Pure Pandysautonomia and Pandysautonomia with Neurological Features

There is a clinical spectrum of acute autonomic neuropathies. Acute panautonomic neuropathy (pandysautonomia), characterized by severe widespread sympathetic and parasympathetic failure, is at one extreme. Guillain-Barré syndrome is at the other end of the spectrum, in which the brunt of the disorder is borne by the somatic nervous system. Pure acute panautonomic neuropathies are relatively rare. Actually, the majority of acute autonomic neuropathies have some minor somatic features. Dysautonomia may be restricted to the cholinergic system (acute cholinergic neuropathy), the adrenergic system, or other organ systems (e.g., motility disorders).⁴⁰

In medical history, a definite entity of pure pandysautonomia involving both sympathetic and parasympathetic nervous systems with a subacute onset, monophasic course, and partial recovery without significant features of somatic peripheral neuropathy was first described by Young and colleagues in 1969. Actually, there had been some earlier reports of the condition in the literature, although it was not clearly defined.⁴⁷ The disorder differs from other neurological causes of autonomic dysfunction in that normal function of the central nervous system is preserved. Furthermore, there are no or only minor features of peripheral somatic nervous system involvement. Since these first descriptions, a number of other cases of acute pandysautonomia have been reported, as well as some cases of pure cholinergic dysautonomia. Some cases of acute dysautonomia with significant sensory disturbances have been described; in some, but not all, there was electrophysiological and pathological evidence of loss of small-diameter myelinated and unmyelinated fibers.⁴¹ In 1994, Suarez and colleagues⁴² clarified the features of acute idiopathic autonomic neuropathy. Both sexes and all ages can be affected. The onset is acute or subacute. In approximately one half of affected patients, there is an antecedent viral infection. Several cases that followed Epstein-Barr virus infection have been described, in one of which Epstein-Barr virus DNA and antibody to the virus were found in the cerebrospinal fluid.⁴³ The most common presenting features are symptomatic orthostatic hypotension (light-headedness, dizziness, syncope) and symptoms of gastrointestinal dysfunction (nausea, vomiting, diarrhea, constipation, and postprandial bloating) or sudomotor dysfunction (failure to sweat, causing heat intolerance and flushing). Other symptoms include numbness, tingling, bladder disturbances, and impotence. Neurological examination findings are normal in about one half the patients; the remainder have depressed reflexes and distal sensory impairment. The clinical course is monophasic. Recovery tends to be gradual and frequently incomplete. The cerebrospinal fluid protein level may be mildly elevated. In rare cases, there may be evidence of sensory neuropathy with sensory symptoms of minimal intensity (mainly thermal and pain hypoesthesia in distal areas). In most cases, nerve conduction studies yield normal results. Sural nerve biopsy in some cases has demonstrated reduction of myelinated fiber density, predominantly of small fibers, and axonal degeneration. Actually, in some cases, there are minimal signs of distal denervation in electromyographic-electroneurographic studies.⁴⁴ In some acute neuropathies, such as pandysautonomia, small-fiber impairment is relatively pure, but it may also appear in disorders with prominent somatic damage, such as Guillain-Barré syndrome, in which autonomic failure worsens the prognosis.⁴⁵

The cause of the condition remains uncertain. Pathological features include the presence of a small inflammatory mononuclear cell infiltrate in the epineurium. It is probably a form of acute idiopathic polyneuritis restricted to autonomic nerves with an immune-mediated pathogenesis similar to that of the Guillain-Barré syndrome. Together, the acute onset, frequent antecedent viral infection, selectivity of involvement by fiber type and autonomic level, and presence of perivascular mononuclear cell infiltration suggest that the underlying mechanism is likely to be immune mediated. The following differential diagnoses have to be kept in mind: botulism, acute autonomic neuropathy associated with Guillain-Barré syndrome, porphyria, diabetes, toxic causes, systemic lupus erythematosus, and other connective tissue diseases.⁴¹

Pure Cholinergic Dysautonomia

In pure cholinergic dysautonomia, clinical and laboratory features indicate only a cholinergic failure. A number of cases of pure cholinergic dysautonomia have been described in children. Clinical features include blurred vision, impaired lacrimation, dry mouth, constipation, urinary retention and incontinence, and absence of sweating. There is no postural hypotension. Excessive salivation and sweat secretion have been described in early disease stages. Cerebrospinal fluid findings are normal.⁴¹

