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Autonomic failure in the degenerative processes of the central nervous system: a critical reappraisal
39
SIS
Autonomic Failure in the Degenerative Processes of the Central Nervous System: a Critical Reappraisal G. Micieli, A. Cavallini, E. Martignoni and G. Nappi Autonomic Unit, III Department of Neurology, 'C. Mondino' Foundation, University of Pavia, Italy
Primary autonomic failure (AF) may characterize a wide spectrum of different degenerative processes defined by a disordered neurovegetative adaptability associated (or not) with signs and symptoms of pyramidal, extrapyramidal, cerebellar and/or 2nd motor neuron disturbances. Although various studies have attempted to describe the distinctive characteristics of 'pure' AF, AF associated with parkinsonism (AF plus PD) or with multiple system atrophy (AF plus MSA, better known as ShyDrager syndrome), many aspects of these pathological entities still remain unclear. An authentic optimization of the diagnostic process can best be realized by accurate clinical assessment. However, the characteristics of autonomic involvement (marked and with early onset in Shy-Drager syndrome, slight and slowly evolving in 'idiopathic' PD, severe and sometimes quickly disabling in 'pure' AF) may offer a key to differential diagnosis, together with experimental investigations (BP/HR and plasma catecholamine (CA) responses, temperature monitoring, sweating pattern, pupillometry) thus demonstrating a mainly central location of the lesion site in MSA plus AF and a more peripheral involvement in 'pure' AF. Pathological analysis demonstrates the presence of Lewy bodies, a typical finding in 'idiopathic' PD, in AF 'pure' and/or associated with PD. Lewy bodies are nearly always absent however in patients with MSA. AF is often characterized by a more or less selective loss of intermediolateral column cells (also present in cases of MSA without AF),
and a loss of neurons of the dorsal nucleus of the vagus, the Edinger-Westphal nucleus and the Onuf nucleus. All AF patients show significant orthostatic and post-prandial systolic fall; CA levels, however, may be normal in patients with MSA plus AF and reduced (or undetectable) in those with 'pure' AF. The latter exhibit a clear 'denervation' supersensitivity, while the former denote an increased sensitivity to pressor agents due to 'decentralization' phenomena. Untreated PD patients more frequently show only slight autonomic involvement and plasma CA levels are intermediate between 'pure' AF and MSA plus AF. In idiopathic parkinsonism, the phenomenon of post-prandial hypotension is detectable in over the two/thirds of the cases and is predictive of a lower tolerance (orthostatic hypotension) to dopaminergic drugs, at least in the early stages of treatment. MSA patients exhibit a contemporary reduction of noradrenaline (NA), MHPG and NPY CSF levels, while untreated PD show low CSF NE and NPY, but not MHPG concentrations. These data suggest the existence of widespread degenerative processes involving the basal ganglia and the CAergic nuclei of the brainstem in MSA plus AF. Other sophisticated approaches have been developed using pharmacological testing which evaluates the response of plasma vasopressin to hemodynamic stimuli and cardiopressor, CAergic and opioid response to insulin-induced hypoglycemia
40 or the release of plasma CA after intravenous edrophonium or clonidine administration. All of these tests have documented different patterns in 'pure' AF, in AF plus PD or in AF plus MSA and thus represent much better tools for differentiating the level (central/peripheral) of autonomic involvement than the simple cardiovascular tests currently used in the assessment of autonomic functioning. Due to the great variability of these test responses, however, only an adequate clinical, pharmacological and instrumental follow-up can provide an exact diagnosis in the majority of the cases.
Autonomic failure can manifest, as a matter of fact, different degrees of severity (and time of onset of different signs/symptoms) in the 'same' pathological entity and thus the instrumental evidence may reflect this great variability of clinical features. On the other hand, in spite of this variability, the degenerative processes of the CNS which define MSA or idiopathic PD or 'pure' AF appear to be a pathological 'continuum' where a severe autonomic involvement may in many cases be considered a predictive marker of a negative outcome of the disease.
