Synucleinopathies

Abstract

PURPOSE OF REVIEW:

This article reviews the α-synucleinopathies pure autonomic failure, multiple system atrophy, dementia with Lewy bodies, and Parkinson disease with respect to autonomic failure.

RECENT FINDINGS:

The pattern and severity of autonomic involvement in the synucleinopathies is related to differences in cellular deposition and neuronal populations affected by α-synuclein aggregation, which influences the degree and manifestation of autonomic failure. Clinical and laboratory autonomic features distinguish the different synucleinopathies based on pattern and severity. These features also determine which patients are at risk for evolution from pure autonomic failure to the synucleinopathies with prominent motor involvement, such as multiple system atrophy, dementia with Lewy bodies, or Parkinson disease.

SUMMARY:

Autonomic failure is a key feature of the synucleinopathies, with varying type and degree of dysfunction from predominantly peripheral involvement in the Lewy body disorders to central involvement in multiple system atrophy.

INTRODUCTION

The synucleinopathies refer to a group of disorders characterized by abnormally misfolded α-synuclein aggregates in the peripheral and central nervous systems. Differences in the cellular location and pattern of α-synuclein deposition lead to clinically distinct entities of synucleinopathies: pure autonomic failure, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson disease.^1,2 Autonomic failure in the synucleinopathies is related to dysfunction and neurodegeneration associated with abnormal α-synuclein aggregation, with accumulating evidence of cell-to-cell spread of α-synuclein in a “prionlike” manner.³ Involvement of the central autonomic network and peripheral neurons controlling autonomic function may manifest as orthostatic hypotension, urogenital dysfunction, gastrointestinal dysmotility, and thermoregulatory dysfunction.⁴ Another unifying feature of synucleinopathies is the occurrence of rapid eye movement (REM) sleep behavior disorder, which may precede the autonomic or motor features.^5,6

Pure autonomic failure is characterized by predominantly peripheral deposition of α-synuclein, whereas central neuronal inclusions, specifically Lewy bodies and Lewy neurites, are the major pathologic inclusions in Parkinson disease and DLB.⁷ MSA is characterized by oligodendroglial cytoplasmic inclusions in the central nervous system.^8,9 While symptoms may overlap, the pattern and severity of autonomic dysfunction with associated clinical symptoms and signs differentiate the various synucleinopathies.

PURE AUTONOMIC FAILURE

Pure autonomic failure was initially described in 1925 by Bradbury and Eggleston in three patients with severe orthostatic hypotension highlighted by syncope; it was previously referred to as Bradbury-Eggleston syndrome or idiopathic orthostatic hypotension.^10,11 Pure autonomic failure is a sporadic, gradually progressive disorder of adult onset. Orthostatic hypotension with a tendency for syncope is the clinical hallmark, although genitourinary dysfunction, bowel dysfunction, or heat intolerance may precede or accompany orthostatic hypotension (CASE 5-1).¹⁰

CASE 5-1.

A 76-year-old woman presented with lightheadedness. Her symptoms began around the age of 72, with progressive orthostatic lightheadedness occurring immediately after standing or walking up steps. She could tolerate standing for up t3 minutes before needing tsit. She had a history of urinary urgency with nincontinence and constipation treated with dietary measures. She had not noticed changes in sweating but reported worsening orthostasis in warm environments.

Her neurologic examination was normal. Autonomic testing revealed cardiovagal failure reflected by severely reduced heart rate responses tValsalva and deep breathing. Severe adrenergic failure was evident based on beat-to-beat blood pressure responses tthe Valsalva maneuver revealing absent late phase II and phase IV with prolonged blood pressure recovery time. Her supine blood pressure was 154/78 mm Hg with pulse of 78 beats/min, which dropped t72/58 mm Hg with pulse of 86 beats/min after 10 minutes of 70-degree head-up tilt, associated with symptoms of lightheadedness and coat-hanger distribution pain. The quantitative sudomotor axon reflex test (QSART) and thermoregulatory sweat test revealed reduced sweating in the lower limbs (FIGURE 5-1¹²). Laboratory causes of autonomic neuropathy or ganglionopathy, including antibodies tthe ganglionic (α₃) nicotinic acetylcholine receptor were negative.

COMMENT

The clinical history in this case is suggestive of pure autonomic failure; the patient demonstrates autonomic failure in the absence of motor findings. Autonomic testing revealed severe cardiovagal and adrenergic failure with orthostatic hypotension. The combination of QSART and thermoregulatory sweat test results in this patient is consistent with a peripheral pattern of sudomotor failure.

Clinical Features

Orthostatic hypotension may be symptomatic or asymptomatic in pure autonomic failure. As pure autonomic failure tends to present insidiously, a shift may occur in the cerebral autoregulatory curve, leading to patients tolerating a substantial drop in blood pressure without obvious symptoms.¹³ When symptoms are present, lightheadedness is commonly reported and may be associated with dizziness, vision changes, weakness, fatigue, and cognitive symptoms. Severe and sustained orthostatic hypotension may lead to syncope, such as with prolonged standing.¹⁴ Postprandial hypotension and accentuation of orthostatic hypotension with high ambient heat and a rise in core temperature are frequently seen in patients with pure autonomic failure.

