear palsy and corticobasal degeneration, multiple system atrophy is a synucleinopathy, not a tauopathy. This may have implications for future treatments.
- Like progressive supranuclear palsy and corticobasal degeneration, there are widespread pathologic abnormalities in multiple system atrophy, but the characteristic inclusions contain α-synuclein, not tau. The first identified abnormality was a glial cytoplasmic inclusion containing α-synuclein, but neuronal inclusions have also been identified. Rarely, Lewy bodies are found in multiple system atrophy.
- There has been an intensive search for genetic risk factors for these conditions. Some candidate genes have been identified, but this has not currently led to any therapeutic innovations. Some genes have been identified that occasionally produce one of these syndromes, but those, so far, have been responsible for only a small percentage of known cases.
- The typical features of progressive supranuclear palsy (supranuclear gaze palsy), corticobasal degeneration (cortical myoclonus and other focal cortical deficits), and multiple system atrophy (autonomic failure and ataxia) suggest the correct diagnosis but do not achieve both sensitivity and specificity.
- Some symptoms of progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy can be treated, such as constipation; blepharospasm and other dystonias (with botulinum toxin injections); orthostasis; depression; pain; pseudobulbar affect; and other symptoms.
1. Lantos PL. The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 1998;57(12):1099–1111.
2. Dejerine J, Thomas AA. L’atrophie olivo-ponto-cerebelleuse. Nouv Iconog Salpetriere 1900;13:330–370.
3. Shy GM, Drager GA. A neurologic syndrome associated with orthostatic hypotension. Arch Neurol 1960;2:511–527. doi: 10.1001/archneur.1960.03840110025004.
4. Van der Eecken H, Adams RD, van Bogaert L. Striopallidal-nigral degeneration. An hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 1960;19:159–161.
5. Adams RD, van Bogaert L, van der Eecken H. Nigro-striate and cerebello-nigro-striate degeneration. (Clinical uniqueness and pathological variability of presenile degeneration of the extrapyramidal rigidity type) [in French]. Psychiat Neurol (Basel) 1961;142:219–259.
6. Graham JG, Oppenheimer DR. Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 1969;32(1):28–34.
7. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964;10:333–359. doi:10.1001/archneur.1964.00460160003001.
8. Rebeiz JJ, Kolodny EH, Richardson EP Jr. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 1968;18(1):20–33. doi:10.1001/archneur.1968.00470310034003.
9. Respondek G, Stamelou M, Kurz C, et al. The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases. Mov Disord 2014;29(14):758–766. doi:10.1002/mds.26054.
10. Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80(5):496–503. doi:10.1212/WNL.0b013e31827f0fd1.
11. Wenning GK, Ben Shlomo Y, Magalhães M. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994;117(pt 4):835–845. doi: 10.1093/brain/117.4.835.
12. Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: the Movement Disorder Society criteria. Mov Disord 2017;32(6):853–864. doi:10.1002/mds.26987.
13. Esteban A, Giménez-Roldán S. Involuntary closure of eyelids in parkinsonism. Electrophysiological evidence for prolonged inhibition of the levator palpebrae muscles. J Neurol Sci 1988;85(3):333–345. doi:10.1016/0022-510X(88)90191-8.
14. Armstrong MJ. Progressive supranuclear palsy: an update. Curr Neurol Neurosci Rep 2018;18(3):12. doi:10.1007/s11910-018-0819-5.
15. Dickson DW, Ahmed Z, Algom AA, et al. Neuropathology of variants of progressive supranuclear palsy. Curr Opinion Neurol 2010;23(4):394–400. doi:10.1097/WCO.0b013e32833be924.
16. Ayers JI, Giasson BI, Borchelt DR. Prion-like spreading in tauopathies. Biol Psychiatry 2018;83(4):337–346. doi:10.1016/j.biopsych.2017.04.003.
17. Kouri N, Whitwell JL, Josephs KA, et al. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011;7(5):263–272. doi:10.1038/nrneurol.2011.43.
18. Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for further study. J Mol Neurosci 2011;45(3):350–353. doi:10.1007/s12031-011-9624-1.
19. Alexander SK, Rittman T, Xuereb JH, et al. Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J Neurol Neurosurg Psychiatry 2014;85(8):923–927. doi:10.1136/jnnp-2013-307035.
20. Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) 2013;19(5, Movement Disorders):1189–1212. doi:10.1212/01.CON.0000436152.24038.e0.
21. McFarland NR. Diagnostic approach to atypical parkinsonian syndromes. (Minneap Minn) 2016;22(4, Movement Disorders):1117–1142. doi: 10.1212/CON.0000000000000348.
