Fig. 9.1
In patients with Lewy body disease, Lewy bodies and Lewy neurites are observed in not only the central nervous system but also the peripheral autonomic nervous system. The peripheral autonomic nervous system, including sympathetic and parasympathetic nerves, innervates various organs such as the esophagus, the stomach, the intestine, the heart, the urinary bladder, and the skin
9.2 Anatomical Structures Involved in Autonomic Dysfunction
Anatomical structures involved in autonomic dysfunction include: forebrain components, the hypothalamus, brainstem components, spinal cord components, and the peripheral autonomic nervous system [8, 9]. Relevant forebrain structures include the insular cortex, the anterior cingulate cortex, and the amygdala. Brainstem components include the periaqueductal gray matter of the midbrain, parabrachial nucleus, locus coeruleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus, ventrolateral medulla, nucleus ambiguous, and nucleus raphe pallidus. Spinal cord structures include the intermediolateral cell column, the sacral parasympathetic nucleus, and the Onuf nucleus [8]. The peripheral autonomic nervous system includes parasympathetic and sympathetic ganglia, as well as parasympathetic and sympathetic nerves, which innervate various organs.
Different structures of the forebrain can be affected in AD and FTD [10, 11]. The hypothalamus and parts of the brainstem are involved in PD, PD with dementia (PDD), and Lewy body disease [12–14]. Spinal cord structures are involved in incidental Lewy body disease (iLBD), PD, PDD, and DLB [2, 15–18]. In the peripheral autonomic nervous system, Lewy bodies and Lewy neurites are found in various bodily regions. In iLBD, PD, and DLB, Lewy bodies and Lewy neurites can be found in the sympathetic ganglia [1, 2, 16, 19]. In iLBD and PD, Lewy bodies and Lewy neurites can be found in the stomach and distal part of the esophagus [20]. In iLBD patients, Lewy bodies and Lewy neurites are also found in Meissner’s plexus and the sympathetic trunk in 82 % of patients [16] and in the epicardial nerve fascicle in 90 % of patients [21]. In one study, Lewy bodies were also found in the sinoatrial node from 33 to 50 % of patients with Lewy body disease [22]. Degeneration of the cardiac nerve fibers in the right atrium and conducting system of the heart has also been observed in Lewy body disease [23]. Minguez-Castellanos examined surgical specimens from 100 patients without apparent neurological disorder, ranging in age from 44 to 84 years, and reported that α-synuclein aggregates were found in the abdominopelvic autonomic plexuses in 9 % of the whole sample, but were more common in vesicoprostatic (26.1 %) than in digestive tract specimens (3.9 %) [24]. Navarro-Otano examined surgical heart specimens from 91 patients without parkinsonism ranging in age from 31 to 84 years and reported that α-synuclein aggregates were found in the epicardial fat tissues in 7.7 % of the whole sample [25]. Recently, Gelpi performed a postmortem histopathological study of the brain and peripheral tissues from 28 patients. All 15 patients with DLB demonstrated α-synuclein aggregates in the peripheral autonomic nervous system via lesions in the stellate, sympathetic ganglia (100 %), the vagus nerve (86.7 %), gastrointestinal tract (86.7 %), adrenal gland, and/or surrounding fat (53.3 %), heart (100 %), and genitourinary tract (13.3 %) [26]. These reports confirm that lesions of the peripheral autonomic nervous system and parts of the central autonomic system cause various symptoms and abnormal findings upon autonomic testing in patients with DLB, even in the very early stages.
9.3 Autonomic Symptoms
Horimoto and colleagues reported autonomic symptoms and signs in nearly all 29 autopsy-confirmed patients with DLB that they investigated [27]. Prior to death, urinary incontinence was observed in 97 % of the patients, constipation in 83 %, hypotension in 66 %, syncope in 28 %, and urinary retention in 28 %. Some autonomic symptoms occur prior to cognitive decline and are thought to be prodromal symptoms of DLB, including constipation (−9.2 years before onset) and orthostatic hypotension (OH) (−1.2 years before onset) [28]. OH is defined as a reduction of systolic blood pressure (BP) of at least 20 mm Hg or a reduction of diastolic BP of at least 10 mm Hg within 3 min of standing [29]. The defining symptom of OH is syncope. Syncope is the abrupt and transient loss of consciousness associated with the absence of postural tone, followed by complete and usually rapid spontaneous recovery.