Supine hypertension accompanies orthostatic hypotension in approximately half of all patients with pure autonomic failure, and patients may record systolic blood pressures well above 200 mm Hg.¹⁵ This seemingly paradoxical phenomenon is incompletely understood, but residual sympathetic activity, denervation hypersensitivity, and impaired baroreflex control are likely involved.¹⁶ The long-term risks of supine hypertension include end organ damage, such as left ventricular hypertrophy¹⁷ and renal impairment.¹⁸ Little is known about cerebrovascular effects in supine hypertension, but the limited available information suggests that supine hypertension may be associated with white matter lesion burden.¹⁹

In addition to orthostatic hypotension, approximately half of all patients with pure autonomic failure report bladder disturbances. Bladder symptoms in pure autonomic failure range from urgency and frequency to urinary retention and incontinence and may require catheterization. Erectile dysfunction is commonly reported in men.²⁰ Constipation can be an early and severe symptom of pure autonomic failure.¹⁸ Half of all patients with pure autonomic failure report abnormal sweating, which may be noted as either hypohidrosis or hyperhidrosis, the latter likely due to anhidrosis with compensatory hyperhidrosis chiefly noted by the patient.²⁰ Anosmia is also frequently detected on objective testing; however, patients rarely report this symptom.^20,21

Diagnosis

The diagnosis of pure autonomic failure is based on consensus criteria by the American Academy of Neurology and American Autonomic Society: pure autonomic failure is an idiopathic sporadic disorder characterized by orthostatic hypotension, usually with evidence of more widespread autonomic failure.¹¹ Bedside testing of orthostatic blood pressure may lead to the diagnosis of orthostatic hypotension, while autonomic function testing can be crucial in determining whether orthostatic hypotension is due to a neurologic cause and helping to localize the site of the lesion.

Autonomic function testing typically reveals a disorder of peripheral autonomic nerves with a reduction in sweat volumes recorded during quantitative sudomotor axon reflex test (QSART) and impaired cardiovagal function. Adrenergic failure is shown on beat-to-beat blood pressure response to Valsalva maneuver, whereas head-up tilt is able to determine the presence of supine hypertension and the degree of orthostatic hypotension. The severity of autonomic failure can be graded using a composite autonomic severity score, with higher scores indicating more severe autonomic failure.²² The thermoregulatory sweat test can be used with QSART to assess for peripheral or central sudomotor failure and determine the degree of anhidrosis. An area of hypohidrosis or anhidrosis on the thermoregulatory sweat test with a normal QSART is indicative of a preganglionic or central lesion, whereas reduced or absent QSART volumes corresponding to an area of hypohidrosis or anhidrosis on the thermoregulatory sweat test is indicative of a postganglionic or peripheral etiology.

Imaging studies in pure autonomic failure may include brain MRI to rule out evidence of central nervous system pathology.¹⁷ Cardiac functional imaging with ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) myocardial single-photon emission CT (SPECT) and 6-[¹⁸F]fluorodopamine positron emission tomography (PET) characteristically demonstrate decreased cardiac sympathetic innervation similar to patients with Parkinson disease and in contrast to patients with MSA, who typically show normal cardiac innervation.^23–25

Low supine norepinephrine levels, with minimal to no increase upon standing, are often seen on laboratory testing in pure autonomic failure. Once a peripheral etiology of neurogenic orthostatic hypotension is confirmed, causes of peripheral neuropathy known to be associated with substantial autonomic involvement, such as amyloidosis, diabetes mellitus, connective tissue disorders, and autoimmune diseases, should be considered and ruled out as appropriate before a diagnosis of pure autonomic failure is made.

Treatment

No disease-modifying therapy has yet been identified for pure autonomic failure; however, individual autonomic symptoms can usually be well managed with a multispecialty team. Patients often respond to treatments aimed at controlling orthostatic hypotension and supine hypertension, using both nonpharmacologic and pharmacologic approaches. For more information on the treatment of orthostatic hypotension, refer to the article “Management of Orthostatic Hypotension” by Jose-Alberto Palma, MD, PhD, and Horacio Kaufmann, MD, FAAN,²⁶ in this issue of Continuum. Treatment of neurogenic bladder dysfunction should be based on urologic testing. If urinary frequency or urgency predominates and patients have no urinary retention, they may benefit from anticholinergic medications or a β₃-adrenergic agonist. If urinary hesitancy and retention predominate, selective α_1A-adrenergic receptor antagonists can theoretically be helpful; however, the associated worsening of orthostatic hypotension often precludes their use. Patients with severe urinary retention may require catheterization. REM sleep behavior disorder can be treated with melatonin or clonazepam, or both, if the condition is frequent or severe enough to cause concern for potential injury.²⁷

Pathophysiology

The classic phenotype of pure autonomic failure is of postganglionic efferent autonomic failure, with dysfunction or degeneration of peripheral sympathetic nerves leading to impaired catecholamine production and release.^28,29 Evidence of low plasma concentrations of norepinephrine with no or marginal increase upon standing is seen. Loss of noradrenergic and cholinergic autonomic nerves leads to impaired vasoconstriction and contributes to venous pooling and orthostatic hypotension as well as anhidrosis. Prominent cardiac sympathetic denervation is seen, similar to other Lewy body disorders.^21,30,31 The prominent peripheral denervation in pure autonomic failure leads to receptor hypersensitivity, and agents with direct peripheral action on sympathetic receptors produce exaggerated responses.³²

Phenoconversion to Other Synucleinopathies

Subtle signs of neurologic motor dysfunction may be present in patients with pure autonomic failure and were even described in one of the original cases by Bradbury and Eggleston.^10,33 Patients with pure autonomic failure may demonstrate hyperreflexia, bradykinesia, tremulousness, or abnormal gait, which do not meet clinical diagnostic criteria for MSA, Parkinson disease, or DLB.^20,34 While not absolute, the presence of subtle motor signs and probable REM sleep behavior disorder may indicate later development of MSA, Parkinson disease, or DLB.^20,34

