Autonomic involvement in extrapyramidal and cerebellar disorders

We reviewed the clinical and autonomic features of all patients with extrapyramidal and cerebellar disorders studied in the Mayo Autonomic Reflex Laboratory from 1983 to 1989. Patients were grouped into the following categories (number in parentheses): Parkinson's disease (35); parkinsonism-plus (54); multiple system atrophy (75); hereditary multisystem degenerations (eleven); progressive supranuclear palsy (32); non-familial cerebellar degeneration (eleven); nonspecific sporadic multisystem degeneration (73). Severe autonomic failure occurred in 97% of patients with multiple system atrophy and 53% of the nonspecific sporadic multisystem degeneration patients respectively. Autonomic involvement was mild or absent in Parkinson's disease while parkinsonism-plus and non-familial cerebellar degeneration patients had moderate autonomic failure. Orthostatic blood pressure reduction, percentage of anhidrosis on thermoregulatory sweat test, quantitative sudomotor axon reflex test, forearm response and heart rate response to deep breathing strongly regressed with severity. A response to levodopa treatment in patients with parkinsonism was more likely if cerebellar signs and cognitive deficits were absent. The presence of levodopa induced dyskinesia was also a marker for a clinically favourable levodopa response. We conclude that there is a spectrum of autonomic involvement in these degenerative disorders and that autonomic studies are useful in separating them and monitoring their course.     

Sweat function in Parkinson's disease

Sweat function was studied in patients with Parkinson's disease and in normal adults by sympathetic skin response, the bromphenol blue printing method and the silicone mould method. In patients with Parkinson's disease, dysfunction of sweating was classified into two types: one type involved the postganglionic fibres and the other involved the preganglionic fibres or the central nervous system. The latter was observed in patients with milder disease and the former was observed in patients with severe disease. The progressive involvement of sweat function in Parkinson's disease may reflect spread from the central nervous system or preganglionic fibres to postganglionic fibres. In a few patients the results of sweat tests were normal. Ceruletide increased sweating in Parkinson's disease patients, and decreased the prolonged latency of the sympathetic skin response. It is hypothesized that ceruletide facilitates the preserved somatosympathetic reflex of sweating.     

Dementia with Lewy bodies and Parkinson's disease

Lewy bodies (LB) in the central nervous system are associated with several different clinical syndromes including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Long term follow up of PD patients finds up to 78% eventually develop dementia, most of these patients exhibiting fluctuating cognition and visual hallucinations similar to DLB and with extensive cortical LB at autopsy. alpha-Synuclein positive, neuritic pathology, in the putamen of DLB and Parkinson's disease dementia (PDD), may contribute to postural-instability gait difficulty, parkinsonism, diminished levodopa responsiveness and increased neuroleptic sensitivity. Cognitive and neuropsychiatric symptoms improve with cholinesterase inhibitor treatment in both patient groups. DLB and PDD should be seen as different points on a spectrum of LB disease. Distinguishing them as separate disorders may be useful in clinical practice, but may be of limited value in terms of investigating and treating the underlying neurobiology.     

Mini-review: multiple developmental forms of parkinsonism. The basis for further research as to the pathogenesis of parkinsonism

Summary. A range of extrapyramidal disturbances have been reported in children following early brain damage. In adults, damage to the basal ganglia can elicit abnormal motor activity in either direction; it would seem reasonable that the same would apply to damage occurring at an earlier developmental stage. The Viennese paediatrician Widhalm described a hypokinetic/parkinsonoid syndrome (‘infantile hypokinetic-hypertonic syndrome with Parkinson symptomatic’) presented by a significant minority of the children with extrapyramidal movement disturbances, corresponding to the mild rigid-akinetic type of Parkinson's disease. In contrast to classical parkinsonism, but consistent with some forms of post-encephalitic parkinsonism, the syndrome was reversible, although only after l-DOPA therapy. Widhalm's observation that at least one form of childhood parkinsonism can be cured with l-DOPA also suggests that the amino acid plays a more active role than mere replacement therapy in children, perhaps also acting as a neurotrophic agent. It is proposed that environmental factors, including viral and risk factors associated with pregnancy and birth, together with genetically determined lability, may increase the incidence of early hypokinesia/parkinsonism in particular and of Parkinson's disease in later life by disturbing the immature basal ganglia at critical developmental stages. The spectrum disorder of Parkinson's disease thereby occurs as a number of various etiopathologically distinct syndrome subtypes, including early onset developmental forms caused by in utero or early post partum trauma. Received September, 2002; accepted October 31, 2002 Authors' address: Prof. Dr. P. Riederer, Clinical Neurochemistry, Clinic for Psychiatry and Psychotherapy, University of Würzburg, Füchsleinstrasse 15, D-97080 Würzburg, Federal Republic of Germany, e-mail: peter.riederer@mail.uni-wuerzburg.de     

