Clinical Vignette

A 71-year-old woman presented with poor balance starting 2 years ago. She would describe multiple episodes where she would suddenly fall backwards. She also recently noted visual blurring especially when she would be reading or going down the stairs. Frequently, she noted her eyes would be closed and she had difficulties opening them. Occasionally while drinking, she would spontaneously cough or choke; her speech became softer and slurred.

Neurologic examination demonstrated her to have a blank staring appearance, and dysarthric speech. She also demonstrated a vertical more than horizontal supranuclear gaze palsy; however, her vertical eye movements were preserved with oculocephalic reflex maneuvers. Blepharospasm, prominent axial rigidity, and mild bradykinesia in all four extremities with minimal cogwheel rigidity and brisk muscle stretch reflexes were also identified. She was able to stand up slowly and walked with erect posture, stiff gait, and bilateral decreased arm swing. She had no postural reflexes and during pull test, she fell backwards easily.

PSP is a sporadic tauopathy that has a progressive clinical course characterized by parkinsonism with supranuclear gaze palsy (Fig. 34-1), early postural instability, falls, bradykinesia, and dysarthria as well illustrated in this vignette. PSP typically does not respond to dopaminergic therapy. Its prognosis is poor, with a median survival of 5–7 years. PSP’s etiology, like that of CBD, is unknown. A genetic susceptibility may be invoked; however, to date, only the H1 MAPT haplotype has been consistently associated with a risk of developing progressive supranuclear palsy

Figure 34-1 Progressive Supranuclear Palsy.

Pathophysiology

PSP is primarily a subcortical neurodegenerative tauopathy in contrast to both CBD and FTPD-17 having involvement of the cerebral cortex. Macroscopically, depigmentation is observable within the substantia nigra (SN) and locus coeruleus (LC), as well as atrophy of the pons, midbrain, and globus pallidum (Fig. 34-2). Microscopically, the most affected regions are brainstem nuclei III, IV, IX, and X, the red nucleus, LC, SN, globus pallidus, and cerebellar dentate nucleus. Tau protein accumulates within neurons as neurofibrillary tangle (NFT) and in glia as spherical neuropil threads.

Figure 34-2 Pathology of Progressive Supranuclear Palsy.

Clinical Presentation

PSP typically occurs between the sixth and seventh decades. Onset before age 40 years is rare. Prevalence varies between 1 and 6.4/100,000. PSP is sporadic in most individuals, but rarely an autosomal dominant inheritance is suggested.

Patients usually present with gait instability and tendency to unexpectedly fall backwards; in contrast, neither of these symptoms occurs early on in Parkinson disease. The parkinsonism of PSP is typically axial and symmetric, unlike the asymmetric often single limb presentation of PD. Most patients with PSP carry an erect posture in contrast to the flexed PD stance (see Fig. 34-1). Often they lack the typical PD tremor. Dystonia is a common finding particularly early on affecting limbs, neck dystonia, or even as blepharospasm.

The hallmark of PSP is the classic and characteristic finding of limited vertical eye movements; eventually a horizontal supranuclear gaze palsy may also become evident. In this clinical setting, the patient usually does not recognize the loss of eye movement per se but rather perceives these limitations as blurry vision particularly manifested by difficulties with routine activities such as reading or walking down the stairs. Dysarthria and dysphagia are also commonly experienced early in the disease course. Cognitive dysfunction is a later development for most PSP patients.

Diagnosis

PSP and other atypical parkinsonian syndromes including CBD, MSA, and dementia with Lewy bodies are often misdiagnosed as PD or as cerebrovascular disease (atherosclerotic parkinsonism). The most important diagnostic clues are (1) the results of a careful clinical evaluation and (2) a poor response to dopaminergic therapy.

Computed tomography (CT) and magnetic resonance imaging (MRI) (Fig. 34-3) often demonstrate generalized or brainstem (dorsal midbrain) atrophy. The combination of atrophy of the midbrain tegmentum with relative sparing of the basis pontis resembles “a lateral view of a standing penguin (especially, the king penguin), with a small head and big body” on a midsagittal MRI scan. Previously, appearance of the midbrain tegmentum was stated to resemble the head of a hummingbird. Whether the penguin or hummingbird sign will take flight remains to be seen, but the implication of both studies is the same: the midbrain in PSP is atrophic and MRI can be helpful to verify the clinical diagnosis.

Figure 34-3 Magnetic Resonance Imaging in Progressive Supranuclear Palsy.