The majority of patients with pure autonomic failure have a slowly progressive course of autonomic dysfunction over many years. However, a 2017 retrospective cohort study describes a subset of patients with pure autonomic failure evolving into another synucleinopathy with motor and cognitive impairment.³⁵ A prospective study found that approximately one-third of patients met clinical criteria for a synucleinopathy, including Parkinson disease, DLB, or MSA, within 4 years of follow-up.²⁰ Patients who did not phenoconvert tended to be slightly younger at onset and had very low plasma norepinephrine levels.²⁰ Clinical features predictive of eventual evolution to a motor synucleinopathy are summarized in TABLE 5-1 and differ between MSA and the Lewy body disorders of Parkinson disease and DLB. Patients who are eventually diagnosed with MSA have evidence of predominantly central dysfunction on autonomic testing and may have subtle motor signs on examination and early evidence of severe bladder dysfunction.^34,35 Characteristics of patients with pure autonomic failure who are eventually diagnosed with Parkinson disease or DLB include less severe autonomic failure on autonomic function testing, subtle signs of parkinsonism on early examination, and anosmia.^20,34 Patients with pure autonomic failure who phenoconvert to MSA tend to do so earlier than those who later manifest Parkinson disease or DLB, typically within 3 years from the original pure autonomic failure diagnosis, whereas evidence of Parkinson disease or DLB was eventually found up to 8 years after pure autonomic failure diagnosis.^20,34,36

TABLE 5-1.

Factors Associated With Evolution From Pure Autonomic Failure to Other Synucleinopathies^a

Conversion to Multiple System Atrophy Subtle motor signs Rapid eye movement (REM) sleep behavior disorder Preserved olfaction Preserved norepinephrine levels Preganglionic pattern of anhidrosis Severe bladder dysfunction

Conversion to Dementia With Lewy Bodies or Parkinson Disease Subtle motor signs REM sleep behavior disorder Impaired olfaction Longer duration of illness

^aData from Singer W, et al, Neurology, 34 and Kaufmann, et al, Ann Neurol.²⁰

MULTIPLE SYSTEM ATROPHY

MSA is a progressive neurodegenerative disorder characterized by autonomic failure with motor signs of predominant parkinsonism (MSA-P) (CASE 5-2) or predominant cerebellar ataxia (MSA-C). The term multiple system atrophy has been used since it was introduced in 1969 by Graham and Oppenheimer³⁷ and encompasses disorders previously referred to as striatonigral degeneration, olivopontocerebellar degeneration, and Shy-Drager syndrome.³⁷

CASE 5-2.

A 55-year-old man presented for evaluation of lightheadedness. His symptoms were characterized by transient lightheadedness upon standing associated with darkening of vision after climbing stairs or when arising from squatting. Six months before presentation, he noticed a fine tremor in his upper extremities.

His past medical history included polysomnogram-confirmed rapid eye movement (REM) sleep behavior disorder since age 48. Erectile dysfunction alsbegan at age 48, with worsening bladder function. Following a transurethral resection procedure, he became incontinent and initiated clean intermittent catheterization.

Neurologic examination revealed hypomimia and a mild hypokinetic dysarthria with antecollis. Tone was increased axially and in all extremities. Brief jerkiness was noted with his arms held in posture, consistent with myoclonus. His gait was characterized by shuffling steps with reduced arm swing bilaterally.

Autonomic testing revealed normal quantitative sudomotor axon reflex test (QSART) volumes. Heart rate responses tValsalva and deep breathing were decreased. Beat-to-beat blood pressure responses tthe Valsalva maneuver revealed absent late phase II and phase IV overshoot and prolonged blood pressure recovery time. Supine blood pressure was 138/86 mm Hg with pulse of 86 beats/min with an immediate and progressive drop t72/48 mm Hg with pulse of 95 beats/min after 5 minutes of 70-degree head-up tilt, in the absence of symptoms. Thermoregulatory sweat test showed global anhidrosis with light acral sweating (FIGURE 5-2³⁸).

COMMENT

The clinical history is suggestive of multiple system atrophy with predominant parkinsonism; the patient demonstrates autonomic failure and REM sleep behavior disorder with motor findings of parkinsonism, dystonia, and myoclonus. Autonomic testing revealed severe adrenergic failure with orthostatic hypotension and cardiovagal impairment. The sudomotor findings are consistent with a central pattern of sudomotor failure, with intact QSART responses over areas of anhidrosis on the thermoregulatory sweat test.

MSA affects an estimated 0.6 per 100,000 people per year, which increases to 3 per 100,000 people per year in those older than 50 years of age,³⁹ with onset typically occurring in the sixth decade.⁴⁰ While generally considered a sporadic disease, a loss-of-function mutation in COQ2, a gene involved in coenzyme Q₁₀ synthesis, has been reported in familial cases and rare sporadic cases from Japan but not in North American or European populations.⁴¹ Survival in MSA is poor, with a progressive course culminating in death with median survival from onset to death ranging from 6 to 10 years.^42–44

