CSF acetylcholinesterase levels are reduced in multiple system atrophy with autonomic failure

Diminished CSF levels of acetylcholinesterase in patients with multiple system atrophy attended by autonomic failure suggest that CNS cholinergic involvement may occur in this disorder. The lack of correlation between the low enzyme levels and low CSF levels of monoamine metabolites in these patients indicates that the acetylcholinesterase reduction is not directly related to disruption in these neurotransmitter systems. Normal CSF acetylcholinesterase levels in those patients with pure autonomic failure are consistent with functional integrity of central cholinergic pathways and support a pathophysiologic involvement limited to the peripheral nervous system.     

Laryngeal electromyography in multiple system atrophy with autonomic failure.

In five patients with multiple system atrophy, electromyographic studies using a new surface electrode technique, showed unequivocal evidence of denervation of the posterior crico-arytenoid muscle, and in three of them, of the interarytenoid muscle or crico-pharyngeal sphincter. By comparison, only minor electromyographic abnormalities were found in one-third of patients with other extra-pyramidal syndromes, though in two cases, the abnormalities were of a different kind from those found in multiple system atrophy.     

Urethro-vesical dysfunction in progressive autonomic failure with multiple system atrophy.

Fourteen patients with progressive autonomic failure and multiple system atrophy have been investigated by urodynamic, electromyographic and neurohistochemical means and the results compared with a series of age-matched controls. Three fundamental abnormalities of lower urinary tract function have been identified: (1) Involuntary detrusor contractions in response to bladder filling. It is suggested that these may be the result of a loss of inhibitory influences from the corpus striatum and substantia nigra. (2) Loss of the ability to initiate a voluntary micturition reflex. This may reflect the degeneration of neurons in pontine and medullary nuclei and in the sacral intermediolateral columns. In addition, these studies have demonstrated a significant reduction in the density of acetylcholinesterase-containing nerves in bladder muscle. (3) Profound urethral dysfunction. This appears to be partly due to a loss of proximal urethral sphincter tone, which causes bladder neck incompetence. In addition, the function of the striated component of the urethral sphincter is impaired. Individual motor units recorded from this muscle were clearly abnormal when compared with controls and suggested that reinnervation had occurred. We suggest that this is the result of degeneration of a specific group of sacral anterior horn cells known as Onuf's nucleus. The evidence that these particular motor units are affected, while others are spared, poses fundamental questions about the nature of selective vulnerability in degenerative diseases of the nervous system.     

Low CSF 5-hydroxyindoleacetic acid in schizophrenic patients with enlarged cerebral ventricles

The authors assayed CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations in 24 chronic schizophrenic patients, 9 of whom had enlarged cerebral ventricles according to computerized tomography scans, and in 15 control subjects with neurological disorders. Although there were no overall differences between the schizophrenic patients and the control subjects, schizophrenic patients with enlarged ventricles had significantly lower 5-HIAA concentrations. Also, ventricular size correlated inversely with 5-HIAA concentrations. The findings are consistent with other evidence that cerebral ventricular size is biologically meaningful in schizophrenic patients.     

Nonhomogeneous distribution of 5-hydroxyindoleacetic acid and homovanillic acid in the lumbar cerebrospinal fluid of man

The volume of the lumbar sac measured in 4 subjects was found to be 15.5 ml. Exactly 15 ml of lumbar cerebrospinal fluid (L-CSF) was permitted to flow freely out during a lumbar puncture in 20 neurological patients and small samples of the L-CSF were collected in the beginning (sample 1), at the middle (sample 2), and at the end (sample 3) of this procedure either for 5-HIAA or HVA measurement. The concentrations of 5-HIAA and HVA increased in an exponential manner from sample 1 to sample 3. These results indicate that CSF in the lumbar sac is not a homogeneous fluid as is generally believed and that certain rules have to be followed in the sampling of the L-CSF to obtain reproducible biochemical data.     

Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression

Depressed patients who had attempted suicide (N = 19) had significantly lower CSF homovanillic acid (HVA) levels than patients who had not attempted suicide (N = 8) and control subjects (N = 41). Intergroup levels of 5-hydroxyindoleacetic acid (5-HIAA) were not significantly different. The ratio of CSF HVA to CSF 5-HIAA was significantly lower in both patient groups than in control subjects, and patients who had attempted suicide had CSF HVA/5-HIAA ratios that were nearly 50% those of the control subjects. The combinations of nonsuppression on the dexamethasone suppression test and either a low CSF HVA level or a low CSF HVA/5-HIAA ratio were significantly more common among patients who had attempted suicide than among those who had not.     

