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 "Autonomic dysfunction in dementia" (7/07 journal 
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Post "Autonomic dysfunction in dementia" (7/07 journal
This abstract was recently published on PubMed. It is about British assessments of autonomic function in those with DLB, PDD (Parkinson's disease dementia), AD, and VAD (vascular dementia). The researchers concluded: "Autonomic dysfunction occurs in all common dementias but is especially prominent in PDD with important treatment implications."

Here's the abstract (see pubmed.gov):

Journal of Neurology, Neurosurgery, and Psychiatry. 2007 Jul;78(7):671-7. Epub 2006 Dec 18.

Autonomic dysfunction in dementia.

Allan LM, Ballard CG, Allen J, Murray A, Davidson AW, McKeith IG, Kenny RA.
Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, UK.

BACKGROUND: There are no studies of autonomic function comparing Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).

AIMS: To assess cardiovascular autonomic function in 39 patients with AD, 30 with VAD, 30 with DLB, 40 with PDD and 38 elderly controls by Ewing's battery of autonomic function tests and power spectral analysis of heart rate variability. To determine the prevalence of orthostatic hypotension and autonomic neuropathies by Ewing's classification.

RESULTS: There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. PDD showed consistent impairment of both parasympathetic and sympathetic function tests in comparison with controls (all p<0.001) and AD (all p<0.03). DLB showed impairment of parasympathetic function (all p<0.05) and one of the sympathetic tests in comparison with controls (orthostasis; p = 0.02). PDD had significantly more impairment than DLB in some autonomic parameters (Valsalva ratio: p = 0.024; response to isometric exercise: p = 0.002). Patients with VAD showed impairment in two parasympathetic tests (orthostasis: p = 0.02; Valsalva ratio: p = 0.08) and one sympathetic test (orthostasis: p = 0.04). These results were in contrast with AD patients who only showed impairment in one sympathetic response (orthostasis: p = 0.004). The prevalence of orthostatic hypotension and autonomic neuropathies was higher in all dementias than in controls (all p<0.05).

CONCLUSION: Autonomic dysfunction occurs in all common dementias but is especially prominent in PDD with important treatment implications.

PubMed ID#: 17178816


I read this full article today. It had more to say on the subjects of symptoms of autonomic failure, similarities and differences in PDD and LBD, the debate about the diagnostic concepts of PDD and DLB, cholinergic dysfunction as a potential cause of autonomic dysfunction (with a related note on Aricept), and the need to study various treatments for preventing falls (due to orthostatic hypotension, a symptom of autonomic failure).

Here are some excerpts that I found interesting:

"Patients with autonomic failure experience disabling postural dizziness, syncope, falls, constipation, and incontinence."

"...the most common dementia subtypes in the elderly (are) Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD)."

"A generalised deficit in cholinergic function would be expected to lead to autonomic dysfunction, and the common dementias have all been associated with underactivity of the cholinergic nervous systems."

"...(Autonomic) failure is a feature of Parkinson's disease."

"We examined autonomic function using a combination of standardised bedside clinical testing and heart rate variability techniques...in comparison with appropriately matched elderly controls. ... We hypothesised that autonomic dysfunction would be more severely impaired in DLB and PDD than in AD, and that the most severe impairment would be present in PDD because of the length of illness and severity of neurodegenerative disease."

"Patients with PDD met...DLB consensus criteria, with motor disorder preceding dementia by at least 12 months."

"Cognitive function was assessed using the...CAMCOG. All assessments took place in the morning."

"Clinical autonomic function tests were carried out according to Ewing's battery."

"Sustained orthostatic hypotension was defined as a fall in systolic blood pressure of greater than 20 mm Hg or diastolic blood pressure of greater than 10 mg Hg which did not return to baseline within 30 s from the start of the active stand."

"There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction."

"The prevalence of autonomic neuropathy, as measured by the Ewing criteria, was more common in all of the dementia subtypes than in controls, but was especially prominent in PDD."