There are no more specific diagnostic studies available. Metabolic positron emission tomographic (PET) studies have demonstrated global reduction in cerebral metabolism; ¹⁸F-fluorodopa PET uptake studies revealed reduced caudate and putamen uptake. Single photon emission computed tomography (SPECT) revealed bifrontal hypometabolism.

Treatment

There are no effective specific therapies available for the PSP patient. Although some of these individuals with slowness, stiffness, and balance problems initially may respond to antiparkinsonian therapies such as levodopa, or levodopa combined with anticholinergic agents, this effect is usually limited and at best a temporary one. Visual limitations, dysarthria, and dysphagia are usually unresponsive to any pharmacologic intervention.

Antidepressant drugs have had modest success in PSP; fluoxetine, amitriptyline, and imipramine are the most commonly used, although their benefit seems to be unrelated to their ability to relieve depression. Botulinum toxin injections are used when blepharospasm is an issue. Physical and occupational therapy are the most important patient management aspects.

PSP has an inexorably progressive course. The average PSP patient has a survival from symptom onset to death of 5–6 years. Head injury and fractures from falls are common. Because of dysphagia, PSP patients are predisposed to other serious complications such as choking and pneumonia, the most common cause of death.

Clinical Vignette

Four years ago, a 68-year-old man started to have difficulties with fine motor activities of the right hand. His hand felt stiff and uncoordinated and was occasionally doing things on its own. His family described it as, “His hand elevates and wanders around without a purpose.” When an object was placed in his right hand, he had difficulties releasing it. Later, his right hand tended to close involuntarily and appeared swollen. Eventually he was really unable to perform any fine motor tasks with this hand. Treatment with high doses of Sinemet 25/100 (total of 15 tablets a day) was ineffective. Two years later, he also noted poor balance and started to fall down. His gait was slow, shuffling, and his right arm was held close to his body in a flexed position. A jerky intention-type tremor developed in the right hand; it was particularly noticeable when he attempted to reach for an object. Concomitantly, his family began to observe that this gentleman was experiencing word-finding difficulties, memory problems, slurred speech, and swallowing difficulties.

His neurologic examination demonstrated very dysarthric bulbar speech, word-finding difficulties with anomia for uncommonly utilized objects, and an apraxia wherein he could not appropriately use a body part as illustrated or not be able to demonstrate how to perform certain common functions such as combing one’s hair. On cranial nerve examination, he had mild difficulty generating vertical more than horizontal saccadic eye movements. He had a reduced blink frequency. Right arm levitation, dystonic posture of the right arm with irregular jerky tremor, striking rigidity and bradykinesia on the right side, brisker right muscle stretch reflexes, and a right Babinski sign were also seen. He also had positive snout and grasp reflexes. His gait was very stiff and so limited that he was unable to walk without the assistance of two people.

CBD is a rare sporadic neurodegenerative tauopathy. It occurs mainly after age 60 years and shows no population clusters; its incidence, prevalence, and etiology are unknown. The typical presentation is that of an asymmetric progressive akinetic rigid syndrome, dystonia and alien hand phenomenon, and signs of cerebral cortex dysfunction. Each one of these various CBD manifestations is poorly responsive to levodopa therapy.

Pathophysiology

CBD primarily affects the cerebral cortex in contrast to PSP. The patient’s clinical presentation correlates well with the later finding of an asymmetric cortical atrophy contralateral to the involved limb. The frontoparietal cortex is the most involved with most prominent changes of cortical atrophy demonstrated within the perirolandic area. A reduction in amount of cerebral white matter is also apparent in the cerebral peduncles and corpus callosum. Additionally, neuronal loss is present within the substantia nigra (SN) and locus ceruleus (LC).

Typical microscopic features include neuronal loss (cortex, subcortical regions, SN), astrocytic gliosis, ballooned (achromatic) neurons, NFT, and tau-positive glial inclusions. The microscopic hallmarks of CBD are the ballooned, swollen, or achromatic neurons lacking Nissl substance.

Clinical Presentation

An asymmetric akinetic-rigid parkinsonism, primarily affecting the arm and hand, is often the major feature. Patients usually present with limb clumsiness, awkward, slow voluntary movements of one arm, with dystonic posturing and tremor. Cortical signs include apraxia, cortical sensory disturbance, and finger myoclonus. The alien limb phenomenon, a failure to recognize ownership of a limb without visual cues, is also a common clinically appreciable sign. Gradually a gait disorder develops, characterized by limb rigidity and impaired position sense. Dementia usually develops late in the course of CBD; however, relatively early on, a declining cognitive function is sometimes a predominant feature. Less commonly, there is an overlap with some similar atypical parkinsonism syndromes. This is particularly related to the typical vertical eye movement abnormalities of the type characteristically associated with PSP. Slowed speech production, dysarthria, swallowing difficulties, and cognitive deficits occur later in this disease. Less common CBD presentations include dementia and altered behavior.