9.3.1 Case Presentation
An 81-year-old man had been suffering from severe constipation. He was admitted to the hospital because of paralytic ileus at 71, 75, and 79 years of age. Upon discharge, he was given medicine for constipation. He also had frequency of urination. Around 80 years of age, he started experiencing occasional hallucinations, stumbling while walking, and his head began to bend forward. Visual hallucinations included viewing small bits of garbage as insects and rolled-up cords as snakes. The patient also felt dizziness upon standing up. He came to our hospital and was diagnosed with probable DLB because of dementia (Mini-Mental State Examination score = 23), recurrent vivid hallucinations, parkinsonism, OH, and reduced cardiac MIBG uptake. The results of a Schellong test showed severe OH (Table 9.1). He was successfully treated with donepezil for dementia and hallucination; amezinium for OH; solifenacin for frequency of urination; mosapride, magnesium oxide, and Daikenchuto (a traditional Chinese medicine) for severe constipation; and levodopa/carbidopa for parkinsonism. He showed several autonomic symptoms and signs prior to cognitive/neuropsychological symptoms.
Table 9.1
Schellong test
10 min after the supine position |
BP146/76 mm Hg HR78/m |
Immediately after standing |
BP 73/52 mm Hg HR86/m,dizziness |
1 min) BP 96/63 mm Hg HR86/m |
2 min) BP102/65 mm Hg HR93/m |
3 min) BP111/65 mm Hg HR88/m |
4 min) BP108/69 mm Hg HR89/m |
5 min) BP108/73 mm Hg HR89/m |
Supine |
1 min) BP148/80 mm Hg HR88/m |
2 min) BP157/83 mm Hg HR83/m |
3 min) BP154/80 mm Hg HR82/m |
9.3.2 Cardiovascular Autonomic Symptoms
9.3.2.1 The Control of Blood Pressure
When BP changes, BP is physiologically stabilized by three time-dependent mechanisms. Acutely, both sympathetic and parasympathetic input regulate baroreceptors that can control BP within a few seconds or minutes. Intermediate BP control occurs within a few minutes and can last a few hours and is caused by vasoconstriction due to cardiopulmonary pressure reflexes and the release of vasopressin humoral factor. The renin-aldosterone system exerts long BP control within a few hours and can last days. The acute phase of neurologic control of BP is mainly achieved by the baroreceptor circuit. When a person stands, around 500–800 ml of blood pools in the lower extremities and visceral circulation, which causes reductions in venous return, cardiac output, and arterial BP, which results in the unloading of the baroreceptors. Reduced baroreceptor activity then leads to increased BP in two ways. One is to inhibit the vagal activity of the heart; the other is to stimulate peripheral and cardiac sympathetic activity. Finally, noradrenaline is released from the sympathetic nerve endings, resulting in increased peripheral arterial resistance, heart rate, and contractility of the heart. Neurogenic OH can occur due to disturbances anywhere in this circuit. In a study of patients with limbic or neocortical stage DLB, Lewy bodies and Lewy neurites were found in the ventrolateral medulla, which controls sympathetic output. Despite this, the number of tyrosine hydroxylase- and tryptophan hydroxylase-immunoreactive neurons was not significantly reduced compared to control subjects [14]. Thus, in DLB, OH may be primarily caused by involvement of sympathetic ganglia and postganglionic sympathetic nerves, rather than ventrolateral medulla neurons [14].