"PDD and DLB cases both showed evidence of parasympathetic dysfunction on clinical testing and, apart from the Valsalva ratio, the degree of impairment was similar. ... (This) study...suggests that there is significant central autonomic involvement of the dorsal vagal nucleus in both conditions."

"...(On) sympathetic testing, patients with PDD were more impaired than patients with DLB... This raises the possibility that there may be a differential susceptibility and order of involvement of central and peripheral autonomic neurons to Lewy body pathology in DLB and PDD. This needs to be addressed in comparative neuropathological studies of the autonomic nervous system, but highlights a potentially important pathological difference between the two conditions."

"There has been considerable debate about the diagnostic concepts of PDD and DLB. It has been suggested that in PD, Lewy body pathology begins in the brainstem and progresses to the neocortex. However, there may be a different pattern of evolution in DLB, with some studies suggesting that cerebro-cortical pathology predominates in DLB, although prominent Lewy body pathology is still evidence in the brainstem..."

"Inevitably, patients with PDD were taking a higher dose of levodopa, reflecting the duration of their disease. In comparisons between PDD and DLB, use of levodopa and dose are not constantly correlated, but the correlation is strong. ... However, this does not necessarily mean that differences between PDD and DLB were solely due to the pharmacological effect of levodopa. It is more likely that they are measuring a similar variable, namely the extent of brainstem disease, as opposed to cortical disease."

"The origin of sympathetic dysfunction in Lewy body diseases has been thought to be mainly a result of peripheral sympathetic denervation." Cardiac (123)I-MIBG "scintigraphy and neuropathological studies have found evidence of cardiac denervation in PD and DLB."

"...the current study identifies an increased prevalence of orthostatic hypotension in all dementias. ...(Autonomic) dysfunction was possibly an attributable cause of orthostatic hypotension... No studies have compared the effects of sustained orthostatic hypotension on the risk of falls in different types of dementia. Our findings highlight...the need for further research into sustained orthostatic hypotension as a modifiable risk factor for falls. In elderly people without cognitive impairment, simple measures such as adequate hydration, support hosiery and pharmacological treatments such as fludrocortisone and midodrine can be used to manage orthostatic hypotension, as part of (an)...intervention to reduce the risk of falls."

"Cholinergic dysfunction has been discussed as a potential cause of autonomic failure in patients with dementia, and may be particularly important in PDD and DLB, where cholinergic deficits are especially pronounced... (It) will be important to determine the impact of cholinesterase inhibitor therapy in patients with dementia with autonomic impairment. Preliminary reports suggest an adverse effect of donepezil on autonomic function, leading to carotid sinus hypersensitivity and falls in some individuals. The general impact of cholinesterase inhibitors on autonomic function is difficult to determine from the existing clinical literature..." (Robin's note: donepezil = Aricept)

"Although controls were slightly older than the PDD groups, this strengthens the finding that dysautonomia is most impaired in PDD..."

"...(We) are able to conclude that there is no substantial dysautonomia in VAD."

"The high prevalence of autonomic neuropathy and sustained orthostatic hypotension in dementia has potentially important implications for patient management."

That's it!
Robin


Wed Jul 04, 2007 4:54 pm
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So if I'm understanding this, Aricept is contra indicated for a patient with cardiovascular autonomic dysfunction, which is most worrisome for my father. He worries about the variations in his heartbeat and it wakes and keeps him up. His irregular heartbeat is also the reason for the trips to the ER, although those have slowed down lately.
I was hoping the Aricept would help him with the dementia symptoms.
Rita


Wed Aug 01, 2007 11:59 pm
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Hi Rita,

This seems to be the key paragraph:
"Cholinergic dysfunction has been discussed as a potential cause of autonomic failure in patients with dementia, and may be particularly important in PDD and DLB, where cholinergic deficits are especially pronounced... Preliminary reports suggest an adverse effect of donepezil on autonomic function, leading to carotid sinus hypersensitivity and falls in some individuals. The general impact of cholinesterase inhibitors on autonomic function is difficult to determine from the existing clinical literature..."