Primary Autonomic Failure

Bradbury and Eggleston⁴⁶ were the first to describe PAF in 1925. They used the term idiopathic orthostatic hypotension. Actually, the name pure autonomic failure was introduced by Oppenheimer as one of the primary autonomic failure syndromes. It is a sporadic, adult-onset, slowly progressive, neurodegenerative disorder of the autonomic nervous system.⁹² Clinically, it is characterized by an isolated impairment of the autonomic nervous system with no other neurological deficits.⁴⁷ PAF affects men slightly more often than women, usually in their sixth decade. Its onset is slow, and symptoms begin developing insidiously for years as minimal impairment (nonspecific weakness and orthostatic intolerance). The patient may recall that symptoms first manifested several years before he or she sought medical treatment. Common symptoms causing the patient to seek medical advice include unsteadiness, lightheadedness, or faintness on standing. Questioning often elicits descriptions of aching in the neck or occiput only when standing; lying down relieves all symptoms. In general, orthostatic symptoms are more prominent after prolonged recumbency, as in the morning hours. Moreover, postural hypotension is exacerbated after mealtimes and physical exertion. Other contributory factors are heat, alcohol ingestion, coughing, and defecation.^48,49 In fact, straining during evacuation or micturition elevates intrathoracic pressure and may result in symptomatic hypotension. Mathias and colleagues⁵⁰ investigated the frequency of symptoms associated with orthostatic hypotension in PAF and MSA and found that more patients with PAF had syncope (91% vs. 45%), visual disturbances (75% vs. 53%), and suboccipital/paracervical “coat hanger” neck pain (81 vs. 53%) than did the patients with MSA. The reasons for this are unclear. Patients with PAF may also develop supine hypertension. Moreover, a decreased ability to sweat may be apparent, particularly in hot climates. Men found to have PAF may have sought advice about urinary tract symptoms (hesitancy, urgency, dribbling, and occasional incontinence). Other signs of dysautonomia, including erectile and ejaculatory dysfunction, an inability to appreciate orgasm, and retrograde ejaculation may be present, too. Women may experience urinary retention or incontinence as early symptoms. In patients with neurally mediated syncope, nausea and pallor, which are prominent signs of autonomic activation, occur before loss of consciousness. In contrast, in patients with PAF, these signs are noticeably absent, and consciousness is lost with little or no warning.⁵¹

Autonomic tests are abnormal: orthostatic hypotension, cardiovagal dysfunction, and hypo- or anhidrosis of the postganglionic type (see “Laboratory Assessment” section). A definitive diagnosis of orthostatic hypotension as the cause of symptoms is made when symptoms are reproduced while declines in systolic blood pressure of at least 20 mm Hg and diastolic pressure of at least 10 mm Hg are documented, within 3 minutes of standing. The diagnosis cannot be excluded with a single measurement of upright blood pressure that does not fulfill these criteria. Several measurements of orthostatic blood pressure, preferably early in the morning or after a meal, may be necessary. Patients with PAF also have decreased sinus arrhythmia and absent blood pressure overshoot during phase IV of the Valsalva maneuver, which indicates parasympathetic and sympathetic efferent dysfunction. PAF affects mainly efferent postganglionic neurons; afferent pathways and somatic neurons are not affected. Nevertheless, there is evidence of a preganglionic disorder in 22% of patients with PAF, which suggests that such patients actually may have some central component.⁴⁴

In terms of differential diagnosis, PAF should be distinguished from other forms of neurogenic orthostatic hypotension, including peripheral somatic neuropathies with autonomic involvement (e.g., diabetes and amyloid), MSA, Parkinson’s disease, and DLB. There are no symptoms or signs of sensory, cerebellar, pyramidal, or extrapyramidal dysfunction in patients with PAF. In general, this allows a clinical distinction from other forms of neurogenic orthostatic hypotension. However, it cannot be determined whether a single patient with PAF will eventually develop more widespread, nonautonomic neuronal damage that leads to a diagnosis of MSA or, in rare cases, DLB. A number of warning signs, or “red flags,” for a clinical diagnosis of MSA have been operationally defined, and their frequency has been determined in a large cohort of European patients with MSA in a natural history study conducted by the European MSA-Study Group. Some of these features that are, if present, suggestive of MSA can be attributed, at least in part, to autonomic nervous system abnormalities. Abnormal respiration occurred in 42% to 60% of patients; its manifestations included inspiratory stridor (19% to 33%), involuntary deep sighs and/or gasps (34% to 37%), sleep apnea (13% to 18%), and excessive snoring (22% to 33%). Rapid eye movement (REM) sleep behavior disorder was present in 35% to 39%. Cold hands and/or feet were noted in 26% to 34%, whereas Raynaud’s phenomenon was recorded in only 6% to 7%.^52,53 Although the specificity and positive predictive value of the red flags for a diagnosis of MSA have not been determined yet, they may serve as useful “soft signs” pointing toward a diagnosis of MSA. Because of the slow disease progression in PAF, most patients probably die before central nervous system involvement can become clinically evident. Apart from dysautonomia, these patients are otherwise normal and have a relatively good prognosis. Complications are usually related to falls and associated disorders.⁵⁴

Parkinson’s Disease and Autonomic Failure

In Parkinson’s disease, extrapyramidal motor problems are the presenting features. Later in the disease process, patients may also suffer severe autonomic failure, which makes the clinical distinction from MSA difficult. As in Parkinson’s disease, some patients with MSA display motor deficits before autonomic failure is apparent, which complicates the distinction further. However, dysautonomia in Parkinson’s disease is rarely as severe as that in MSA. The uncommonly encountered patients with both Parkinson’s disease and autonomic failure are usually older and are often responsive to L-dopa. Although in most cases autonomic failure occurs late, there is a subgroup of patients with Parkinson’s disease who have clinically significant autonomic failure early in the course of the disease. Orthostatic hypotension is often the key clinical feature suggestive of autonomic failure. However, there are many causes of orthostatic hypotension, including side effects of antiparkinsonian therapy (such as L-dopa or selegiline), coincidental disease causing autonomic dysfunction (e.g., diabetes mellitus), or concomitant administration of drugs for an allied condition (e.g., antihypertensives or α-adrenoceptor blockers).⁵⁵ Studies on patients with Parkinson’s disease indicate that selegiline can cause orthostatic hypotension independently of autonomic failure through mechanisms that are not clearly defined.⁵⁶ Together, the confounding effect of antiparkinsonian drugs that often worsens orthostatic hypotension and difficulties in the differential diagnosis (particularly between Parkinson’s disease and MSA) make it difficult to estimate accurately the prevalence of autonomic dysfunction in patients with Parkinson’s disease. Studies that mistakenly include patients with MSA-P may overestimate the frequency of autonomic dysfunction in Parkinson’s disease or underestimate it if patients with both Parkinson’s disease and autonomic dysfunction are diagnosed as MSA-P.⁵⁴