Parkinsonism and multiple sclerosis-Is there association?

Association between multiple sclerosis (MS) and parkinsonism is rarely reported. We describe clinical, radiological and DAT scan findings in two patients presenting with parkinsonism. MRI revealed demyelinating lesions of the central nervous system consistent with MS in both patients. On the other hand, DAT scan findings were supportive of Parkinson's disease. There is still an open debate whether MS lesions can cause parkinsonism, or these are just coincidental findings of two different diseases in the same patient. Although there are cases of causal relationship between parkinsonism and MS, some literature reports and our observations suggest that Parkinson's disease and MS can coexist as two separate diseases in the same patient. It is possible that the symptoms of Parkinson's disease can be aggravated by MS plaques, explaining the favorable response to corticosteroids in some patients.     

Neurological comorbidity in parkinsonism

We studied the neurological comorbidity of parkinsonism in 368 consecutive patients from the Lausanne Movement Disorders Registry. Only 6 patients had no neurological comorbidity. We found that 23p.100 of our patients had ischemic strokes, especially large vessel strokes, i.e three times more than in an age-matched control study performed in a recent survey in our country, which is a new finding in contradiction with previous reports mentioning that Parkinson's disease may be a protective factor against stroke. This finding opens new directions for further studies concerning some shared mechanisms in both diseases associated with age. Predominantly tremulous parkinsonism (46p.100) and progressive supranuclear palsy patients (PSP) (40p.100) had the highest prevalence of cerebrovascular disease of all subgroups of parkinsonism, especially lacunar infarcts, which is in accord with a higher frequency of hypertension in these subgroups according to a recent study of ours. Transient ischemic attacks or hemorrhages were not more frequent than in the general population. We did not find a higher frequency of head trauma except for Parkinson's disease, but a trend for a higher frequency of headache and migraine. Brain tumors were more frequent in Parkinson's disease and hydrocephalus and radiculopathies in parkinsonism in general when compared to age-matched populations from the literature. Polyneuropathies were more frequently observed in familial parkinsonism only, but myopathies and cranial neuropathies were not more frequent in our patients. Epilepsy was significantly less frequent in parkinsonism, especially in Parkinson's disease, infectious diseases of the nervous system were rarely encountered, and restless legs syndrome was surprisingly not more frequent than in a normal population. Dementia was associated in 20p.100, but multiple sclerosis is noticeably absent.     

Regional cerebral blood flow in patients with Parkinson's disease.

Regional cerebral blood flow (rCBF) was measured by the xenon 133 inhalation method in 60 patients with Parkinson's disease and compared with flow data obtained in 51 age-matched normal control subjects. Mean brain rCBF was significantly reduced in patients with parkinsonism (9.5%, P less than .001). The most marked and significant rCBF decreases were observed in the older patients (18.8%, P less than .001). There was no correlation between degree of rCBF reduction and duration of parkinsonism. Decreases in hemispheric mean rCBF values were similar in both hemispheres even in patients with unilateral signs. The present study provides additional evidence for involvement of the cerebral cortex in Parkinson's disease. The rCBF decline may be associated in part with high prevalence of mental impairment and cortical atrophy and with diminished cerebral metabolic rate due to brain dopamine deficiency in patients with parkinsonism.     