The reference for the statement "Preliminary reports suggest...." is:
McLaren AT, Allen J, Murray A, et al
Cardiovascular effects of donepezil in patients with dementia
Dementia and Geriatric Cognitive Disorders 2003;15:183-8.

Are you working with a cardiologist who specializes in autonomic dysfunction? I'd suggest giving that referenced paper to the cardiologist and ask him for his opinion as to whether it's an issue in your case.

Another drug that effects cognitive symptoms that is not an AChEI is Namenda. My guess is that there are no studies of Namenda's effect on autonomic function or cardiovascular autonomic function. You could try a PubMed search (pubmed.gov) with those key terms to find out.

Robin


Thu Aug 02, 2007 12:34 am
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Location: Seattle, WA
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Irregular heartbeat can have a zillion other causes - there's an age-related risk of atrial fibrilation, for example, independent of neurological conditions.

Research, especially coming out of Asia, is showing electrical changes in the heart as a result of Lewy bodies, but it's early-stage research, and yes, acetylcholine does play a role in heart regulation.

With any drug there are risks and benefits, but overall, in DLB, the *only* agent that is marketed as effective treatment is a cholinesterase inhibitor.

Eric

_________________
Cal is not the real name of a real 84 year old with DLB. I don't speak for LBDA, nor do I have clever initials behind my name, so information is provided without warranty. Caveat everybody. I blog at http://PragmaticCaregiver.blogspot.com


Thu Aug 02, 2007 1:38 pm
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Today's post is about an '04 article that looks at autonomic dysfunction in DLB, MSA, and PD. The authors state: "(A) comparison of the degree of autonomic involvement among [DLB, MSA, and PD] may additionally aid in the correct diagnosis. The main findings of the present study are that symptoms of orthostatic intolerance are common in all three conditions. However, the severity and distribution of autonomic failure is quite different, with MSA being the most, PD the least severely affected, with DLB having intermediate severity. The latency from onset to disease to orthostatic hypotension appears to be delayed in DLB."

What follows is the abstract (from pubmed.gov) and excerpts on the '04 article.

Robin


Neurology. 2004 May 25;62(10):1804-9.

Autonomic dysfunction in dementia with Lewy bodies.

Thaisetthawatkul P, Boeve BF, Benarroch EE, Sandroni P, Ferman TJ, Petersen R, Low PA.
Department of Neurology, Mayo Clinic, Rochester, MN.

OBJECTIVE: To assess autonomic function in patients with dementia with Lewy bodies (DLB).

METHODS: The authors compared data from 20 DLB patients evaluated from 1995 to 2000 to 20 age-matched multiple system atrophy (MSA) and Parkinson disease (PD) patients evaluated from 1999 to 2002. Analysis of variance, Fisher exact test, and Student t-test were applied to compare disease characteristics, autonomic symptoms, and function tests on the Composite Autonomic Scoring Scale (CASS) and Thermoregulatory Sweat Test (TST).

RESULTS: In DLB, mean age at onset of autonomic symptoms was 70.3 +/- 8.9 years. Orthostatic symptoms were common and orthostatic hypotension occurred in 10/20 DLB, 17/20 MSA, and 1/20 PD patients (p = 0.023, 0.003). CASS-sudomotor for DLB, MSA, and PD were 1.6 +/- 1.2, 2.5 +/- 0.7, and 0.9 +/- 0.8 (p < 0.00001). CASS-cardiovagal were 1.4 +/- 0.9, 2.1 +/- 0.8, and 0.7 +/- 0.6 (p < 0.00001). CASS-adrenergic function were 2.4 +/- 1.2, 3.5 +/- 0.9, and 0.5 +/- 0.6 (p < 0.00001). Total CASS were 5.2 +/- 2.0, 8.1 +/- 1.3, and 2.2 +/- 1.2 (p < 0.00001). The most common pattern of TST in DLB was distal anhidrosis. Mean duration of follow-up was 3.0 +/- 1.8 years. Six patients needed medication to maintain blood pressure and five had good response.
[Robin's note....when they say "six patients," they are referring to the six DLB patients who needed medication.]