In a retrospective study, almost one third of patients with Parkinson’s disease confirmed with post mortem examination had autonomic dysfunction documented in their clinical records.⁵⁷ However, it has to be kept in mind that this retrospective method may underestimate the frequency of autonomic failure. Actually, bladder dysfunction (such as urgency, frequency, and incontinence) and decreased gastrointestinal motility represent the most frequent autonomic problems in Parkinson’s disease. Constipation is extremely common. Moreover, intestinal pseudo-obstruction and toxic megacolon may occur. Sexual dysfunction (loss of libido and erectile failure) is common in this disorder.⁵⁴

In a study of patients whose Parkinson’s disease was diagnosed by means of clinical criteria, almost two thirds of subjects had orthostatic hypotension with symptoms of cerebral hypoperfusion, including syncope, when tested on a tilt table for 40 minutes or until symptoms developed.⁵⁸ Because patients with normal responses and with orthostatic hypotension were taking similar drug regimens, antiparkinsonian medication was not the main cause of orthostatic hypotension. Senard and colleagues⁵⁹ found a fall of at least 20 mm Hg of systolic blood pressure in almost 60% of patients with Parkinson’s disease. There was symptomatic orthostatic hypotension in 20% of the patients. It was related to duration and severity of the disorder, as well as with the use of higher daily L-dopa and bromocriptine dosages.⁵⁹ A higher prevalence of symptomatic orthostatic hypotension (78%) was found in a retrospective study on patients with neuropathologically confirmed Parkinson’s disease.⁶⁰ In an earlier study, vagal control of the heart and hemodynamic response to standing were impaired and related to duration of the clinical features of Parkinson’s disease.⁶¹

Between 20% and 40% of patients with Parkinson’s disease become demented in the course of their illness.⁶² Operational criteria defining the clinical boundaries between Parkinson’s disease and Parkinson’s disease with dementia (PDD) are lacking, although this distinction may have profound clinical implications for prognosis and treatment strategies.⁶³ The criteria in Diseases and Statistical Manual of Mental Disorders (Fourth Edition, DSM-IV™) are incomplete and descriptive and do not describe several core clinical features associated with dementia in Parkinson’s disease. Peralta and colleagues showed that orthostatic hypotension is more frequent and more severe in patients with PDD than in those with Parkinson’s disease. Attentional scores during tilt testing were also more reduced in patients with PDD in comparison with those with Parkinson’s disease, which suggests that orthostatic hypotension may exacerbate cognitive dysfunction in patients with PDD.⁶⁴

Dementia with Lewy Bodies

DLB is the most frequent cause of degenerative dementia after Alzheimer’s disease. Whether DLB and PDD are the same or different disorders is uncertain.⁶⁵ Clinically, the central feature required for a diagnosis of DLB is progressive cognitive decline, severe enough to cause social and occupational functional impairment. Core features of DLB are fluctuating cognition, recurrent and persistent visual hallucinations, and extrapyramidal motor symptoms. Supportive features may increase diagnostic sensitivity. They include repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, systematized delusions, and hallucinations in other modalities.

The two main differential diagnoses are Alzheimer’s disease and PDD. In order to improve the differential diagnosis of DLB, consensus criteria that establish possible and probable levels of diagnostic accuracy have been developed.^12,66 In general, their sensitivity is variable and low, but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. With the use of operationally defined criteria, DLB can be clinically diagnosed with an accuracy similar to that achieved for Alzheimer’s disease or Parkinson’s disease.

Autonomic failure is frequent in DLB. A retrospective analysis of autonomic symptoms in neuropathologically diagnosed DLB showed that 62% of affected patients had significant autonomic failure.⁶⁷ Patients with DLB may suffer vocal cord palsy, which results in sudden death. However, autonomic function has not been well documented in patients with DLB. Some of the supportive features, including repeated falls, syncope, and transient loss of consciousness, can be attributed in part to autonomic nervous system abnormalities. Orthostasis, either asymptomatic or associated with syncope, may be observed in these patients, although symptomatic orthostatic hypotension has been found in a lower frequency (15%) than in other types of parkinsonism.⁶⁰

