Investigations

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The diagnosis of MSA still rests on the clinical history and neurological examination. Attempts have been made, however, to improve diagnostic accuracy through analysis of cerebrospinal fluid (CSF) and serum biomarkers, autonomic function tests, structural and functional neuroimaging and neurophysiological techniques.

Table 2

"Red Flags": Warning Features of MSAa

Motor Red Flags Definition

Orofacial dystonia Atypical spontaneous or L-dopa-induced dystonia predominantly affecting orofacial muscles, occasionally resembling risus sardonicus of cephalic tetanus.

Pisa syndrome Subacute axial dystonia with a severe tonic lateral flexion of the trunk, head, and neck (contracted and hypertrophic paravertebral muscles may be present).

Disproportionate antecollis Chin-on-chest, neck can only with difficulty be passively and forcibly extended to its normal position. Despite severe chronic neck flexion, flexion elsewhere is minor.

Jerky tremor Irregular (jerky) postural or action tremor of the hands and/or fingers.

Dysarthria Atypical quivering, irregular, severely hypophonic or slurring high-pitched dysarthria, which tends to develop earlier, be more severe, and be associated with more marked dysphagia compared to PD.

Nonmotor Red Flags

Abnormal respiration Nocturnal (harsh or strained, high-pitched inspiratory sounds) or diurnal inspira tory stridor, involuntary deep inspiratory sighs/gasps, sleep apnea (arrest of breathing for >10 s), and excessive snoring (increase from premorbid level, or newly arising).

REM sleep behavior disorder Intermittent loss of muscle atonia and appearance of elaborate motor activity

(striking out with arms in sleep often with talking/shouting) associated with dream mentation.

Cold hands/feet Coldness and color change (purple/blue) of extremities not resulting from drugs with blanching on pressure and poor circulatory return.

Raynaud's phenomenon Painful "white finger," which may be provoked by ergot drugs.

Emotional incontinence Crying inappropriately without sadness or laughing inappropriately without mirth.

Excluding cardinal diagnostic features of MSA such as orthostatic hypotension, urinary incontinence/retention, levodopa-

unresponsive parkinsonism, cerebellar (ataxia) and pyramidal signs. Also excluding nonspecific features suggesting atypical parkinsonism such as rapid progression or early instability and falls.

Reproduced with kind permission from John Wiley & Sons, Inc.: Wenning et al., Multiple system atrophy: an update. Mov

Disord 2003;18(suppl 6):34-42.

CSF Analysis

Studies have attempted to identify biomarkers in the CSF to achieve early and accurate diagnosis, as well as to monitor response to treatment. Proteins in the CSF, including glial fibrillary acidic protein (GFAP) and neurofilament (NFL) protein have been studied. No difference was found in CSF concentrations of GFAP between patients with PD and MSA, but high concentrations of NFL seem to differentiate atypical parkinsonian disorders from PD (31). Furthermore, CSF-NFL and levodopa tests combined with discriminant analysis may contribute even better to the differential diagnosis of parkinsonian syndromes (32). Whereas the CSF-NFL and levodopa tests predicted 79 and 85% correct diagnoses (PD or non-PD [MSA and progressive supranuclear palsy—PSP]) respectively, the combined test predicted 90% correct diagnoses.

Hormonal Testing

In vivo studies in MSA, which involved testing of the endocrine component of the central auto-nomic nervous systems (the hypothalamopituitary axis) with a variety of challenge procedures, provided evidence of impaired humoral responses of the anterior and the posterior part of the pituitary gland with impaired secretion of adrenocorticotropic hormone (ACTH) (33), growth hormone (34), and vasopressin/ADH (35). Although these observations can be made in virtually all advanced patients, their prevalence during the early course of MSA is unknown.

There is an ongoing debate about the diagnostic value of the growth hormone (GH) response to clonidine (CGH-test), a neuropharmacological assessment of central adrenoceptor function, in PD and MSA. Clonidine is a centrally active a2-adrenoceptor agonist that lowers blood pressure predominantly by reducing CNS (central nervous system) sympathetic outflow. In an early study, there was no increase in GH levels after clonidine in patients with MSA compared to those with PD or pure autonomic failure (36). Kimber and colleagues confirmed a normal serum GH increase in response to clonidine in 14 PD patients (without autonomic failure) and in 19 patients with pure autonomic failure, whereas there was no GH rise in 31 patients with MSA (34). However, these findings have been challenged subsequently (37). More studies in well-defined patient cohorts are needed before the clonidine challenge test can be recommended as a helpful diagnostic test in patients with suspected MSA.

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