CONCLUSIONS: Autonomic dysfunction is frequent in dementia with Lewy bodies and the severity is intermediate between that of multiple system atrophy and Parkinson disease.

PubMed ID#: 15159482


Here are excerpts:

In DLB, "autonomic dysfunction can occur and is actually included as a supportive feature for clinical diagnosis."

Study participants were either diagnosed as probable DLB, probable MSA, or clinically definite PD (with some modified criteria).

"Autonomic function tests evaluated the severity and distribution of sudomotor, cardiovagal, and adrenergic deficits. The Thermoregulartory Sweat Test (TST) defined the distribution of anhidrosis. Severity of anhidrosis was quantitated as loss of sweating area (0 to 100%)."

"The autonomic reflex screen was performed and consisted of five components.
1. Quantitative Sudomotor Axon Reflex Test (QSART): one upper and three lower limb sites.
2. Orthostatic blood pressure and heart rate response to head-up tilt.
3. Heart rate response to deep breathing.
4. The Valsalva ratio.
5. Beat-to-beat BP measurements during the Valsalva maneuver, tilt, and deep breathing."

"The Composite Autonomic Severity Score (CASS) is a score of the severity and distribution of autonomic deficits (adrenergic, sudomotor, cardiovagal) demonstrated in the autonomic studies that corrects for the confounding effects of age and sex."

"All DLB subjects underwent the Kokmen Short Test of Mental Status (STMS) within weeks before or after autonomic testing, in which a score above 29 is considered within normal limits, and a score of 20 to 29 is considered consistent with mild to moderate cognitive impairment. The median score on the STMS was 28 (range 17 to 38), with all but two patients scoring 21 or higher, reflecting mild to moderate impairment in almost every subject."

"Five (25%) of the DLB subjects were taking carbidopa/levodopa. The mean dose was 280 mg. ... Ten out of 20 patients with PD took carbidopa/levodopa... The mean dose of L-dopa was 565 mg. ... In the MSA group, only three patients took carbidopa/levodopa and only two patients were taking vasoactive drugs near the time of testing."

"In the DLB group, the age of onset of neurologic and autonomic symptoms was 65.6 +/- 8.2 and 70.3 +/- 8.9 years. At initial evaluation, Hoehn & Yahr scale of DLB was not different from PD but was less than that of MSA. In the DLB group, the most common neurologic symptom was parkinsonism and cognitive impairment (20/20)."

"Autonomic symptoms occurred in 19 (95%) DLB, 20 (100%) MSA, and 12 (60%) PD patients. The most common autonomic symptom was orthostatic symptom (OS), which occurred in 17 DLB patients. However, the number of DLB patients who developed orthostatic hypotension was only 10. The severity of adrenergic impairment in DLB patients with OS varied [with 5 (29%) patients with an adrenergic index at 4]. In contrast, 10 (78%) MSA patients with OS had adrenergic index at 4 and all 6 PD patients with OS had adrenergic index at 1. Interestingly, 5 (72%) MSA patients without OS symptoms had adrenergic index at 4. That finding did not occur in any DLB or PD patients."

"Urinary symptoms were recorded in 7 (35%) DLB, 14 (70%) MSA, and 5 (25%) PD patients. Symptoms of neurogenic bladder were recorded in 1 (5%) DLB patient, 13 (65%) MSA patients, and 1 (5%) PD patient. All but three MSA patients with symptoms of neurogenic bladder had a urodynamic study confirming the dysfunction. Self-catheterization was carried out by one DLB, one PD, and seven MSA patients. No patient was recorded to have fecal incontinence. There was no difference in incidence of impotence, dry eyes, and dry mouth between DLB, MSA, and PD patients. Only one DLB patient had symptoms of sweat loss."

"Out of nine domains of autonomic symptoms recorded (OS, neurogenic bladder, urinary incontinence, fecal incontinence, constipation, impotence, sweat loss, dry eyes, and dry mouth), 4 (25%) DLB patients had three or more domains involved compared to 12 (60%) MSA patients and 1 (5%) PD patient.