Mean age at onset is 75 years; the age range is 50 to 80 years, with a slight male predominance.⁶⁸ Although dementia is the most frequent presenting feature, psychiatric symptoms or transient alterations of consciousness are other early features. Indeed, affected patients may present with recurrent visual hallucinations even without exposure to dopaminergic antiparkinsonian agents and may have marked diurnal fluctuations in cognitive performance, which have been the most difficult feature of the disease to define but are often conspicuous in the environment. Although parkinsonism is common in DLB, occurring at some point during the course of the illness in 75% to 80% of cases,^69,70 a minority of patients present with parkinsonism alone. In general, autonomic features occur later in the course of the disease, but some cases have been described in which dysautonomia was the initial and prominent feature, leading to an initial misdiagnosis of MSA.⁷¹ Fluctuating cognition, probably related to fluctuations in attention, is characteristic of DLB, occurring in 58% of cases at the time of presentation and observed during the disease course in 75%.⁷² The natural history of the neuropsychological changes in DLB is not well characterized, although differences with Alzheimer’s disease appear particularly pronounced in the early stages and lessen as the disease progresses. A rapidly progressive dementia, accompanied by aphasia, dyspraxia, and spatial disorientation suggestive of temporoparietal dysfunction can be seen as the disease progresses. Disability in DLB progresses at a rate similar to that in Parkinson’s disease (approximately 10% decline per year) or even at a significantly faster rate. The latency to onset of orthostatic hypotension in a postmortem series of the National Institute of Neurologic Disorders and Stroke were short in MSA patients, intermediate in patients with DLB, corticobasal degeneration, and progressive supranuclear palsy (PSP) and long in those with Parkinson’s disease.⁶⁰ These data underpin the rapidly progressive nature of the disease process in DLB in comparison with that of Parkinson’s disease. As a result, mean length of survival in a series of patients with DLB confirmed with post mortem examination has been less than 10 years. It is similar to that for Alzheimer’s disease, although some patients with DLB show rapid symptom progression and die within 1 to 2 years of onset. Risk factors for increased mortality in DLB that are present at disease onset include older age, dementia, fluctuating cognition, and hallucinations.⁷³ Strikingly, patients with DLB with neuroleptic sensitivity reactions show a twofold to threefold increase in mortality.

Multiple-System Atrophy

This disease affects both men and women, usually starts in the sixth decade, and progresses relentlessly, with a mean survival length of 6 to 9 years.^74–77 There is considerable variation in disease progression, with survival lengths of more than 15 years in some instances.

Clinically, cardinal features include autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in various combinations. Previous studies suggest that 29% to 33% of patients with isolated late-onset cerebellar ataxia and 8% of patients with parkinsonism eventually develop MSA.^78–80 Of importance, both motor presentations of MSA are associated with similar survival times.⁷⁶ However, patients with MSA-P have a more rapid functional deterioration than do patients with MSA-C.⁷⁴

MSA-P associated parkinsonism is characterized by progressive akinesia and rigidity. Jerky postural tremor and, less commonly, tremor at rest may be superimposed. Frequently, patients exhibit orofacial or craniocervical dystonia in association with a characteristic quivering, high-pitched dysarthria. Postural stability is compromised early on; however, recurrent falls at disease onset are unusual, in contrast to PSP. Differentiating between MSA-P and Parkinson’s disease may be exceedingly difficult in the early stages because of a number of overlapping features such as rest tremor or asymmetrical akinesia and rigidity. Furthermore, L-dopa–induced improvement of parkinsonism may be seen in 30% of MSA-P patients. However, the benefit is transient in most of these subjects, leaving 90% of the MSA-P patients unresponsive to L-dopa in the long term. L-Dopa–induced dyskinesias affecting orofacial and neck muscles occur in 50% of MSA-P patients, sometimes in the absence of motor benefit.⁸¹ In most instances, a fully developed clinical picture of MSA-P evolves within 5 years of disease onset, allowing a clinical diagnosis during follow-up.⁸²

The cerebellar disorder of MSA-C comprises gait ataxia, limb kinetic ataxia, and scanning dysarthria, as well as cerebellar oculomotor disturbances. Patients with MSA-C usually develop additional noncerebellar symptoms and signs but, before doing so, may be indistinguishable from other patients with idiopathic late-onset cerebellar ataxia, many of whom have a disease restricted clinically to cerebellar signs and pathologically to degeneration of the cerebellum and olives.⁷⁸

Dysautonomia is characteristic of both MSA motor presentations, comprising primarily urogenital and orthostatic dysfunction. During the early stages of MSA, autonomic deficits may be the sole clinical manifestation, thus resembling PAF, but after a variable period of time (sometimes 2 or 3 years, always less than 5), extrapyramidal or cerebellar deficits or both invariably develop. Early impotence (erectile dysfunction) is virtually universal in men with MSA, and urinary incontinence or retention, often early in the course or as presenting symptoms, are frequent.⁷⁷ Disorders of micturition in MSA are caused by changes in the complex peripheral and central innervation of the bladder⁸³ and generally occur more commonly, earlier, and to a more severe degree than in Parkinson’s disease. In fact, patients with MSA have early dysuria with or without chronic retention, frequently associated with a hypoactive detrusor muscle and low urethral pressure. In contrast, patients with Parkinson’s disease have urgency to void, with or without difficulty, but without chronic retention, in association with detrusor hyperreflexia and normal urethral sphincter function. Constipation occurs in equal percentages of patients in Parkinson’s disease and MSA. Symptomatic orthostatic hypotension is present in 68% of patients with clinical diagnoses of MSA, but recurrent syncope emerges in only 15%.⁷⁷ L-Dopa or dopamine agonists may provoke or worsen orthostatic hypotension.

Structural Imaging

Routine 1.5-T MRI, including diffusion-weighted imaging, should be performed in all patients with suspected MSA, because basal ganglia and/or brainstem abnormalities suggestive of MSA may be observed even during early disease stages. These changes include an OPCA-like atrophy pattern indistinguishable from autosomal dominant cerebellar ataxia.¹²⁶ MRI measures of basal ganglia pathology in MSA are less well established, and naked eye assessments are often unreliable. In advanced cases, putaminal atrophy may be detectable, and its extent may be correlated with severity of extrapyramidal symptoms.