22. Ali F, Josephs KA. Corticobasal degeneration: key emerging issues. J Neurol 2018;265(2):439–445. doi:10.1007/s00415-017-8644-3.
23. Palma JA, Norcliffe-Kaufmann L, Kaufmann H. Diagnosis of multiple system atrophy. Auton Neurosci 2018;211:15–25. doi:10.1016/j.autneu.2017.10.007.
24. Sima AA, Caplan M, D’Amato CJ, et al. Fulminant multiple system atrophy in a young adult presenting as motor neuron disease. Neurology 1993;43(10):2031–2035. doi:10.1212/WNL.43.10.2031.
25. Koga A, Dickson DW. Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy. J Neurol Neurosurg Psychiatry 2018;89(2):175–184. doi:10.1136/jnnp-2017-315813.
26. Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71(9):670–676. doi:10.1212/01.wnl.0000324625.00404.15.
27. Erkkinen MG, Kim MO, Geschwind MD. Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb Perspect Biol 2018;10(4):a033118. doi:10.1101/cshperspect.a033118.
28. Coyle-Gilchrist ITS, Dick KM, Patterson K, et al. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology 2016;86(18):1736–1743. doi:10.1212/WNL.0000000000002638.
29. Respondek G, Kurz C, Arzberger T, et al. Which ante mortem clinical features predict progressive supranuclear palsy pathology? Mov Disord 2017;32(7):995–1005. doi:10.1002/mds.27034.
30. Baizabal-Carvallo JF, Jankovic J. Parkinsonism, movement disorders and genetics in frontotemporal dementia. Nature Rev Neurol 2016;12(3):175–185. doi:10.1038/nrneurol.2016.14.
31. Stamelou M, Bhatia KP. Atypical parkinsonism—new advances. Curr Opin Neurol 2016;29(4):480–485. doi:10.1097/WCO.0000000000000355.
32. Saeed U, Compagnone J, Aviv RI, et al. Imaging biomarkers in Parkinson’s disease and parkinsonian syndromes: current and emerging concepts. Transl Neurodegener 2017;6:8. doi:10.1186/s40035-017-0076-6.
33. Mueller C, Hussle A, Krismer F, et al. The diagnostic accuracy of the hummingbird and morning glory sign in patients with neurodegenerative parkinsonism. Parkinsonism Relat Disord 2018;54:90–94. doi:10.1016/j.parkreldis.2018.04.005.
34. Horimoto Y, Aiba I, Yasuda T, et al. Longitudinal MRI study of multiple system atrophy–when do the findings appear, and what is the course? J Neurol 2002;249(7):847–854. doi:10.1007/s00415-002-0734-0.
35. Way C, Pettersson D, Hiller A. The ‘hot cross bun’ sign is not always multiple system atrophy: etiologies of 11 cases. J Mov Disord 2019;12(1):27–30. doi:10.14802/jmd.18031.
Video shows a 75-year-old woman clinically diagnosed with corticobasal syndrome. Among other features, she illustrates an asymmetric parkinsonism with a markedly dystonic right arm, myoclonus, ideomotor apraxia, and cortical sensory loss.
Reproduced with permission from Williams DR, Litvan I, Continuum (Minneap Minn). © 2013 American Academy of Neurology.
Video shows an 80-year-old man demonstrating progressive asymmetric limb dysfunction, rigidity, bradykinesia, dystonia, apraxia, and cortical sensory deficits consistent with probable corticobasal degeneration.
Reproduced with permission from McFarland NR, Continuum (Minneap Minn). © 2016 American Academy of Neurology.
Multiple system atrophy
Video shows a man with signs of a mild cerebellar syndrome. On initial presentation (not shown), he had a hint of facial masking, decreased arm swing, and some dystonic posturing with his right arm when walking. He developed bowel and bladder dysfunction, erectile dysfunction, temperature dysregulation, and a cerebellar syndrome (primarily scanning speech and ataxia). Video shows mild flattening of the left nasolabial fold, depression of the left corner of the mouth and, at times, a widened left palpebral fissure. Video also shows his mildly broad-based stance and gait and his difficulty standing with feet together and eyes closed. When walking, occasionally either foot will be placed either laterally or medially, especially when walking quickly. His right arm tends to be flexed, and his stride and arm swing are reduced on the right (most obviously when walking quickly). When pulled backward, he moves his feet quickly to recover, which may throw him off balance. The patient later developed clear signs of parkinsonism (not shown) that were not responsive to levodopa, and he did not develop orthostasis until late in the disease course.
© 2019 American Academy of Neurology.