Impact of recent genetic findings in Parkinson's disease

PURPOSE OF REVIEW: Parkinson's disease is the second most common age-related neurodegenerative disorder and is characterized clinically by classical parkinsonism and pathologically by selective loss of dopaminergic neurons in the substantia nigra and Lewy bodies. Although for most classical parkinsonism the etiology is unknown, a clear genetic component has been determined in a minority. Mutations in five causative genes combined [alpha-Synuclein (SNCA), Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, Leucine-rich repeat kinase 2 (LRRK2)] account for 2-3% of all cases with classical parkinsonism, often clinically indistinguishable from idiopathic Parkinson's disease. RECENT FINDINGS: The functional role of PINK1 and LRRK2 as kinases has been clearly established. Further, mutations in the ATP13A2 gene have been linked to Kufor-Rakeb syndrome (PARK9), a form of atypical parkinsonism. ATP13A2 encodes a lysosomal ATPase and shows elevated expression levels in the brains of sporadic patients, suggesting a potential role in the more common idiopathic Parkinson's disease. Finally, first promising pilot studies have been performed to identify differentially expressed genes and proteins as biomarkers for parkinsonism. SUMMARY: The identification of single genes and their functional characterization has enhanced our understanding of the pathogenesis of parkinsonism, has led to improvement of diagnostic tools for genetic parkinsonism, and allows for the purposeful consideration of novel therapeutic targets.     

Olfactory function in atypical parkinsonian syndromes

Introduction – Olfaction is markedly impaired in patients with idiopathic Parkinson's disease (IPD). This deficit contrasts with reports of preserved or only mildly reduced olfaction in patients with atypical parkinsonism. However, the sensitivity and specificity of olfactory function testing in the differential diagnosis of parkinsonian syndromes has not been studied. In addition, olfactory function in patients with corticobasal degeneration (CBD) is unknown. Material and methods — Using the University of Pennsylvania Smell Identification Test (UPSIT) with a test score ranging from 0 to 40 we studied olfactory function in patients with IPD as well as other parkinsonian syndromes including CBD and progressive supranuclear palsy (PSP). Results — UPSIT scores in 118 patients with IPD, 29 with MSA, 15 with PSP, and 7 patients with CBD, as well as in 123 healthy control subjects revealed a marked impairment in the IPD group in contrast to mild impairment in MSA patients and normal olfaction in PSP and CBD patients. An UPSIT score of 25/40 was associated with a sensitivity of 77% and a specificity of 85% in differentiating IPD from atypical parkinsonism. Conclusions — These results indicate that olfactory function is differentially impaired or preserved in distinct parkinsonian syndromes and that it might also have some value as a diagnostic pointer. Thus, preserved or mildly impaired olfactory function in a parkinsonian patient is more likely to be related to atypical parkinsonism such as MSA, PSP or CBD, whereas markedly reduced olfaction is more suggestive of IPD.     

Juvenile parkinsonism: ventricular CSF biopterin levels and clinical features.

Total biopterin (T-BP) levels in the ventricular cerebrospinal fluid (CSF) and clinical features of 19 patients with juvenile parkinsonism (JP: Parkinson's disease manifesting below the age of 40) were evaluated and compared with 61 patients with classical Parkinson's disease (classical PD: symptoms developing at the age of 40 or above). The JP patients were divided into two subgroups: JP-I; those with good response to levodopa followed by marked motor fluctuations and dopa-induced dyskinesias (DID), JP-II; those with milder response than JP-I with less fluctuations and DID being more similar to classical PD. Both of the mean ventricular CSF T-BP concentrations in the JP and classical PD patients were significantly lower than that in neurological controls. Moreover, the mean T-BP level in the JP-I was markedly lower than that in the JP-II or classical PD. Total biopterin levels revealed a gaussian distribution in the classical PD. However, a bimodal distribution was noted in the JP, with the lower peak consisting of only JP-I patients. These results seem to indicate that JP-II represents early-onset classical PD, while JP-I represents a distinct subgroup having a different physiopathology from classical PD.     