Abnormalities on MRI may include not only OPCA¹²⁶ or putaminal atrophy¹²⁷ but also signal abnormalities on T2-weighted images. Signal hyperintensities within the pons and middle cerebellar peduncles are believed to reflect degeneration of pontocerebellar fibers; these changes occasionally produce an appearance resembling a hot cross bun.¹²⁷ Nonspecific putaminal hypointensities in patients with atypical parkinsonism, including MSA, were first reported in 1986 by two groups who used 1.5-T T2-weighted images.^128,129 This change has subsequently been confirmed by other authors in cases of pathologically proved MSA.^130–132 Similar MRI abnormalities may occur in patients with classic Parkinson’s disease.¹³³ However, Kraft and colleagues demonstrated that hypointense putaminal signal changes were more frequent in MSA than in Parkinson’s disease, by using T2*-weighted gradient echo instead of T2-weighted fast-spin echo images; this indicates that T2*-weighted gradient echo sequences are of better diagnostic value for patients with parkinsonism.¹³⁴ Increased putaminal hypointensities may be associated with a slitlike hyperintense band lateral to the putamen.^134,135 This finding appears to be more specific for MSA than is putaminal hypointensity^127,136; however, further studies in larger cohorts of patients are needed to confirm this. The hyperintense slit signal was correlated with reactive microgliosis and astrogliosis in a case of pathologically proved MSA.¹³²

Diffusion-weighted imaging may represent a useful diagnostic tool that can provide additional support for a diagnosis of MSA-P. Diffusion-weighted imaging is able to discriminate patients with MSA-P from both patients with Parkinson’s disease and healthy volunteers on the basis of putaminal regional apparent diffusion coefficients (rADC) values.¹³⁷ The increased putaminal rADC values in MSA-P probably reflect ongoing striatal degeneration, whereas most neuropathological studies reveal intact striatum in Parkinson’s disease. However, because rADCs were also significantly increased in both putamen and globus pallidus in PSP in comparison with Parkinson’s disease,¹³⁸ increased putaminal rADC values do not discriminate MSA-P from PSP.

Schulz and associates¹³⁹ found significant reductions in mean striatal and brainstem volumes in patients with MSA-P, MSA-C, and PSP, whereas patients with MSA-C and MSA-P also showed a reduction in cerebellar volume. More recently, voxel-based morphometry confirmed previous region of interest–based volumetric studies¹³⁹ showing basal ganglia and infratentorial volume loss in MSA-P patients.¹⁴⁰ These data also revealed prominent cortical volume loss in MSA-P, comprising mainly the cortical targets of striatal projections such as the primary sensorimotor cortices, lateral premotor cortices, and the prefrontal cortex. MRI-based volumetry is a helpful tool to investigate the progression of cortical and subcortical atrophy patterns in MSA in comparison with other disorders; however, it cannot be applied for routine diagnostic workups of individual patients.

Structural brain imaging with MRI reveals a relative preservation of the medial temporal lobes and the hippocampus in 40% of patients with DLB, in contrast to Alzheimer’s disease.¹⁴¹ There is no difference from Alzheimer’s disease in terms of degree of ventricular enlargement or presence of white matter changes on MRI.¹⁴² MRI shows atrophy of the putamen in DLB but not in Alzheimer’s disease.¹⁴³ Additional features such as generalized atrophy¹⁴¹ and rates of progression of whole-brain atrophy¹⁴⁴ are not helpful in differential diagnosis. In volumetric studies, frontal brain atrophy was described in DLB patients, which was correlated with increasing Lewy body densities.¹⁴⁵ Voxel-based morphometry of gray matter revealed significant atrophy of the basal forebrain in DLB, which discriminates it from Alzheimer’s disease.¹⁴⁶

Functional Imaging

Functional imaging methods for the differential diagnosis of parkinsonian disorders can be divided into investigations of receptor binding and the investigation of glucose metabolism. In studies of receptor binding in disorders with parkinsonism, investigators examine the presynaptic nigrostriatal neurons by evaluating the dihydroxyphenylalanine decarboxylase activity and the dopamine transporter, and they examine postsynaptic dopaminergic function by evaluating the dopamine D₂ receptor. Scintigraphic studies focus on the cardiac sympathetic innervation and are discussed previously. Despite the lack of comparative studies, iodobenzamide (IBZM) and MIBG SPECT, as well as fluorodeoxyglucose PET (when available), appear to be helpful functional imaging tools that may support an early clinical diagnosis of MSA.

PET imaging in MSA reveals a generalized reduction in glucose utilization rate, which indicates hypometabolism, most prominently in the cerebellum, brainstem, striatum, and frontal and motor cortices. In contrast, none of these findings was present in PAF.⁹² In fact, the Hammersmith Cyclotron Unit, using PET, found that putaminal uptake of the presynaptic dopaminergic markers [¹⁸F]fluorodopa and S-[¹¹C]nomifensine^147,148 was similarly reduced in MSA and Parkinson’s disease; in approximately one half the patients with MSA, caudate uptake was also markedly reduced, as opposed to only moderate reduction in Parkinson’s disease. However, discriminant function analysis of striatal [¹⁸F]fluorodopa uptake distinguished patients with MSA from those with Parkinson’s disease poorly.¹⁴⁹ Measurements of striatal dopamine D₂ receptor densities with raclopride and PET failed to differentiate between Parkinson’s disease and atypical parkinsonian disorders, demonstrating a similar loss of densities in patients with advanced Parkinson’s disease, MSA, and PSP.¹⁵⁰ PET studies with other ligands such as [¹¹C]diprenorphine (nonselective opioid receptor antagonist)¹⁵¹ and [¹⁸F]fluorodeoxyglucose^152–154 have proved more consistent in detecting striatal degeneration and in distinguishing patients with MSA-P from those with Parkinson’s disease, particularly when combined with a dopamine D₂ receptor scan.¹⁵⁵ Widespread functional abnormalities in MSA-C have been demonstrated through [¹⁸F]fluorodeoxyglucose and PET.¹⁵⁶ Reduced metabolism was most marked in the brainstem and cerebellum, but other areas such as the basal ganglia and cerebral cortex were also involved, which is evidence of its nosological status as the cerebellar subtype of MSA.