Diagnosis

CBD is relatively easy to diagnose because of its stereotypic clinical presentation, particularly the alien hand phenomenon. Some conditions clinically mimic CBD, including PSP, Pick’s disease, Alzheimer’s disease, some vascular lesions, and rarely adult-onset leukodystrophies. Neuropathologic evaluation is necessary to confirm the diagnosis.

Imaging studies are not diagnostic. MRI and CT can show asymmetric cortical atrophy in the frontoparietal region, maximal on the side contralateral to the involved limb. The asymmetrically reduced pattern in frontoparietal cerebral cortical metabolism, CBF, or both, coupled with bilateral reduction of fluorodopa uptake in the caudate and putamen on PET scanning, provide strong evidence for CBD.

Treatment

There is no definitive treatment; dopaminergic therapy is of limited benefit, clonazepam can be used for finger myoclonus, and botulinum toxin improves dystonia. Occupational, physical, and speech therapy may also help. There is a significant average survival of usually 5–6 years from symptom onset to death.

Pathophysiology and Clinical Presentation

Pathologically the neocortex is degenerated with marked frontal and temporal lobe atrophy. The subcortical basal ganglia and brainstem nuclei are also concomitantly affected.

FTDP-17 is a highly variable neurodegenerative disease. The first symptoms typically occur in the fifth decade but range from the third to the sixth decades. The clinical onset is an insidious one. Often there is significant history of similar problems among multiple family members. Behavioral disturbances are often the initial and typical features, including disinhibition, inappropriate behavior, and poor impulse control (Fig. 34-4). Other individuals present with apathetic, socially withdrawn behavior and often neglect personal hygiene. Some individuals’ prominent psychosis, similar to schizophrenia with auditory hallucination, delusion, and paranoia, is sometimes apparent.

Figure 34-4 Other Tauopathies. Corticobasal Degeneration and Frontotemporal Dementia.

Cognitive impairment affecting executive function, judgment, planning, and reasoning may be the initial sign of FTDP-17. Surprisingly, patients with this variant do have preservation of memory, orientation, and visual spatial functions. The typical patient develops disinhibited behavior in the fifth decade without impairment of memory or orientation. However, there is progressive worsening over several years, eventually associated with severe dementia, bradykinesia, rigidity, and evidence of frontal or temporal atrophy or both.

Motor disturbance usually does not occur early on in this disorder. Later patients have parkinsonism-type findings, including bradykinesia, axial and limb rigidity, and postural instability. Resting tremor is uncommon.

Diagnosis and Treatment

Other conditions that present with parkinsonism and dementia include Pick’s disease, CBD, PSP, and Alzheimer’s disease. The prominent family history of FTDP-17 is usually lacking in these other disorders. Careful attention to the family history and the clinical presentation per se provide the diagnostic keys. DNA genetic testing demonstrates the chromosome 17 gene mutation. PET scanning, used infrequently, shows a reduction of caudate and putamen fluorodopa uptake.

There is no therapy for FTDP-17. As with other tauopathies, the response to dopaminergic therapy is poor. The disease duration averages 10-12 years.

Clinical Vignette

A 62-year-old man first noted poor balance and right-hand clumsiness during his job as a carpenter 2 years ago. He observed poor fine motor control of the right hand as well as several unexpected falls while climbing a ladder. His wife noted his poor balance with a tendency to walk “as a drunk person.” He also described a feeling of lightheadedness when he stood up quickly, urinary urgency, and sexual dysfunction. He had to retire from his job. An initial trial of low doses of levodopa produced no benefit. When the dose of levodopa was increased to Sinemet 25/100 (nine tablets a day), he noted some benefit in fine motor control, but within several months prominent orofacial and lower extremity dyskinesia developed. Despite a continued response of his right upper extremity akinesia to levodopa, his gait and balance deteriorated and he started to have slowness on the opposite left side of his body. Because his balance deteriorated rather quickly, leading to multiple falls, he became wheelchair bound within the next year. He also experienced several fainting spells later in the course of the disease.