Esophageal Manometry in Patients with Unilateral Hemispheric Cerebrovascular Accidents or Idiopathic Parkinsonism

The relative importance of cortical and infracortical neural control of deglutition was investigated in nine patients with unilateral cortical or internal capsule stroke, six patients with idiopathic parkinsonism, and seven healthy volunteers. Ten dry then 10 wet swallows were requested, during a right and left electromyographic recording of the mylohyoideus muscles, coupled to a manometric recording of the pharynx, upper esophageal sphincter, esophageal body, and lower esophageal sphincter (LES). Six hemiplegic patients, but no patient with Parkinson's disease, had asynchronous contractions of the mylohyoideus muscle at the onset of swallowing. Four hemiplegic patients and one with Parkinson's disease were unable to trigger dry swallows, but wet swallows were always initiated in all subjects. Four hemiplegic patients and one with Parkinson's disease had nonperistaltic esophageal contractions with either dry or wet swallows. LES relaxation was complete after dry swallows in none of the hemiplegic patients and in two with Parkinsons disease, and after wet swallows in six hemiplegic patients and four with Parkinson's disease. We conclude that a unilateral stroke may abolish the synchronism of mylohyoideus muscle contractions during swallowing, and that both pharyngeal and esophageal stages of deglutition are impaired in either cortical or striatonigral lesions.     

Diffuse Lewy body disease: clinical features in nine cases without coexistent Alzheimer's disease.

OBJECTIVE--To further elucidate the relation between diffuse Lewy body disease and Parkinson's disease. METHODS AND RESULTS--The clinical features of nine cases of pure diffuse Lewy body disease without pathological evidence of coexisting Alzheimer's neuritic pathology were reported. All patients were aged less than 70 years at onset (mean 62 years). Five patients presented with clinical features, which included assymetric resting tremor had levodopa responsiveness, which were initially indistinguishable from idiopathic Parkinson's disease. All five patients later became demented (mean of three years after presentation). Two further patients presented with parkinsonism and dementia and two patients presented with dementia and developed parkinsonism at a later stage. Hallucinations appeared 2.5-9 years after the onset of symptoms in six patients and were a presenting feature in one patient. All patients met the pathological criteria of idiopathic Parkinson's disease, with respect to the midbrain changes, in addition to having diffuse cortical Lewy bodies. CONCLUSIONS--Diffuse Lewy body disease may present a parkinsonism, dementia, or both depending on whether the Lewy body pathology begins in the midbrain, the cortex, or both together. When it begins in the midbrain, diffuse Lewy body disease is indistinguishable initially from idiopathic Parkinson's disease. Diffuse Lewy body disease may be a common cause of dementia complicating Parkinson's disease.     

Diffuse Lewy body disease searched out from 114 patients with parkinsonism]

From 114 patients who had been previously diagnosed as Parkinson's disease, we diagnosed six cases as clinically definite "diffuse Lewy body disease (DLBD)" according to McKeith's criteria with more strict modifications. Besides a central feature, dementia, and core features including parkinsonism, fluctuating cognition, and recurrent visual hallucinations, the patients presented some of supportive features, that is, repeated falls (4 cases), syncope (5 cases), and transient loss of consciousness (all cases). Autopsy, which was performed in 2 of the cases, revealed Lewy bodies in various nervous tissues including autonomic nervous systems in both cases. 7 cases of probable DLBD and 8 cases of possible DLBD, which lacked fluctuating cognition and/or visual hallucinations, demonstrated neither of repeated falls, syncope, nor transient loss of consciousness. Episodes of these supportive features, which seem to be associated with autonomic dysfunctions and/or fluctuating cognition, should be important in the differential diagnosis of DLBD.     

Parkinsonism due to a basal ganglia lacunar state: clinicopathologic correlation

We report a patient with a clinical syndrome indistinguishable from Parkinson's disease in which postmortem examination revealed extensive lacunar infarction of the basal ganglia without evidence of coexistent Parkinson's disease. This case provides pathologic confirmation of the concept of vascular parkinsonism.     