Clinical Features

MSA begins with motor symptoms in the majority of patients. These may manifest as parkinsonism with bradykinesia, rigidity, and a jerky postural tremor, whereas an asymmetric “pill-rolling” resting tremor as classically seen in Parkinson disease is rare in MSA-P. When initially presenting with predominantly cerebellar features such as ataxic limb movements, wide-based gait, and nystagmus, the phenotype is referred to as MSA-C.⁴⁵ With progression of disease, however, parkinsonism and ataxic signs and symptoms tend to overlap.⁴³ The irregular postural and action tremor is frequently seen in patients with MSA with evidence of minipolymyoclonus on neurophysiologic examination.⁴⁶ Pyramidal tract dysfunction may manifest as hyperreflexia, spasticity, and extensor plantar responses. Dystonia may be prominent, with disproportionate antecollis, camptocormia, or dystonia affecting hand or foot.⁴⁷ Motor impairment frequently leads to falls, and approximately half of all patients require gait aids within 3 years from the onset of motor symptoms.⁴⁸ Speech is often affected and may demonstrate hypokinetic, ataxic, spastic, or mixed characteristics. As the disease advances, dysarthria may progress to anarthria and dysphagia may also become prominent.

Autonomic dysfunction in MSA tends to be severe and widespread early in disease. Orthostatic hypotension may be associated or manifest first with supine hypertension. Some patients may not exhibit symptoms even with severe drops in blood pressure, whereas others may experience recurrent syncope. Genitourinary failure may also be early and severe. Sexual dysfunction frequently manifests as erectile dysfunction in males and genital hyposensitivity in females. Neurogenic bladder may initially manifest as frequency and urgency and progress to incontinence and incomplete bladder emptying. Thermoregulatory disturbances may be clinically silent, or patients may have symptoms of heat intolerance due to anhidrosis or excessive sweating due to compensatory hyperhidrosis.⁴⁹

Respiratory and sleep disturbances are common in MSA. Approximately half of all patients develop diurnal or nocturnal inspiratory laryngeal stridor; nocturnal stridor may occur in association with sleep apneas.⁵⁰ Periodic limb movements and excessive daytime sleepiness may be noted.

Awareness of cognitive impairment in MSA is increasing, which most commonly presents as frontal-executive impairment followed by memory and visuospatial dysfunction. However, early and prominent multidomain cognitive deficits or visual hallucinations make the diagnosis of MSA unlikely.^51,52

Diagnosis

The current diagnostic criteria for MSA include the categories of definite, probable, and possible. Definite MSA requires confirmed neuropathologic findings on postmortem examination.⁴⁵ Criteria for probable and possible MSA are shown in TABLE 5-2. Core criteria include evidence of autonomic failure in addition to characteristic motor involvement.

TABLE 5-2.

Diagnostic Criteria for Multiple System Atrophy^a

Probable Multiple System Atrophy (MSA) Sporadic, progressive, adult-onset disease characterized by Autonomic failure involving urinary incontinence with erectile dysfunction in males or an orthostatic decrease of blood pressure within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic, AND Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability), OR A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction)

Possible MSA Sporadic, progressive, adult-onset disease characterized by Parkinsonism, OR A cerebellar syndrome, AND At least one feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure decline that does not meet the level required in probable MSA), AND At least one of the additional features

Additional Features Possible MSA-P or MSA-C Babinski sign with hyperreflexia Stridor Possible MSA-P Rapidly progressive parkinsonism Poor response to levodopa Postural instability within 3 years of motor onset Gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction Dysphagia within 5 years of motor onset Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum Possible MSA-C Parkinsonism (bradykinesia, rigidity) Atrophy on MRI of putamen, middle cerebellar peduncle, or pons Hypometabolism on fludeoxyglucose positron emission tomography (FDG-PET) in putamen Presynaptic nigrostriatal dopaminergic denervation on single-photon emission CT (SPECT) or PET

Supporting Features Orofacial dystonia Disproportionate antecollis Camptocormia (severe anterior flexion of the spine) and/or Pisa syndrome (severe lateral flexion of the spine) Contractures of hands or feet Inspiratory sighs Severe dysphonia Severe dysarthria New or increased snoring Cold hands and feet Pathologic laughter or crying Jerky, myoclonic postural/action tremor

Nonsupporting Features Classic pill-rolling resting tremor Clinically significant neuropathy Hallucinations not induced by drugs Onset after 75 years of age Family history of ataxia or parkinsonism Dementia White matter lesions suggesting multiple sclerosis

CT = computed tomography; MRI = magnetic resonance imaging; MSA-C = multiple system atrophy with predominant cerebellar ataxia; MSA-P = multiple system atrophy with predominant parkinsonism.

^aModified with permission from Gilman S, et al, Neurology.⁴⁵ © 2008 American Academy of Neurology.

Autonomic function testing in MSA generally reveals evidence of central autonomic dysfunction. On autonomic function testing, adrenergic failure is frequently the most pronounced finding, whereas head-up tilt is used to detect supine hypertension and the degree of orthostatic hypotension. The thermoregulatory sweat test typically shows a high degree of anhidrosis that is in a predominantly central pattern but, with time, may demonstrate peripheral involvement.⁵³ Urologic testing in MSA classically shows large postvoid residuals (>100 mL), and urodynamic studies may reveal an atonic bladder with low urethral pressure and detrusor-sphincter dyssynergia.

Polysomnography is recommended for the diagnosis of REM sleep behavior disorder, and screening for nocturnal stridor is also recommended. The presence of stridor should lead to direct laryngoscopy, which may reveal vocal cord motion abnormalities or paralysis.⁵⁴

Characteristic MRI findings in MSA may vary based on the clinical subtype (FIGURE 5-3). Patients with MSA-P frequently show putaminal atrophy with the putaminal rim sign, a hyperintense T2 border of the lateral putamen, often with T2 hypointensity of the body of the putamen with diffusion-weighted abnormalities. The hot cross bun sign is the classic sign in patients with MSA-C and refers to cruciform T2 hyperintensities of the pons.^55,56

FIGURE 5-3.