Furthermore, assessing nigrostriatal dopaminergic function with ¹⁸F-fluorodopa PET may be a useful diagnostic aid in cases of DLB, inasmuch as there is a pronounced reduction of striatal dopamine uptake.¹⁵⁷ PET examination of the cerebral glucose metabolism with ¹⁸F-fluorodeoxyglucose demonstrated that among widespread cortical regions showing glucose hypometabolism in patients with DLB, the metabolic reduction was most pronounced in the visual association cortex, in comparison with that in patients with Alzheimer’s disease.¹⁵⁸ Therefore, among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the occipital cortex may be an informative diagnostic aid to distinguish DLB from Alzheimer’s disease.^158,159

SPECT evaluation of the dopamine transporter with 2β-carboxymethoxy-3β-(4-iodophenyl)tropane ([¹²³I]β-CIT) reflects the disruption of the nigrostriatal pathway, and therefore MSA and PSP cannot be distinguished from Parkinson’s disease with this method alone.¹⁶⁰ However, dopamine transporter SPECT may be useful in differentiating parkinsonism from controls.¹⁶¹ In another SPECT study, striatal [¹²³I]β-CIT uptake was markedly reduced in both the patients with Parkinson’s disease and those with MSA,¹⁶² but patients with MSA showed a more symmetrical dopamine transporter loss, consistent with the more symmetrical clinical motor dysfunction observed in this condition.

SPECT studies using [¹²³I]IBZM as D₂ receptor ligand have revealed significant reductions of striatal IBZM binding in subjects with clinically probable MSA in comparison with patients with Parkinson’s disease or controls.^163–165 However, striatal IBZM binding is also reduced in other atypical parkinsonian disorders such as PSP,¹⁶⁴ which limits its predictive value for an early diagnosis of MSA.

IBZM SPECT imaging in patients with early parkinsonism seems to distinguish between L-dopa–responsive and L-dopa–unresponsive parkinsonism in patients not previously treated with dopaminergic drugs.¹⁶⁶ A good response to apomorphine challenge and subsequent benefit from chronic dopaminergic therapy was observed in subjects with normal IBZM binding, whereas subjects with reduced binding failed to respond. Some of these patients developed other atypical clinical features suggestive of MSA during follow-up.¹⁶⁷

Functional neuroimaging with technetium 99m–hexamethylpropyleneamine oxime and SPECT reveals occipital hypoperfusion in DLB, differentiating it from Alzheimer’s disease.^168,169 In DLB, as well as in PDD, bilateral temporal and parietal perfusion deficits have been reported. Dopamine transporter loss in the caudate and putamen, a marker of nigrostriatal degeneration, can be detected by dopaminergic SPECT.¹⁷⁰ [¹²³I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT) and SPECT reveal significant reduction in striatal uptake of a ligand for the presynaptic dopamine transporter site (FP-CIT) in DLB but not in Alzheimer’s disease, and this may prove to be a highly specific and widely applicable diagnostic test.^171,172

Motor Disorder

Treatment of the motor abnormalities is fairly successful in Parkinson’s disease but remains dismal in MSA patients. These patients often do not respond to antiparkinsonian medications and fail to benefit from current surgical treatments for Parkinson’s disease. Although less effective than in Parkinson’s disease, L-dopa replacement represents the mainstay of antiparkinsonian therapy in MSA. However, a sufficiently powered double-blind controlled trial has never been performed. Results of open-label studies suggest that, in contrast to patients with Parkinson’s disease, most patients with MSA fail to benefit from treatment with L-dopa in the long run, although a transient response may occur in some cases. However, the assumption that patients with MSA are generally not responsive or poorly responsive to L-dopa is certainly misleading. L-Dopa responsiveness should be tested by administering escalating doses (with a peripheral decarboxylase inhibitor) over a 3-month period up to at least 1000 mg per day (if necessary and if tolerated).²³ Reports of open-label L-dopa therapy in MSA have documented L-dopa efficacy in up to 80% of patients with clinical diagnoses.^{75,77,81,176–184} Data obtained from series with pathological confirmation are more variable, with rates of beneficial L-dopa response ranging between 30% and 70%.^{32,77,179,185–188} On occasion, a beneficial effect is evident only when seemingly unresponsive patients deteriorate after L-dopa withdrawal.¹⁷⁹ Whatever response there is usually declines after a few years of treatment.¹⁸⁹ The effectiveness of L-dopa on motor symptoms in DLB has not been established but is probably less than in uncomplicated Parkinson’s disease, possibly because there is additional intrinsic striatal pathology and dysfunction.¹⁹⁰ But, although this limited L-dopa responsiveness has generally been reported in DLB, it may reflect either a failure to treat or underdosing, because of concerns about exacerbating psychotic symptoms. In fact, there are reports showing that 70% to 100% of patients with DLB do have a good response.^191–193 In comparison with Parkinson’s disease, L-dopa–related motor complications appear to be less common in DLB. L-Dopa is the preferred antiparkinsonian drug in DLB because dopamine agonists may increase the occurrence of hallucinations.¹⁹⁴ Reviews of the therapeutic values of both dopaminergic and nondopaminergic drugs for the management of the motor disorder in Parkinson’s disease, MSA, and DLB are covered in more detail elsewhere.^195–198