123I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson's disease

OBJECTIVES: (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is clinically used to estimate local myocardial sympathetic nerve damage in some forms of heart disease, autonomic nerve disturbance in diabetic neuropathy, and disturbance of the autonomic nervous system in neurodegenerative disease. In the present study, examinations were performed to clarify (1) the proportion of cardiac sympathetic nerve disturbance in Parkinson's disease, (2) the usefulness of (123)I-MIBG myocardial scintigraphy to detect sympathetic nerve disturbances compared with autonomic function tests, (3) cardiac function in patients who have a decreased MIBG uptake in (123)I-MIBG myocardial scintigraphy, (4) the usefulness of (123)I-MIBG myocardial scintigraphy to differentiate Parkinson's disease from the other neurological diseases mimicking it. METHODS: (123)I-MIBG myocardial scintigraphy was performed, together with autonomic function tests and cardiac examinations in 46 patients with Parkinson's disease and 25 patients with vascular parkinsonism, essential tremor, or multiple system atrophy. RESULTS: In an anterior image study, the average count per pixel in heart to mediastinum (H/M) ratio decreased in 80% of the patients with Parkinson's disease in the early phase and 84% in the late phase. The mean H/M ratio in Parkinson's disease was significantly lower than that in controls and the other diseases. The H/M ratio tended to decrease with the disease progression. In almost half of the patients in Hoehn and Yahr stage I, the H/M ratio was already decreased. The sympathetic skin response in upper and lower limbs, head up tilt test, and coefficient of variation of R-R interval were abnormal in 17%, 31%, 30%, and 17% of the patients, respectively. All the patients with abnormal autonomic functions were in Hoehn and Yahr stage III, IV, or V. Echocardiography showed normal left ventricular function. Twenty four hour Holter electrocardiography detected no serious arrhythmias except for one patient with non-sustained ventricular tachycardia. CONCLUSION: (123)I-MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in Parkinson's disease and might give useful diagnostic information to differentiate vascular parkinsonism, essential tremor, and multiple system atrophy from Parkinson's disease.     

Clinical and pathological aspects of parkinsonism in Alzheimer's disease. A role for extranigral factors?

To examine the natural history and pathogenesis of parkinsonism in Alzheimer's disease, 44 subjects with clearly established senile dementia of the Alzheimer type were studied during a 66-month period. Sixteen subjects (36%) developed idiopathic parkinsonism, and 12 subjects (27%) developed drug-induced parkinsonism; the chief clinical features of both types were bradykinesia and rigidity, but not resting tremor. The presence of parkinsonism was associated with global (rather than selective) cognitive impairment, as determined by psychometric testing, and with more rapid progression to advanced stages of dementia. The pathological correlates of clinical parkinsonism were heterogeneous in 10 subjects with Alzheimer's disease who were examined post mortem. Coexistent Parkinson's disease was observed in five cases and nonspecific nigral degenerative lesions were present in another three; however, two cases had neither histological changes nor reduced neuronal densities in the substantia nigra. These two cases suggested that extranigral lesions, possibly involving mesocortical dopaminergic pathways, may contribute to the development of parkinsonism in subjects with Alzheimer's disease.     

Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson's disease

BACKGROUND: Formal laboratory testing of autonomic function is reported to distinguish between patients with Parkinson's disease and those with multiple system atrophy (MSA), but such studies segregate patients according to clinical criteria that select those with autonomic dysfunction for the MSA category. OBJECTIVE: To characterise the profiles of autonomic disturbances in patients in whom the diagnosis of Parkinson's disease or MSA used criteria other than autonomic dysfunction. METHODS: 47 patients with parkinsonism and autonomic symptoms who had undergone autonomic laboratory testing were identified and their case records reviewed for non-autonomic features. They were classified clinically into three diagnostic groups: Parkinson's disease (19), MSA (14), and uncertain (14). The performance of the patients with Parkinson's disease was compared with that of the MSA patients on five autonomic tests: RR variation on deep breathing, heart rate changes with the Valsalva manoeuvre, tilt table testing, the sudomotor axon reflex test, and thermoregulatory sweat testing. RESULTS: None of the tests distinguished one group from the other with any statistical significance, alone or in combination. Parkinson's disease and MSA patients showed similar patterns of autonomic dysfunction on formal testing of cardiac sympathetic and parasympathetic, vasomotor, and central and peripheral sudomotor functions. CONCLUSIONS: This study supports the clinical observation that Parkinson's disease is often indistinguishable from MSA when it involves the autonomic nervous system. The clinical combination of parkinsonism and dysautonomia is as likely to be caused by Parkinson's disease as by MSA. Current clinical criteria for Parkinson's disease and MSA that direct patients with dysautonomia into the MSA group may be inappropriate.     

How valid is the clinical diagnosis of Parkinson's disease in the community?