MRI findings in multiple system atrophy. Axial MRIs show characteristic changes in multiple system atrophy with predominant parkinsonism of abnormal T2 hyperintensity adjacent to the putamen with putaminal atrophy (A, arrow) and low signal on gradient recalled echo (GRE) sequence (B, arrow). Patients with multiple system atrophy with prominent cerebellar ataxia may demonstrate abnormal T2 hyperintensity in a cruciform pattern in the central pons (the hot cross bun sign) as shown on axial T2-weighted imaging (C, circle), as well as marked cerebellar and pontine atrophy as shown on a sagittal T1-weighted image (D, arrows).

Cardiac functional imaging with ¹²³I-MIBG and 6-[¹⁸F]fluorodopamine PET typically show normal cardiac innervation, but this is not invariably the case.^23–25,57

Treatment

While no disease-modifying therapy for MSA is currently available, individual symptoms may be managed with a subspecialty team. Supine hypertension and orthostatic hypotension may be managed with nonpharmacologic and pharmacologic approaches. For more information on the treatment of supine hypertension and orthostatic hypotension, refer to the article “Management of Orthostatic Hypotension” by Jose-Alberto Palma, MD, PhD, and Horacio Kaufmann, MD, FAAN,²⁶ in this issue of Continuum. Often, patients with severe urinary retention eventually require catheterization. Patients should be treated for REM sleep behavior disorder with involvement of sleep medicine specialists guiding polysomnography for screening of stridor and apneas. When present, sleep apnea or stridor should be treated with continuous positive airway pressure (CPAP) or, potentially, bilevel positive airway pressure (BiPAP). When stridor is severe with evidence of vocal cord paralysis, tracheostomy may be indicated.^58,59

Levodopa should be trialed for treatment of parkinsonism but should be used cautiously to avoid worsening of orthostatic hypotension and dyskinesia, which can be severe in patients with MSA. No treatments have proven effective for cerebellar features of MSA, although clonazepam may improve myoclonus or action tremor.⁴⁹ A comprehensive neurorehabilitation team, including physical, occupational, and speech therapy, is recommended. Neuropalliative specialists also have a role in caring for patients with MSA.⁶⁰

Pathophysiology

The neuropathologic hallmark of MSA is oligodendroglial cytoplasmic inclusions, with the principal autonomic manifestations relating to degeneration of preganglionic autonomic brainstem and spinal cord neurons (FIGURE 5-4).^8,61,62 Neurons in the rostral ventrolateral medulla are severely affected, leading to orthostatic hypotension, whereas bladder involvement is likely linked to involvement of the pontine micturition center and the sacral Onuf nucleus.^63–66 Glial cytoplasmic inclusions in the basal ganglia, substantia nigra, cerebellum, and brainstem likely underlie the motor involvement in MSA.

FIGURE 5-4.

Neuropathologic features of multiple system atrophy. Immunostaining for α-synuclein reveals a characteristic glial cytoplasmic inclusion (arrow).

Trends

Progression in synucleinopathies is increasingly considered to be due to cell-to-cell transmission of α-synuclein. In Parkinson disease and DLB, misfolded α-synuclein aggregates spread through stereotypic patterns related to staging of disease.^67–69 In MSA, aggregated α-synuclein deposits are predominantly found within glial cells, and etiologic and pathogenic factors and mechanisms remain incompletely understood.⁷⁰ Beginning in 2013, Prusiner and colleagues^3,71–73 published a series of articles suggesting that α-synuclein aggregates in experimental models of MSA act as prions, leading to debate as to whether MSA may be a prion disorder. However, the lack of known infectivity of α-synuclein aggregates in humans argues against the use of this exact terminology.⁷⁴ Regardless, our understanding of seeding and propagation mechanisms of α-synuclein has significantly increased over the past decade, with implications for understanding the onset and progression of the synucleinopathies.⁷⁵

LEWY BODY DISORDERS

The Lewy body disorders of dementia with Lewy bodies (DLB) and Parkinson disease are characterized by neuronal α-synuclein inclusions in the form of Lewy bodies (FIGURE 5-5).

FIGURE 5-5.

Neuropathologic features of dementia with Lewy bodies and Parkinson disease. Immunostaining for α-synuclein reveals a characteristic Lewy body (arrow).

Dementia With Lewy Bodies

Lewy bodies were named after Friedrich Lewy, who described cytoplasmic inclusions in a 1923 publication on a series of patients with parkinsonism, half of whom had manifestations of dementia.⁷⁶ The syndrome of dementia that precedes parkinsonism or occurs within 1 year of the onset of Parkinson disease was termed dementia with Lewy bodies in 1996.⁷⁷ DLB is the second most common form of dementia, with an incidence of 3.5 cases per 100,000 person-years.⁷⁸

CLINICAL FEATURES.