9.3.2.2 Symptoms and Signs Related to OH
Syncope can increase the risk for bone fracture or head trauma due to fall. Another symptom of OH is orthostatic intolerance, manifested by transient postural dizziness, lightheadedness, blurred vision, cognitive slowing, fatigue, weakness of the legs, and loss of attention. In elderly subjects, OH may occur in various non-neurogenic conditions such as dehydration and volume depletion and may be caused by various kinds of drugs, including alcohol, alpha blockers (terazosin), antidepressant drugs (selective serotonin receptor reuptake inhibitors, trazodone, monoamine oxidase inhibitors, tricyclic antidepressants), antihypertensive drugs (sympathetic blockers), antiparkinsonism drugs (levodopa, pramipexole, ropinirole), antipsychotic drugs (olanzapine, risperidone), beta-blocker drugs (propranolol), diuretic drugs (hydrochlorothiazide, furosemide), muscle relaxant drugs (tizanidine), narcotic analgesic drugs (morphine), phosphodiesterase inhibitors (sildenafil, tadalafil), and vasodilator drugs (hydralazine, nitroglycerin, calcium channel blockers) [30]. All these conditions may also aggravate preexisting OH [31, 32]. Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) may cause syncope due to bradyarrhythmia [33]. Furthermore, long-standing hypotension may worsen the process of dementia [34, 35]. In patients with DLB, OH is found in 42–70 % [7, 36, 37] and symptomatic OH is found in 31–50 % [7, 36–38] of patients. Syncope is found in 17 % of patients [28] and was found present before death in 28 % of autopsy-confirmed patients with DLB [27]. Patients with persistent OH have a significantly shorter survival time compared to those with no or nonpersistent OH [38]. OH is less frequent in patients with AD and FTD [7].
9.3.2.3 Postprandial Hypotension
Postprandial hypotension (PPH) is a reduction in BP during or after food intake and is sometimes observed in patients with autonomic dysfunction. Symptoms include cognitive slowing, loss of attention, dizziness, and decreased consciousness during or after food intake. PPH can be a risk for aspiration or suffocation. The pathophysiology of PPH is related to splanchnic vasodilation and the release of vasodilatory gut peptides such as neurotensin and is not accompanied by compensatory changes in cardiac output or skeletal muscle resistance vessels [39]. PPH is defined as a reduction of systolic BP of more than 20 mm Hg while being in the supine position [40]. In our studies, the incidence of PPH in DLB was 3/27 (11.1 %) compared to 1/15 (0.07 %) in AD [41]. Figure 9.2 shows a 24-h ambulatory electrocardiogram (ECG) and BP of an 85-year-old man with DLB. PPH is clearly found after breakfast and supper.
Fig. 9.2
The results of a 24-h ambulatory ECG and BP of an 85-year-old man with DLB are shown. They show OH and PPH after breakfast and supper together with SH in sleep. OH orthostatic hypotension, PPH postprandial hypotension, SH supine hypertension
9.3.2.4 Supine (Recumbent) Hypertension
Patients with OH sometimes exhibit hypertension while lying down. This paradoxical hypertension is called supine hypertension (SH) or recumbent hypertension. The exact criteria for SH have not been defined. SH often goes undetected because BP is usually measured only in the seated position; therefore, the actual prevalence of this complication is not known. In an experiment where SH was defined as a systolic BP ≥ 150 mm Hg or diastolic BP ≥ 90 mm Hg in patients with OH, 65 of 117 (56 %) patients with severe autonomic failure like MSA and pure autonomic failure showed SH, despite normal seated and low upright BPs [42]. SH can be severe, and it complicates the treatment of OH. In particular, medications used for the treatment of OH may worsen SH. Possible explanations of SH are impaired baroreflex buffering of the BP, inappropriate natriuresis, higher blood volume, and residual sympathetic tone acting on hypersensitive postsynaptic adrenoreceptors [42–45]. In our studies, the incidence of OH and SH in patients with DLB was 13/27 (48 %) and 4/27 (0.15 %) compared to 1/15 (0.07 %) and 1/15 (0.07 %) in patients with AD, respectively [41]. Figure 9.2 shows a 24-h ambulatory ECG and BP of an 85-year-old man with DLB. SH is shown during sleep.