BACKGROUND: Many patients diagnosed with Parkinson's disease are later found to have an erroneous diagnosis, often only when they come to necropsy; conversely, many patients with Parkinson's disease in the community remain undiagnosed. OBJECTIVE: To assess the validity of a clinical diagnosis of parkinsonism in the general population according to strict published criteria. METHODS: As part of a population based study on the prevalence of Parkinson's disease in London, all patients were identified with a diagnosis of parkinsonism, tremor with onset over age 50 years, or who had ever received antiparkinsonian drugs. All patients who agreed to participate were diagnosed according to strict clinical diagnostic criteria, after a detailed neurological interview and examination and discussion of the findings with examination of their video recordings. Follow up information was obtained over a period of at least one year, and atypical cases were reviewed at the end of the study. RESULTS: A diagnosis of probable Parkinson's disease was confirmed in 83% of patients with this diagnosis, including three (2%) in whom atypical features were found that were insufficient to discard a diagnosis of Parkinson's disease. Two additional patients (2%) were found to have possible Parkinson's disease. However, in 15% of patients the diagnosis was unequivocally rejected. Conversely, 13 patients who had previously not been diagnosed with Parkinson's disease (19%) were found to have this disorder. CONCLUSIONS: At least 15% of patients with a diagnosis of Parkinson's disease in the population do not fulfil strict clinical criteria for the disease, and approximately 20% of patients with Parkinson's disease who have already come to medical attention have not been diagnosed as such.     

Nerve conduction studies, skeletal muscle EMG, and sphincter EMG in multiple system atrophy.

Although autonomic failure, parkinsonism, and cerebellar and pyramidal signs are well documented in multiple system atrophy, much less is known about the frequency and severity of involvement of the peripheral nervous system. The frequency and nature of peripheral nerve involvement has therefore been determined in 74 patients with multiple system atrophy using nerve conduction studies and skeletal muscle EMG. These findings were compared with those on sphincter EMG. Ninety per cent of the patients had an abnormal sphincter EMG, indicating denervation and reinnervation consistent with anterior horn cell loss in Onuf's nucleus, but only 40% had either abnormal nerve conduction studies (mixed sensorimotor axonal neuropathy in 17.5%) or abnormal skeletal muscle EMG (suggesting partial denervation in 22.5%). These data indicate a remarkable selective vulnerability of the anterior horn cells of Onuf's nucleus innervating external sphincter muscles relative to those supplying skeletal muscle in patients with multiple system atrophy. If this selective pattern of involvement can be explained it may be a clue to pathogenetic mechanisms in multiple system atrophy.     

Depression and Parkinson's disease: a review.

OBJECTIVE: The purpose of this review is to provide an update of the research regarding depression in Parkinson's disease and to synthesize the information into a neurobiological model relating the structural and biochemical changes in this disorder to the behavioral manifestations. METHOD: The author used a computer-based search of the literature, augmented by extensive bibliography-guided article reviews, to find information on depression and Parkinson's disease. FINDINGS: Depression occurs in approximately 40% of patients with Parkinson's disease; depression in Parkinson's disease is distinguished from other depressive disorders by greater anxiety and less self-punitive ideation. Lower CSF levels of 5-hydroxyindoleacetic acid, a past history of depression, and greater functional disability are associated with a greater risk of depression in Parkinson's disease. Female gender, early age at onset of Parkinson's disease, and greater left brain involvement may also be risk factors. Approximately half of depressed patients with Parkinson's disease meet criteria for major depressive episodes; half have dysthymia. Depression is more common in Parkinson's disease with prominent bradykinesia and gait instability than in tremor-dominant syndromes. Depressed patients with Parkinson's disease have greater frontal lobe dysfunction and greater involvement of dopaminergic and noradrenergic systems than nondepressed patients with the disease. Mood changes in Parkinson's disease respond to treatment with conventional tricyclic antidepressants or ECT. CONCLUSIONS: Neurobiological investigations suggest that depression in Parkinson's disease may be mediated by dysfunction in mesocortical/prefrontal reward, motivational, and stress-response systems. Neuropsychological, metabolic, clinical, pharmacological, and anatomical studies support the involvement of frontal dopaminergic projections in patients with Parkinson's disease and depression.