Progressive and severe cognitive decline, with disproportionate attentional and executive dysfunction with visual processing deficits, is required for the diagnosis of DLB.⁷⁹ Core clinical features include fluctuating cognition, recurrent visual hallucinations, and REM sleep behavior disorder with at least one cardinal feature of parkinsonism (bradykinesia, resting tremor, or rigidity). Along with autonomic dysfunction, neuroleptic sensitivity, postural instability with repeated falls, and neuropsychiatric manifestations are supportive clinical features.⁷⁹

Autonomic dysfunction is commonly found in DLB; however, the degree is typically less severe than in MSA but more prominent than in Parkinson disease. Symptoms of orthostatic intolerance are frequently encountered in DLB, whereas the degree of blood pressure drop is considered moderate.⁸⁰ While the time from onset of disease to orthostatic hypotension is typically later than in other parkinsonian syndromes, some patients may have initial manifestations of orthostatic hypotension.^81,82 Constipation is also common in DLB, as are genitourinary symptoms, which occur in approximately one-third of patients.^80,83

DIAGNOSIS.

Current diagnostic criteria for DLB include autonomic dysfunction as a supportive clinical feature. Autonomic function testing tends to show postganglionic sudomotor failure with moderate cardiovagal and adrenergic failure.^80,81 The degree of sweat loss on the thermoregulatory sweat test tends to follow a distal pattern as in Parkinson disease with a greater degree of anhidrosis than in Parkinson disease but less than in MSA. Postganglionic sympathetic cardiac denervation is classically seen on ¹²³I-MIBG, similar to Parkinson disease.⁸⁴

Characteristic head imaging findings include relative preservation of medial temporal lobe structures with generalized low uptake with reduced occipital activity on SPECT/PET perfusion/metabolism scan. The cingulate island sign may be demonstrated on fludeoxyglucose (FDG)-PET corresponding to preserved posterior cingulate cortex metabolism.⁸⁵

TREATMENT.

Management of DLB is multifaceted. While orthostatic intolerance is common in DLB, most patients may respond to nonpharmacologic treatments such as volume expansion. It is also suggested that patients with DLB may respond to treatment of orthostatic hypotension better than patients with MSA, supporting the lesser degree of autonomic impairment in DLB.⁸⁰

Cognitive and neuropsychiatric symptoms in DLB may respond to the cholinesterase inhibitors rivastigmine and donepezil.^86,87 Parkinsonism may respond to dopaminergic treatments; however, patients with DLB often have a less robust response than those with Parkinson disease, and treatment may worsen orthostatic intolerance.

Parkinson Disease

The syndrome first described by James Parkinson in 1817 is characterized by bradykinesia, resting tremor, rigidity, and postural and gait impairment. In his original work, An Essay on the Shaking Palsy, Parkinson described autonomic dysfunction referring to constipation and urination disorders in addition to the movement disorder.⁸⁸ The incidence of Parkinson disease is the highest of the synucleinopathies at 14 per 100,000 person-years, which increases with age.⁸⁹

CLINICAL FEATURES.

In addition to the motor features of parkinsonism, approximately 90% of patients with Parkinson disease will develop at least one nonmotor symptom.^90,91 Autonomic symptoms are common nonmotor symptoms (CASE 5-3) and may even be the presenting symptom of disease.^82,92 Constipation is frequently noted by patients with Parkinson disease, as are symptoms of neurogenic bladder with urinary urgency and incontinence and orthostasis.

CASE 5-3.

A 71-year-old woman with a 6-year history of Parkinson disease presented with postural lightheadedness and three episodes of syncope over the past year. Her parkinsonism symptoms responded well tcarbidopa/levodopa on a regimen of twtablets of 25 mg/100 mg immediate release every 4 hours, starting at 7 am.

An autonomic reflex screen identified orthostatic hypotension, with supine blood pressure of 118/72 mm Hg dropping t84/66 mm Hg after 10 minutes of tilt with a blunted heart rate response. Cardiovagal function was normal. Quantitative sudomotor axon reflex test (QSART) values were reduced at the distal leg and foot sites and normal elsewhere. Blood pressure monitoring for 24 hours showed a maximum supine systolic blood pressure of 125 mm Hg. After her dose of carbidopa/levodopa, systolic blood pressures were frequently recorded in the 80s mm Hg and associated with orthostatic symptoms.

Examined off carbidopa/levodopa, the patient had parkinsonism with hypomimia, hypophonic dysarthria, asymmetric bradykinesia with upper limb rigidity, and resting tremor. Her gait was characterized by stooped posture and reduced arm swing. Reflexes and sensory examination were normal. On the Montreal Cognitive Assessment (MoCA), the patient’s score was 30/30; Laboratory evaluations for reversible causes of autonomic neuropathy were negative.

COMMENT

This patient has Parkinson disease responding tdopaminergic therapy with nred flags for multiple system atrophy and ncognitive or behavioral involvement. However, low standing blood pressures with a history of syncope are a concern. In this setting, initiating midodrine with morning and early afternoon carbidopa/levodopa doses is indicated. The patient was counseled not tlie supine for 4 hours after taking midodrine because of the risk of supine hypertension. Additionally, the patient was counseled on nonpharmacologic measures tcombat orthostatic hypotension.

Constipation may precede the onset of motor symptoms in Parkinson disease by over 2 decades.⁹² In patients with Parkinson disease, colonic motility is reduced, resulting in reduced frequency of defecation; pelvic floor dyssynergia may also play a role.⁹³ Involvement of the upper gastrointestinal tract may lead to gastric retention of food, leading to symptoms of nausea, early satiety, and abdominal distention. Additionally, delayed gastric emptying may slow the delivery of levodopa to the duodenum where it is absorbed and offers one explanation for fluctuations that develop later in disease.⁹⁴ Swallowing may also be affected in Parkinson disease and typically involves disruption of all three swallowing phases (oral phase, pharyngeal phase, and esophageal stage). Sialorrhea is frequently a distressing problem to patients with later-stage Parkinson disease and is related to a reduction in swallowing frequency leading to saliva accumulation rather than excessive salivation.