Orthostatic Hypotension

The concept to treat symptoms of orthostatic hypotension is based on the increase of intravasal volume and the reduction of volume shift to lower body parts when a patient changes to an upright position. The selection and combination of the following options, including both nonpharmacological and pharmacological measures, depend on the severity of symptoms and their practicability in the single patient, but not on the extent of blood pressure drop during the tilt-table test. Nonpharmacological options include sufficient fluid intake, high-salt diet, more frequent but smaller meals per day to reduce postprandial hypotension by spreading the total carbohydrate intake, and as the ultima ratio custom-made elastic body garments. During the night, head-up tilt increases intravasal volume up to 1 L within a week, which is particularly helpful in improving hypotension early in the morning. This is achieved by an increased secretion of renin as a result of reduced renal perfusion pressure and by reduced atrial natriuretic hormone levels because of lower atrial filling pressure. This approach is successful, particularly in combination with the mineralocorticoid fludrocortisone, which further supports sodium retention. Indeed, medical treatment begins with attempting to increase blood volume by increasing sodium intake unless the patient is at risk for congestive heart failure or has renal insufficiency. The next group of drugs to use is the sympathomimetics. They include ephedrine (with both direct and indirect effects), which is often valuable in central autonomic failure as occurs in MSA. In fact, ephedrine can be helpful through its peripheral vasoconstrictor effects. With high doses, side effects include tremulousness, loss of appetite, and in men, urinary retention. Orthostatic hypotension is often successfully treated with midodrine,^199–202 an adrenergic agonist activating α₁ receptors on arterioles and veins. Midodrine increases peripheral resistance, thereby significantly reducing orthostatic hypotension. Side effects are usually mild and only rarely lead to discontinuation of treatment because of urinary retention or pruritus predominantly on the scalp. Furthermore, L-threo-3,4-dihydroxyphenyl serine has been used with some success in short clinical trials.²⁰³ It represents a precursor of norepinephrine and has been used for this indication in Japan for years. Mathias and associates showed its efficacy in an open-label, dose-finding trial in patients with MSA and PAF.²⁰⁴ If the above drugs do not produce the desired effect, then selective targeting is needed. The somatostatin analogue octreotide is often beneficial in postprandial hypotension,²⁰⁵ presumably because it inhibits release of vasodilatory gastrointestinal peptides;²⁰⁶ of importance, it does not enhance nocturnal hypertension.²⁰⁵ The vasopressin analogue desmopressin, which acts on renal tubular vasopressin-2 receptors, reduces nocturnal polyuria and improves morning postural hypotension.²⁰⁷ Recombinant erythropoietin, used to reverse the anemia common in MSA, increases upright blood pressure and ameliorates symptoms of orthostatic hypotension^208–211 by secondarily improving cerebral oxygenation.^209,211,212

Supine Hypertension

In more than one half of patients with PAF or MSA, supine hypertension is present, complicating their management. Actually, the treatment of patients with primary autonomic failure is aimed primarily at improving orthostatic hypotension, and the need to treat supine hypertension in these patients is disputed. As a matter of fact, all antihypertensive agents may worsen orthostatic hypotension and trigger symptoms of cerebral hypoperfusion. However, the finding of left ventricular hypertrophy in hypertensive patients with primary autonomic failure suggests that this question should be reconsidered.²¹³ Effective treatment of supine hypertension can be easily accomplished simply by avoiding the supine position, at least during daytime. Sleeping in the head-up tilt position reduces nocturnal sodium loss, which improves orthostatic hypotension in the morning (see previous discussion).^214,215 Although head-up tilt may reduce hypertensive cerebral perfusion pressure, it is often not sufficient to treat supine hypertension. Theoretically, a result similar to that with head-up tilt at night could be obtained pharmacologically by reducing blood pressure with antihypertensive agents. An ideal agent would decrease blood pressure and natriuresis during the night. Furthermore, it would have a short half life, in order to avoid worsening of orthostatic hypotension in the morning.⁵⁴ In any case, supine hypertension does not necessitate drug treatment if systolic blood pressure is below 200 mm Hg. Patients with primary autonomic failure are particularly sensitive to transdermal nitroglycerin.¹²⁴ It can be applied at bedtime and removed on arising in the morning. Short-acting calcium antagonists²¹⁶ such as nifedipine given at nighttime have also been used in PAF. However, nifedipine increased the nocturnal sodium loss in a study by Jordan and colleagues,²¹⁷ and nifedipine but not nitroglycerin worsened orthostatic hypotension in the morning. Oral hydralazine can also be used.⁵⁴