"Thirteen DLB, 17 MSA, and 7 PD patients had TST. ... However, only one DLB patient had global anhidrosis compared to seven MSA patients and one PD patient. The most common abnormal TST pattern in DLB was distal pattern, found in 7 (54%) patients, while in MSA the most common pattern was global pattern (41%)."

"Of the patients with symptoms of orthostatic intolerance, 6 (35%) in the DLB group required specific treatment with one or two types of medications (two used fludrocortisone acetate only, two used midodrine only, and two used both) compared to 11 (85%) in the MSA group and none in the PD group. In those who used medications, all 6 (100%) DLB patients with OS responded to treatment while only 4 (37%) MSA patients responded. Eleven DLB patients with OS responded well to fluid and postural management."

"Five DLB patients were deceased by the time the study was conducted, two of whom had autopsy done. The autopsy in one case...showed combined neocortical Lewy body and Alzheimer pathology. The other case's autopsy showed neocortical Lewy body disease."

"(A) comparison of the degree of autonomic involvement among [DLB, MSA, and PD] may additionally aid in the correct diagnosis. The main findings of the present study are that symptoms of orthostatic intolerance are common in all three conditions. However, the severity and distribution of autonomic failure is quite different, with MSA being the most, PD the least severely affected, with DLB having intermediate severity. The latency from onset to disease to orthostatic hypotension appears to be delayed in DLB. We used the CASS score to quantify severity and distribution of autonomic dysfunction, since it has been shown to differentiate PD from MSA."

"Although dopaminergic agents can act on central structures to augment sweating, tests of sudomotor and cardiovagal deficit should be unaffected."

"The most common autonomic symptom in DLB was orthostatic intolerance. Compared to PD, the frequency of orthostatic intolerance was greater in DLB but was comparable to MSA. ... Most MSA patients with orthostatic symptoms needed medications while most DLB patients responded to volume expansion alone. When the DLB patients were treated, they responded better to medications than MSA patients, providing support that the autonomic deficits were less severe overall."

"Frequency of urinary symptoms in DLB was comparable to that of PD but much less than MSA. The highest frequency of neurogenic bladder in MSA patients relates to the almost uniform finding of para-sympathetic cell loss in the sacral intermediolateral cell column. Detrusor hyperreflexia is caused by loss of inhibitory input to pontine micturition center and urinary sphincter tone is affected by degeneration of Onuf's nucleus in the sacral spinal cord. In PD, urinary incontinence was also common. A videourodynamic study showed that detrusor hyperreflexia was frequent in PD."

"The pattern of sweat loss shown by TST in DLB was comparable to PD with predominantly distal involvement and greater median percentage of area involved. In MSA, the most common pattern was global anhidrosis. In general, if TST is abnormal and QSART is normal, this indicates a central preganglionic autonomic sweat problem. ... This may mean that sweat problem in DLB is peripheral in origin, a finding that is consonant with a recent report showing postganglionic denervation of the heart. However, in sweat loss due to a longstanding central autonomic problem, QSART could be abnormal as well due to transsynaptic effects."

"The role of Lewy bodies in autonomic dysfunction in primary progressive autonomic failure and PD has been clarified by many reports that showed the presence of Lewy bodies in autonomic ganglia, intermediolateral cell column, and autonomic brainstem nuclei associated with degeneration of intermediolateral cell columns in those patients who had had symptoms of autonomic failure in their lives. In MSA with autonomic faiilure, depletion of catecholaminergic neurons of the rostral ventrolateral medulla has been found, although this finding was not consistent in PD. There has been no report on the lesion of brainstem nuclei that cause autonomic failure in DLB. This warrants more clinicopathologic correlation studies on autonomic aspects of DLB. In our DLB patients, plasma NE studies revealed patterns that are suggestive of both central and peripheral autonomic involvement, although the number of tests was limited."


Fri Aug 24, 2007 10:10 pm
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