9.3.3 Urinary Autonomic Symptoms
Normal urinary storage is dependent on the sacral autonomic reflex and is facilitated by several brain regions, including the pontine storage center, the hypothalamus, the cerebellum, the basal ganglia, and the frontal cortex [46]. Normal micturition is dependent on the spino-bulbo-spinal autonomic reflex, which is related to the midbrain periaqueductal gray matter and the pontine micturition center [46]. Bladder dysfunction can occur as a result of deficits in any of these regions. In PD, bladder dysfunction is related to altered dopamine-basal ganglia circuits [47]. This is likely the case in DLB, as well [48]. Urinary autonomic dysfunction includes both storage and voiding dysfunctions.
The symptoms of storage dysfunction are increased urinary frequency during the day and at night (nocturia), urgency, and urge incontinence. The symptoms of voiding dysfunction are difficulty of voiding, residual urine, and urinary retention. In patients with DLB, the frequencies of storage dysfunction symptoms are urgency in 93 % of patients, urge incontinence in 53 %, and overactive bladder in 92 % [49]. These symptoms tend to be much more severe than in PD patients [49]. On the other hand, the symptoms of voiding dysfunction characterized by residual urine are only found in 27 % of patients [48].
9.3.4 Gastrointestinal Autonomic Symptoms
The extrinsic gastrointestinal tract is innervated by the parasympathetic nerve from the dorsal motor nucleus of the vagus in the medulla, the sacral nucleus of the spinal cord, and the paravertebral sympathetic ganglia. Intrinsic innervation of the intestine depends on the enteric nervous system including the Meissner’s and Auerbach’s plexuses. Lewy bodies and Lewy neurites are found in both extrinsic and intrinsic intestinal innervation in PD and DLB [50]. In the gastrointestinal tract, one study showed a rostrocaudal gradient of decreasing Lewy body and Lewy neurite frequency and density, with the lower esophagus and submandibular gland showing the greatest involvement and the colon and rectum showing the lowest [2]. Lewy bodies and Lewy neurites play a significant role in esophageal dysmotility, delayed gastric emptying, and colonic dysfunction [27, 51].
Gastrointestinal autonomic dysfunction includes dysphagia, abdominal distention, fecal incontinence, and constipation. Aggravating factors are dehydration, immobility, a diet low in fiber, and medications such as diuretics, iron, antihypertensive, antipsychotics, anticholinergics, anticonvulsants, and opioids analgesics [51]. In patients with PD, PDD, and DLB, complications include gastric retention, fecal impaction, and paralytic ileus. As described in 9.3.1 case presentation, paralytic ileus can be an initial manifestation of DLB patients. Delayed gastric emptying slows the absorption of levodopa into the duodenum and reduces its bioavailability. Constipation is the most prominent gastrointestinal manifestation [52, 53] and is observed in 28–86 % of patients with DLB [27, 28, 52]. Figure 9.3 shows a chest CT scan of an 83-year-old woman with PDD. She was admitted to our hospital because of vomiting. The CT scan shows retention of foods in the lower esophagus.
Fig. 9.3
A chest CT scan of an 83-year-old woman with PDD is shown. She was admitted to our hospital because of vomiting. The CT scan shows retention of foods in the lower esophagus
9.3.5 Sudomotor Autonomic and Thermoregulatory Symptoms
Thermoregulatory and emotional sweating are controlled by several regions of the central nervous system including the hypothalamus, the limbic areas, and the brainstem, as well as the intermediolateral column of the spinal cord, in the sympathetic ganglia, and the postganglionic fibers to the sweat glands [51]. In DLB, sudomotor dysfunction is related to either central or peripheral lesions, according to the wide distribution of Lewy bodies and Lewy neurites [54]. Ikemura and colleagues reported that phosphorylated α-synuclein immunoreactivity was found in the skin from 20 of 85 autopsy-confirmed patients with DLB. These aggregates were localized to the blood vessels and arrector pili muscles together with what appeared to be eccrine glands [55]. Thermoregulatory dysfunction is caused by sudomotor dysfunction and skin vasomotor dysfunction.