His examination was notable for hypophonic speech, stridor, square wave jerks seen during eye movement exam, orofacial dyskinesia, and antecollis. He had asymmetric akinetic rigid syndrome with more involvement of the right-sided extremities with brisker muscle stretch reflexes and the presence of a right Babinski sign. Bilateral right greater than left, finger-to-nose-to-finger and heel-to-shin ataxia was identified, right more prominent than left. He was unable to ambulate independently and required two people to support him. His gait was characterized by a wide base with significant slowness, bilateral loss of arm swing, and poor postural stability. MRI demonstrated lateral putamen and pontine cruciate patterns of T2 hyperintensity (Fig. 34-5). He had abnormal autonomic testing.

Figure 34-5 Diagnosis of Multiple-System Atrophy.

MSA is a sporadic, degenerative CNS disease classified as a synucleinopathy. It presents with a combination of extrapyramidal, pyramidal, cerebellar, and autonomic symptoms and signs. Its clinical manifestations may change as it evolves.

MSA comprises three clinical conditions previously classified as (1) striatonigral degeneration (SND) with predominant parkinsonism and a poor response to levodopa; (2) Shy-Drager syndrome (SDS), parkinsonism or cerebellar syndrome, or both with predominant autonomic dysfunction; and (3) sporadic olivopontocerebellar atrophy (OPCA) with predominant cerebellar dysfunction. MSA is a specific condition with a specific pathology, regardless of previous SND, SDS, or OPCA labels. It is characterized by oligodendroglial cytoplasmic inclusions that stain for alpha-synuclein. The etiology of MSA is unknown.

Pathophysiology

Macroscopically, neuronal loss and gliosis are primarily seen in many subcortical areas such as the SN, LC, putamen, globus pallidus, inferior olive nucleus, pons, cerebellar cortex, autonomic nuclei of the brainstem, and intermediolateral columns of the spinal cord. Glial cytoplasmic inclusions (GCIs) are major microscopic findings that are characteristic of, but not specific for, MSA. These GCIs represent the accumulation of the protein alpha-synuclein within previously normal oligodendrocytes. These inclusions are distributed selectively within the basal ganglia, motor cortex, reticular formation, middle cerebellar peduncle, and the cerebellar white matter.

Clinical Presentation

MSA affects a slightly younger age group than PD, with peak onset in the sixth decade. The clinical syndromes corresponding to the previously named SND, OPCA, and SDS are parkinsonism, cerebellar dysfunction, and autonomic failure. Any one of these subcategories may be clinically predominant but still fall within the clinical spectrum of MSA.

The parkinsonism of SND tends to be more symmetric, rest tremor is less common, and postural instability develops earlier than in classic PD. Early stages, however, can be identical to the presentation of idiopathic PD. Similarly, an initial positive response to levodopa as well as negative fluctuations and dyskinesias may occur. Clinical “red flags” that should alert the clinician to a diagnosis of possible MSA include orthostatic hypotension, urinary retention or incontinence, ataxia, unexpected falls, stimulus-sensitive myoclonus, antecollis, slurred speech, stridor, and corticospinal tract signs.

MSA is a chronically progressive disorder characterized by the gradual onset of symptoms. Patients who present initially with extrapyramidal features commonly progress to develop autonomic disturbances, cerebellar disorders, or both. Conversely, patients whose first symptoms are cerebellar dysfunction often later develop extrapyramidal or autonomic disorders or both.

Diagnosis

Distinguishing MSA from idiopathic PD and PSP is often challenging early in the illness. Some features such as autonomic dysfunction, poor or marginal response to levodopa with early clinical fluctuations, and dyskinesia can help to differentiate MSA from early PD. Autonomic failure is common in MSA and rare in early PD, whereas dementia and psychiatric features are more common in PD.

Cerebellar atrophy can be demonstrated even with brain CT scans. Characteristic MRI abnormalities include hypointensity on T1 or hyperintensities on T2 in the lateral border of the putamen or putaminal atrophy. Cerebellar and pontine atrophy with the hot cross bun sign (see Fig. 34-5) in the pons are seen; however, MRI is not specific and is often normal.

Other tests used in diagnosis of MSA include autonomic testing, external anal or urethral sphincter electromyography (EMG), and dopamine transporter scan.

Treatment

Only symptomatic therapy is available. Parkinsonism is treated with levodopa despite its inconsistent efficacy. Orthostatic hypotension may respond to conservative measures such as raising the head of the bed, binding stockings, and liberal salt intake. Medications such as fludrocortisone or midodrine are commonly required. Urinary dysfunction can be treated with antispasmodics such as oxybutynin and self-catheterization. Typical disease duration is 3–10 years. Breathing problems such as aspiration and cardiopulmonary arrest are common causes of death.