Somatic and autonomic function in progressive autonomic failure and multiple system atrophy

We studied 62 consecutive patients with progressive autonomic failure (PAF) or multiple system atrophy (MSA) (26 PAF; 36 MSA). Patients were well matched in age (67 vs 66 years), duration (39 vs 36 months), and severity of autonomic failure (median values for PAF and MSA). Peripheral somatic neuropathy occurred in 2 patients with PAF and 7 patients with MSA. Postganglionic sudomotor and vasomotor functions were studied using the quantitative sudomotor axon reflex test and supine plasma norepinephrine. The extent and severity of autonomic failure were assessed by the thermoregulatory sweat test, by heart rate responses to deep breathing and the Valsalva maneuver, and by blood pressure recordings. Severe and widespread anhidrosis was found in both PAF and MSA patients. Postganglionic sudomotor failure occurred at the forearm in 50% each of PAF and MSA patients and at the foot in 69% and 66% of PAF and MSA patients, respectively. However, postganglionic sudomotor function was preserved in some patients with anhidrosis on thermoregulatory sweat test, indicating a preganglionic lesion. Vagal abnormalities were found in 77% and 81% of PAF and MSA patients. Supine plasma free norepinephrine values were significantly reduced in PAF (p less than 0.001), but not in MSA, patients. Standing plasma norepinephrine values were reduced in both PAF (p less than 0.001) and MSA (p less than 0.001) patients. We conclude the following: (1) PAF is characterized by combined postganglionic sudomotor and adrenergic failure. (2) MSA is associated with a similar frequency of postganglionic sudomotor failure, but postganglionic adrenergic denervation was uncommon. (3) Preganglionic neuron is also involved in both disorders, but more severely in MSA. (4) Somatic neuropathy may occur.     

Differential effect of L-threo-3,4-dihydroxyphenylserine in pure autonomic failure and multiple system atrophy with autonomic failure

Summary Treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-dops), a synthetic precursor of norepinephrine, significantly increased upright blood pressure in patients with multiple system atrophy but had no effect on the upright blood pressure of patients with pure autonomic failure. These results suggest that the site of action of L-threo-dops is central and that its pressor effect requires intact peripheral sympathetic neurons.     

CSF monoamine metabolites in dementia of the Alzheimer type and controls: Evidence for lower levels of homovanillic acid and 5-hydroxyindoleacetic acid in patients

The monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in lumbar cerebrospinal fluid (CSF) were measured in 15 patients with dementia of the Alzheimer type (DAT) and 48 controls by means of a sensitive liquid chromotagraphic method. Relative to a large group of control subjects, the mean CSF 5-HIAA and HVA levels in patients with DAT appeared to be significantly lower. This finding appeared to be sex-related, in that the decrease in CSF monoamine metabolite levels could be attributed predominantly to male patients. A statistically significant relationship was found between 5-HIAA and HVA in both patients and controls. Linear regression analysis revealed a statistically significant positive relationship between age and CSF HVA in female controls only. No relationship was found between 5-HIAA and age either in patients or in controls. It is concluded that CSF 5-HIAA and HVA levels are decreased in male patients with DAT, probably signalling a sex-related change in serotonin and probably dopamine functioning in the central nervous system.     

REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure

Ten patients with primary autonomic failure, followed up in aprospective clinical and laboratory study, were finally diagnosed aspure autonomic failure or multiple system atrophy with autonomic failure. Polysomnographic studies were performed in all patients. Whereas all four patients with multiple system atrophy complained ofsleep related episodes suggesting REM sleep behaviour disorder (RBD)confirmed by polysomnography, RBD remained absent in the remaining sixpatients with pure autonomic failure. The data indicate that RBD is animportant clinical feature, often heralding multiple system atrophy,but which is absent throughout the course of pure autonomic failure;its recognition can thus be useful in the prognostic evaluation ofearly primary autonomic failure syndromes.

     

Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients

Plasma levels of ACTH, cortisol and monoamines were examined in 23 depressed patients and 31 healthy subjects. Patients showed increased plasma cortisol levels, but not plasma adrenocorticotropic hormone (ACTH) levels. The plasma levels of a dopamine metabolite, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), were significantly decreased in the patients. In contrast, the plasma levels of a serotonin (5-HT) metabolite, hydroxyindoleacetic acid (5-HIAA), and 5-HT turnover (5-HIAA/5-HT) were increased in the depressed patients. Therefore, plasma levels of HVA and 5-HIAA are proven to be dissociable. Furthermore, plasma levels of 5-HIAA and L-DOPA have positive relationships with severity of depression. On the basis of this and the previous studies, we speculate that an increase in the plasma 5-HIAA levels might be a compensatory mechanism for stress, whereas 5-HT turnover might reflect depressive state. Taken together, plasma levels of HVA and 5-HIAA, and 5-HT turnover (5-HIAA/5-HT) could be good markers for evaluating depression.     

Decreased CSF levels of homovanillic acid in ALS patients

Levels of homovanillic acid (MVA) were measured in lumbar cerebrospinal fluid from 24 patients affected by amyotrophic lateral sclerosis (ALS) and compared with those found in 11 patients with Parkinson's disease (PD) and 10 patients with lumbar disc herniations who served as controls. Mean HVA levels were significantly decreased in ALS and PD patients. These findings are consistent with impairment of central dopaminergic systems in ALS as well as suggesting degeneration of neuroanatomical structures other than motor neurons.     

Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy

The symptoms caused by or relating to orthostatic hypotension (over 20 mmHg systolic blood pressure) were evaluated using a questionnaire in 72 patients with primary chronic autonomic failure, 32 of whom had pure autonomic failure (PAF, and 40 multiple system atrophy (MSA). The most common posturally related symptoms were dizziness (84% PAF, 83% MSA), syncope (91% PAF, 45% MSA), visual disturbances (75% PAF, 53% MSA) and suboccipital/paracervical ‘coat-hanger’ neck pain (8 l% PAF, 53% MSA). Chest pain occurred mainly in patients with PAF (44% PAF, 13% MSA). Improvement occurred with sitting or lying flat. Non-specific symptoms (weakness, lethargy and fatigue) were common in both groups (91% PAF, 85% MSA); six patients (one PAF, five MSA) had these symptoms only. Postural symptoms (mainly dizziness and neck pain) were worse in the morning and with warm temperature, straining, exertion, arm movements and food ingestion; they were more common in PAF. Compensatory autonomic symptoms, such as palpitations and sweating, did not occur in either group. In conclusion, orthostatic hypotension caused symptoms of cerebral hypoperfusion (syncope, dizziness and visual disturbances); neck pain, presumably due to muscle hypoperfusion, also occurred frequently. These symptoms were exacerbated by various factors in daily life and were relieved by returning to the horizontal. Non-specific symptoms (such as fatigue) also were common. In MSA, despite substantial orthostatic hypotension, fewer patients had syncope, visual disturbance and neck pain; the reasons for this are unclear. Lack of these features does not exclude the need to assess and investigate orthostatic hypotension and possible autonomic failure. Received: 12 December 1998 Received in revised form: 18 February 1999 Accepted: 17 March 1999     

Sympathetic skin response and cardiovascular autonomic function tests in Parkinson's disease and multiple system atrophy with autonomic failure.

The relationship between sympathetic skin response (SSR) and cardiovascular autonomic function tests (CVTs) was investigated in 15 patients with idiopathic Parkinson's disease (PD), 15 patients with clinical evidence of multiple system atrophy (MSA) with autonomic failure, and in 15 healthy control subjects. SSR was elicited by electrical stimulation of the right and left median nerves and simultaneously recorded on the palms of both hands. CVTs included the following sympathetic and parasympathetic tests: orthostatism, head-up tilt, cold pressor test, deep breathing, Valsalva maneuver, and hyperventilation. The SSR was normal in all patients with PD and control subjects but was abnormal or absent in all patients with MSA. For patients with MSA, SSR latency was significantly longer and amplitude was significantly smaller than that of patients with PD and control subjects. For patients with PD, SSR did not differ from that of control subjects. In these patients, SSR latency was significantly longer and SSR amplitude was smaller when the side with more marked motor symptoms was stimulated, both ipsilaterally and contralaterally to the side of stimulation. A statistically significant difference in SSR latencies and amplitudes was found between patients with PD and control subjects only when motor asymmetries were considered. CVTs showed severe sympathetic and parasympathetic hypofunction in patients with MSA, but not in patients with PD or control subjects. No correlation was found between SSR and CVTs that assess sympathetic function in patients and control subjects. SSR is indicated as an additional test for the evaluation of sympathetic degeneration in patients with MSA.     

Cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid in the pediatric opsoclonus-myoclonus syndrome

To study the purported role of central monoamine disturbances in the pathophysiology of the opsoclonus-myoclonus syndrome, the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid were measured in cerebrospinal fluid samples from 27 affected children and 47 age- and gender-matched control subjects by high-pressure liquid chromatography with elecrochemical detection. 5-Hydroxyindoleacetic acid and homovanillic acid concentrations in the cerebrospinal fluid were approximately 30 to 40% lower in opsoclonus-myoclonus patients compared to control subjects, and the normal inverse correlation between age and monoamine metabolite concentrations in the cerebrospinal fluid of control subjects was not found in opsoclonus-myoclonus patients. Patients with the lowest values were less than 4 years old, and a subgroup had extremely low levels, but differences in older children were not significant. Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and homovanillic acid were more positively correlated in control subjects than in opsoclonus-myoclonus patients. None of the patients exhibited high levels of monoamine metabolites. Homovanillic acid levels were slightly lower in the cerebrospinal fluid of patients receiving corticotropin or steroids at the time of lumbar puncture. Clinical variables that could be excluded were paraneoplastic etiology, anesthetic for lumbar puncture, syndrome duration, age at onset, gender, response to steroids, length of time until initiation of corticotropin or steroids, presence of seizures, opsoclonus, and functional impairment. These data suggest a disturbance and possible altered ontogeny of serotonin or dopamine neurotransmission in a subpopulation of children with opsoclonus-myoclonus with low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and homovanillic acid. Biochemical heterogeneity for this clinical phenotype may have implications for responsiveness to treatment with serotonergic and other drugs.