Orthostatic hypotension is found in up to 50% of all patients with Parkinson disease (CASE 5-3).^95,96 Orthostatic hypotension may be detected early in the disease and may be caused by autonomic failure, although non-neurogenic causes such as hypovolemia, deconditioning, and medication effects often contribute.⁹⁷ Dopaminergic agents, including levodopa and dopamine agonists, may contribute to orthostatic hypotension. Levodopa, when metabolized in the periphery, has a diuretic action and induces vasodilation. In the setting of patients with autonomic failure from Parkinson disease, this can contribute to a reduction in blood pressure and orthostatic intolerance.

Urinary symptoms affect up to 85% of patients with Parkinson disease.⁹⁸ Classic urinary symptoms include neurogenic detrusor overactivity. Patients may report irritative bladder symptoms, including urgency, frequency, and nocturia, whereas retention is less commonly noted. The degree of urinary dysfunction tends to remain mild or moderate in comparison to the severe and early dysfunction in MSA. Erectile dysfunction is reported in up to 79% of males with Parkinson disease. Women report sexual dysfunction including vaginal dryness, decreased libido, and difficulty reaching orgasm. While sexual dysfunction can be a premotor symptom of disease, the severity typically increases with longer disease duration.⁹⁹

Clinically, patients with Parkinson disease may manifest thermoregulatory dysfunction. The spectrum of thermoregulatory symptoms includes heat or cold intolerance, intermittent hyperhidrosis episodes such as night sweats, and hyperhidrosis or hypohidrosis. The underlying neurodegenerative disorder and medication effect may contribute to thermoregulatory symptoms. For example, hyperhidrosis episodes are more frequently reported by patients with Parkinson disease during off periods or times of motor fluctuations.¹⁰⁰

DIAGNOSIS.

The diagnosis of Parkinson disease remains clinical, with evidence of parkinsonism defined as bradykinesia in combination with resting tremor and/or rigidity.¹⁰¹ Various levels of certainty are established using the current Movement Disorder Society’s Clinical Diagnostic Criteria for Parkinson’s Disease, including clinically established and clinically probable.¹⁰¹ Evaluation of autonomic function in patients with Parkinson disease may include evaluation for orthostatic hypotension, which can be done at the bedside or with autonomic function testing or prolonged blood pressure monitoring. The use of prolonged blood pressure monitoring can be useful when suspicion exists that medication effect, such as from levodopa, is contributing to orthostatic hypotension; prolonged blood pressure monitoring may also screen for supine hypertension. The degree of orthostatic hypotension in Parkinson disease tends to be less severe than that found in DLB or MSA.⁸⁰

Urodynamic studies in patients with Parkinson disease frequently reveal a high prevalence of detrusor overactivity.⁹⁸ The thermoregulatory sweat test typically shows distal postganglionic sudomotor impairment, which is usually of mild severity.⁸⁰

Brain MRI may be useful in patients with Parkinson disease with significant autonomic features to assess for atypical parkinsonism such as MSA. Most patients with Parkinson disease, and especially patients with Parkinson disease with neurogenic orthostatic hypotension, demonstrate loss of sympathetic innervation of the heart on MIBG testing.^36,102

TREATMENT.

While Parkinson disease has no known cure, dopaminergic agents are the mainstay of treatment. Additionally, aerobic exercise may slow progression of the disease.^103,104 This makes treatment of orthostatic intolerance imperative in improving quality of life in patients with Parkinson disease and providing the best potential to modify the disease course. Use of nonpharmacologic and pharmacologic measures to improve orthostatic hypotension may be done concomitantly with the use of dopaminergic agents for motor symptoms.

Bladder symptoms of neurogenic detrusor overactivity may be managed with antimuscarinic agents, with caution to avoid worsening of other autonomic symptoms, as well as the β₃-adrenergic agonist mirabegron. Treatment of constipation in patients with Parkinson disease involves both nonpharmacologic measures, including dietary measures such as fiber supplements and increasing water intake, and pharmacologic measures. Pyridostigmine, when prescribed for orthostatic hypotension, may help constipation; other pharmacologic measures include stimulants, osmotic laxatives, stool softeners, and the use of enemas and suppositories. Sexual dysfunction symptoms in males may be treated with phosphodiesterase-5 inhibitors, with caution to reduce the chance of orthostatic hypotension due to systemic vasodilation. For more information on the management of bladder and gastrointestinal symptoms, refer to the article “Lower Urinary Tract and Bowel Dysfunction in Neurologic Disease” by Jalesh N. Panicker, MD, DM, FRCP, and Ryuji Sakakibara, MD, PhD, FAAN,¹⁰⁵ in this issue of Continuum.

PATHOPHYSIOLOGY.