Bladder Dysfunction

Nocturnal voiding frequency can be lessened by curtailing fluid intake after the evening meal. If this is not effective, and if there is no significant postmicturition residual, peripherally acting anticholinergics (oxybutynin, propantheline, or tolterodine) are the initial pharmacological therapeutics to be administered.⁵⁴ Anticholinergic agents alleviate detrusor hyperreflexia or sphincter-detrusor dyssynergy, but commonly at the expense of inducing urinary retention.⁸³ Muscarinic receptors of the detrusor muscle are the common target of anticholinergics, and their M₁, M₂, or M₃ subreceptor profile seems to have little influence on their clinical efficacy. Several anticholinergics are available, but for most cases, clinical use is based on the results of open-label trials. Propantheline bromide is nonselective for muscarinic receptor subtypes and has low bioavailability. It was a first-choice agent for detrusor overactivity in the 1980s but has been largely supplanted by newer agents since. Trospium chloride is a very efficacious nonselective quaternary ammonium compound showing tissue selectivity for the bladder over the salivary glands. Oxybutynin has antimuscarinic, muscle relaxant, and local anesthetic actions. It has been demonstrated to have a higher affinity for muscarinic M₁ and M₃ receptors than for M₂ receptor, but the clinical significance of this is unclear. Side effects are typically antimuscarinic, including dry mouth, constipation, blurred vision, and drowsiness. The administration of desmopressin at night may improve nocturia (see previous discussion). In patients with MSA and incomplete bladder emptying, clean intermittent catheterization three to four times per day is a widely accepted approach to prevent myogenic overdistension and secondary consequences from failure to micturate. In the advanced stages of MSA, a permanent urethral or transcutaneous suprapubic catheter may become necessary, when motor symptoms of MSA or mechanical obstruction in the urethra prevent uncomplicated catheterization. Pharmacological options with cholinergic or adrenergic substances are usually not successful to adequately reduce postvoid residual volume in MSA. However, α-adrenergic receptor antagonists (prazosin and moxisylyte) have been shown to improve voiding with reduction of residual volumes in patients with MSA.²¹⁸ Urological surgery must be avoided in these patients because worsening of bladder control postoperatively is most likely.⁸³

Erectile Dysfunction

The necessity of a specific treatment of sexual dysfunction needs to be evaluated individually in each MSA patient. Sildenafil is an orally active inhibitor of the type V cyclic guanosine monophosphate–specific phosphodiesterase (the predominant isoenzyme in the human corpus cavernosum) and has shown remarkable success in clinical trials.^219–221 In fact, preliminary evidence in patients with Parkinson’s disease²²⁰ suggests that sildenafil citrate may also be successful in treating erectile failure in patients with MSA. A double-blind, placebo-controlled trial confirmed the efficacy of this compound in MSA but also suggested caution because of the frequent cardiovascular side effects.²²¹ Erectile failure in MSA may also be improved by oral yohimbine, by intracavernosal injection of papaverine, or by a penile implant.⁸³ Moreover, erectile dysfunction can be treated with intracavernosal injections or transurethral suppositories of alprostadil, a synthetic prostaglandin E₁.²²² Dopaminergic agents may also help with sexual dysfunction, probably by alleviating bradykinesia, as well as increasing desire. On high doses of antiparkinsonian medication, some patients may become hypersexual—even despite their inability to perform.⁵⁴

Constipation

Constipation affects overall well-being and can be managed with dietary changes, adequate liquid intake, exercise, and pharmacotherapy. In fact, at least two meals per day should include high-fiber raw vegetables. Furthermore, increasing physical activity can also be helpful. Constipation can be relieved by increasing the intraluminal volume, which may be achieved with a macrogol-water solution. Indeed, it is already shown that macrogol 3350 plus electrolytes improves constipation in Parkinson’s disease and MSA.²²³ Stool softeners given with meals can be helpful. Lactulose may be beneficial for some patients. Bowel motility may be increased by discontinuing anticholinergic agents.

REM Sleep Behavior Disorder

In many patients, REM sleep behavior disorder is responsive to low-dose clonazepam. In patients with DLB, precipitation or aggravation of hallucinations with dopaminergic agents may occur. L-Dopa has less of a propensity to cause hallucinations and somnolence and is therefore preferred over dopamine agonists.⁵⁴ Although clonazepam may be regarded as the treatment of choice for REM sleep behavior disorder, an alternative treatment is desirable for affected patients whose condition is refractory to clonazepam, who experience intolerable side effects with clonazepam, or in whom clonazepam precipitates or aggravates obstructive sleep apnea. In a series by Boeve and colleagues,²²⁴ a persistent benefit with melatonin beyond 1 year of therapy occurred in most patients, which suggests that melatonin may be considered as a possible sole or add-on therapy in selected patients with REM sleep behavior disorder.

Cognitive and Psychiatric Problems

In patients with DLB, cholinesterase inhibitor drugs are commonly used for the treatment of cognitive dysfunction. These drugs may reduce hallucinations and other neuropsychiatric symptoms of DLB, too. According to a Cochrane Database review,²²⁵ DLB patients who suffer from behavioral disturbances or psychiatric problems may benefit from rivastigmine if they tolerate it. However, the evidence is weak, and further trials with rivastigmine or other cholinesterase inhibitors in DLB are needed.⁵⁴ Another important issue that has to be kept in mind is that about one third to one half of patients with DLB develop severe side effects when treated with typical or atypical neuroleptics.^191,226,227 The reported side effects include increased rigidity, immobility, confusion, sedation, and postural falls.^{191,226–232} It is not possible to predict these neuroleptic sensitivity reactions in an individual patient before treatment starts. Severe neuroleptic sensitivity probably also occurs in about 25% of PDD patients, and caution in their use is also urged.²³³ Selective serotonin reuptake inhibitors have shown some effectiveness for the management of depression and for behavioral and psychological disorders in patients with dementia (particularly in Alzheimer’s disease).⁵⁴