Sweating symptoms include hyperhidrosis, hypohidrosis, or anhidrosis. Hypo- and anhidrosis are usually observed in the extremities, especially lower extremities. Hyperhidrosis is observed in the face, neck, and trunk of patients with DLB and is caused by compensatory mechanisms adjusting for the hypohidrosis and anhidrosis in the extremities [56]. Heat retention can also be observed in patients with Lewy body disease. A 71-year-old man with PD showed high fever (38–39 °C) in July, due to heat retention caused by anhidrosis below the trunk and lower limbs [57]. Slight fever was found in 72 % of autopsy-confirmed patients with DLB [27].
9.3.6 Sexual Dysfunction
The genital organs primarily share lumbosacral innervation with the lower urinary tract [46]. Sexual dysfunction includes erectile dysfunction, ejaculation difficulty, and change in libido [46]. Comprehensive assessment of sexual dysfunction in patients with DLB showed that change of libido was the most frequent symptom [58].
9.3.7 Prodromal Symptoms
In patients with DLB, some symptoms manifest prior to the onset of cognitive decline. Subjects with these symptoms have what is considered prodromal DLB. The DSM-5 has proposed the definition, “mild neurocognitive disorder due to Lewy bodies,” which is roughly equivalent to prodromal DLB [59]. Symptoms of prodromal DLB are divided in three categories: cognitive impairment, behavioral/psychiatric phenomena, and physical symptoms [60]. Physical symptoms include parkinsonism, hyposmia, constipation, and OH. Constipation occurs approximately 9.2 years and OH occurs approximately 1.2 years prior to memory disturbance [28]. Thus, the presence of symptoms and signs associated with autonomic dysfunction is very important to differentiate DLB from other dementias even in the very early stage.
9.4 Autonomic Function Tests
9.4.1 Tests for Orthostatic Dysregulation
There are two kinds of head-up postural challenge tests, which can test for OH. One is the Schellong test and the other is a head-up tilt test. A head-up tilt test is performed using a tilt table. In both tests, each subject is in the supine position for 10 min. In the Schellong test, subjects then stand up by themselves. In the head-up tilt test, subjects are lifted in the head-up position at least 60° using a tilt table within 15 s of lift up (head-up tilt test). When a reduction of systolic BP of at least 20 mm Hg or diastolic BP of at least 10 mm Hg occurs within 3 min after the upright position, they are diagnosed with OH [29]. OH is found in 42–70 % of patients with DLB [7, 36, 37], and symptomatic OH is found in 31–50 % [7, 36–38] of patients.
9.4.2 Heart Rate Variability
Heart rate variability (HRV) is the variation in the time intervals between heartbeats. It is measured by the variation in the beat-to-beat interval using an ECG. HRV parameters include time-domain and frequency-domain variables [61]. Time-domain variables are (1) standardized deviation of all normal-to-normal (NN) (SDNN) intervals as an estimate of overall HRV, (2) root mean square successive differences of NN (RMSSD) intervals as an indicator of parasympathetic activity, and (3) percentage of consecutive RR intervals differing by more than 50 ms (pNN50) as an indicator of parasympathetic activity. Frequency-domain variables are the following: (1) High-frequency domain (HF, 0.15–0.4 Hz) reflects the respiratory sinus rhythm mediated by cardiac vagal control. (2) Low-frequency domain (LF, 0.04–0.15 Hz) is associated with both sympathetic and parasympathetic activity. (3) Very low frequency (VLF, <0.04 Hz) may involve thermoregulatory and peripheral vascular mechanisms. (4) Total spectral power (total power) shows the balance of NN intervals over the temporal segment and the global measure of HRV. (5) The LF/HF ratio may indicate sympathovagal balance [61].
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