SIS
Autonomic Failure in the Degenerative Processes of the Central Nervous System: a Critical Reappraisal G. Micieli, A. Cavallini, E. Martignoni and G. Nappi Autonomic Unit, III Department of Neurology, 'C. Mondino' Foundation, University of Pavia, Italy
Primary autonomic failure (AF) may characterize a wide spectrum of different degenerative processes defined by a disordered neurovegetative adaptability associated (or not) with signs and symptoms of pyramidal, extrapyramidal, cerebellar and/or 2nd motor neuron disturbances. Although various studies have attempted to describe the distinctive characteristics of 'pure' AF, AF associated with parkinsonism (AF plus PD) or with multiple system atrophy (AF plus MSA, better known as ShyDrager syndrome), many aspects of these pathological entities still remain unclear. An authentic optimization of the diagnostic process can best be realized by accurate clinical assessment. However, the characteristics of autonomic involvement (marked and with early onset in Shy-Drager syndrome, slight and slowly evolving in 'idiopathic' PD, severe and sometimes quickly disabling in 'pure' AF) may offer a key to differential diagnosis, together with experimental investigations (BP/HR and plasma catecholamine (CA) responses, temperature monitoring, sweating pattern, pupillometry) thus demonstrating a mainly central location of the lesion site in MSA plus AF and a more peripheral involvement in 'pure' AF. Pathological analysis demonstrates the presence of Lewy bodies, a typical finding in 'idiopathic' PD, in AF 'pure' and/or associated with PD. Lewy bodies are nearly always absent however in patients with MSA. AF is often characterized by a more or less selective loss of intermediolateral column cells (also present in cases of MSA without AF),
and a loss of neurons of the dorsal nucleus of the vagus, the Edinger-Westphal nucleus and the Onuf nucleus. All AF patients show significant orthostatic and post-prandial systolic fall; CA levels, however, may be normal in patients with MSA plus AF and reduced (or undetectable) in those with 'pure' AF. The latter exhibit a clear 'denervation' supersensitivity, while the former denote an increased sensitivity to pressor agents due to 'decentralization' phenomena. Untreated PD patients more frequently show only slight autonomic involvement and plasma CA levels are intermediate between 'pure' AF and MSA plus AF. In idiopathic parkinsonism, the phenomenon of post-prandial hypotension is detectable in over the two/thirds of the cases and is predictive of a lower tolerance (orthostatic hypotension) to dopaminergic drugs, at least in the early stages of treatment. MSA patients exhibit a contemporary reduction of noradrenaline (NA), MHPG and NPY CSF levels, while untreated PD show low CSF NE and NPY, but not MHPG concentrations. These data suggest the existence of widespread degenerative processes involving the basal ganglia and the CAergic nuclei of the brainstem in MSA plus AF. Other sophisticated approaches have been developed using pharmacological testing which evaluates the response of plasma vasopressin to hemodynamic stimuli and cardiopressor, CAergic and opioid response to insulin-induced hypoglycemia
40 or the release of plasma CA after intravenous edrophonium or clonidine administration. All of these tests have documented different patterns in 'pure' AF, in AF plus PD or in AF plus MSA and thus represent much better tools for differentiating the level (central/peripheral) of autonomic involvement than the simple cardiovascular tests currently used in the assessment of autonomic functioning. Due to the great variability of these test responses, however, only an adequate clinical, pharmacological and instrumental follow-up can provide an exact diagnosis in the majority of the cases.
Autonomic failure can manifest, as a matter of fact, different degrees of severity (and time of onset of different signs/symptoms) in the 'same' pathological entity and thus the instrumental evidence may reflect this great variability of clinical features. On the other hand, in spite of this variability, the degenerative processes of the CNS which define MSA or idiopathic PD or 'pure' AF appear to be a pathological 'continuum' where a severe autonomic involvement may in many cases be considered a predictive marker of a negative outcome of the disease.