In the Lewy body disorders of DLB and Parkinson disease, α-synuclein tends to have earlier and more extensive involvement of peripheral autonomic structures, although a degree of central autonomic involvement is present. Involvement of the enteric nervous system contributes to constipation, which may be the earliest manifestation of disease.¹⁰⁶ Degeneration of peripheral postganglionic noradrenergic fibers causes reductions in plasma norepinephrine concentrations and likely accounts for the orthostatic hypotension seen in these patients.^107,108 In DLB, orthostatic hypotension may be more severe and is likely also related to central involvement of the rostral ventrolateral medulla and medullary raphe controlling sympathetic outflow.¹⁰⁹

CONCLUSION

Autonomic failure is a key feature of the synucleinopathies of pure autonomic failure, MSA, DLB, and Parkinson disease. Involvement of the autonomic nervous system varies from predominantly peripheral involvement in the Lewy body disorders to predominantly central involvement in MSA. The severity of autonomic dysfunction also varies, with the most severe involvement in MSA, moderate involvement in DLB, and less severe impairment classically seen in Parkinson disease. Patients with pure autonomic failure typically manifest a severe degree of autonomic failure, and certain clinical and laboratory features may predict evolution into other synucleinopathies.

FIGURE 5-1.

Pure autonomic failure. Autonomic testing demonstrates reduced heart rate responses (red) to deep breathing and Valsalva maneuver, indicative of severe cardiovagal failure. Beat-to-beat blood pressure responses to Valsalva maneuver show adrenergic failure with absent late phase II and phase IV with prolonged blood pressure time, whereas tilt shows immediate and sustained orthostatic hypotension. The thermoregulatory sweat test demonstrates anhidrosis over the abdomen and lower extremities, and the quantitative sudomotor axon reflex test (QSART) shows reduction in sweat volumes over the lower extremity sites, indicative of postganglionic sudomotor failure.

FIGURE 5-2.

Multiple system atrophy with predominant parkinsonism. Autonomic testing demonstrates severe cardiovagal failure with reduced heart rate responses (red) to deep breathing and Valsalva maneuver. Severe adrenergic failure is shown on beat-to-beat blood pressure responses to Valsalva maneuver, with absent late phase II and phase IV with prolonged blood pressure time. Orthostatic hypotension is immediate and progressive on tilt. Thermoregulatory sweat test demonstrates global anhidrosis with acral hypohidrosis. In conjunction with the quantitative sudomotor axon reflex test (QSART) showing intact postganglionic sudomotor function, this pattern is indicative of a central autonomic disorder.

KEY POINTS.

• α-Synuclein aggregation in central and peripheral autonomic structures may lead tautonomic manifestations of orthostatic hypotension, urogenital dysfunction, gastrointestinal dysmotility, or thermoregulatory dysfunction.

• Rapid eye movement sleep behavior disorder is a unifying feature of the synucleinopathies and may precede autonomic or motor features in the various diseases.

• Pure autonomic failure is a sporadic, gradually progressive neurodegenerative disorder characterized by orthostatic hypotension with a tendency for syncope.

• Supine hypertension is found in approximately half of all patients with pure autonomic failure; it may be severe and often complicates treatment of orthostatic hypotension.

• The diagnosis of pure autonomic failure is based on detection of orthostatic hypotension, usually with clinical history or evaluation consistent with widespread autonomic failure.

KEY POINTS.

• Evaluation in pure autonomic failure reveals peripheral involvement with decreased uptake on cardiac functional imaging and low levels of supine norepinephrine that have minimal tnincrease upon standing.

• A subset of patients with pure autonomic failure phenoconvert ta synucleinopathy with motor or cognitive impairment, or both. Greater severity and earlier autonomic symptoms with central autonomic failure on autonomic testing predicts conversion tmultiple system atrophy (MSA).

• MSA is characterized by autonomic failure with motor symptoms of predominant parkinsonism (MSA-P) or predominant cerebellar ataxia (MSA-C), although parkinsonism and ataxia often overlap later in disease.

KEY POINTS.

• Autonomic dysfunction in MSA tends toccur early and be severe, with orthostatic hypotension that may have concomitant supine hypertension and genitourinary failure characterized by sexual dysfunction and urinary retention leading tincontinence.

• Autonomic function testing in MSA generally shows orthostatic hypotension with central autonomic dysfunction characterized by a large degree of anhidrosis on thermoregulatory sweat test with relatively preserved quantitative sudomotor axon reflex test volumes.

• Characteristic brain MRI findings in MSA include the putaminal rim sign, which is more commonly seen in MSA-P, and the hot cross bun sign, which is more commonly seen in MSA-C.

• Treatment for MSA involves a multidisciplinary team managing autonomic failure, motor features, sleep, and respiratory dysfunction.

• The neuropathologic hallmark of MSA is oligodendroglial cytoplasmic inclusions, which are frequently found in the substantia nigra, basal ganglia, brainstem, cerebellum, and spinal cord.

KEY POINTS.

• The diagnosis of dementia with Lewy bodies (DLB) is based on the presence of dementia, often with early prominent deficits in attention, executive function, and visuoperceptual ability along with core clinical features that include fluctuating cognition, visual hallucinations, rapid eye movement sleep behavior disorder, and parkinsonism. Syncope and severe autonomic dysfunction are supportive clinical features.

• The degree of autonomic failure in DLB is less severe than MSA but more prominent than typically seen in Parkinson disease.

• Constipation, neurogenic bladder, and orthostasis are common nonmotor symptoms in Parkinson disease reflecting autonomic dysfunction.

KEY POINTS.

• Orthostatic hypotension is found in 30% t50% of all patients with Parkinson disease, and treatment with dopaminergic medications may contribute tblood pressure drop.

• Thermoregulatory dysfunction in Parkinson disease may manifest as heat or cold intolerance, intermittent hyperhidrosis episodes, and hypohidrosis.

KEY POINT.

• The Lewy body disorders typically have early and more extensive peripheral α-synuclein involvement, although central involvement of autonomic structures likely contributes torthostatic hypotension in DLB.