Differential diagnosis of parkinsonism and tremor disorders : basal ganglia imaging with a novel isotope.

There have been continual changes in medical diagnosis and treatment throughout the generations. Present medical practice emphasises accuracy and accountability, and an evidence base for diagnosis and therapeutic intervention. The differential diagnosis of tremor disorders and parkinsonism serves as a good example of evolving concepts and treatment approaches, and is the subject of the present thesis. It is necessary first to review present knowledge about the accuracy of diagnosis and why this is important (Chapter 1), then to review how imaging techniques have contributed to the knowledge base (Chapter 2) and then report current understanding of the dopamine transporter (Chapter 3) - as it is at this site that the new isotope -123I-N-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane (123I-FP-CIT) is known to work. It is the aim of the present thesis to examine an advanced phase of clinical application of the technique of SPECT imaging with 123I-FP-CIT to the differential diagnosis of selected movement disorders as follows: In study 1 (Chapter 4) the design and result of study of 220 subjects with idiopathic Parkinson's disease (iPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), essential tremor (ET) and healthy volunteers are presented. A new technique of assessing 123I-FP-CIT SPECT by visual inspection was developed which proved to be useful in differentiating essential tremor from other parkinsonian syndromes. Semi-quantitative analysis showed limited usefulness of 123I-FP-CIT SPECT in differentiating iPD from atypical parkinsonism. This study provides evidence against significant association between iPD and ET. Study 2 (Chapter 5) addressed the issue of the correlation of severity, staging and duration of parkinsonian features with 123I-FP-CIT striatal uptake in 41 patients with iPD. A positive correlation of striatal uptake was identified for these variables and for bradykinesia, but not for tremor suggesting that tremor could have an origin outwith the dopamine transporter system. The clinical lateralisation of parkinsonian signs was studied in relation to striatal uptake with the finding that clinical asymmetry in iPD was more marked than the degree of the asymmetry in 123I-FP-CIT uptake. The patterns of 123I-FP-CIT uptake in iPD, 8 MSA, 3 PSP and 6 healthy volunteers were reported, confirming that the posterior putamen is the most affected part in iPD and showing that there are limitations in attempting to differentiate parkinsonism subtypes using this technique. In study 3 (Chapter 6) 10 patients with tremor and/or clinical features suggesting possible parkinsonism (but not fulfilling diagnostic criteria for either iPD or ET) were compared to 9 unilateral patients fulfilling diagnostic criteria for iPD and 6 healthy volunteers. Reduced 123I-FP-CIT striatal uptake was found bilateral in 7 tremor patient and all 9 of the unilateral iPD patients, confirming the presymptomatic phase of the illness not only in early parkinsonism cases but even in monosymptomatic cases who have yet to develop definitive clinical features. Of the 10 tremor cases, 3 showed striatal uptake values above the range established for iPD patients fulfilling clinical criteria, even although the duration of disease in the tremor patients was similar to that in definite iPD patients. Three of the 10 tremor patients showed normal striatal uptake. This indicated the usefulness of this technique in demonstrating the nigrostriatal change at a very early stage of disease, helping to exclude or confirm the diagnosis of parkinsonism. In study 4 (Chapter 7) the relationship between cerebrovascular disease and parkinsonism was studied. 123I-FP-CIT striatal uptake in 12 patients with vascular parkinsonism was compared to 6 healthy volunteers. Also an index case of isolated tremor related to ischaemic lesion was reported. A reduction in uptake was shown in all vascular parkinsonism patients except one. Two distinct patterns of dopaminergic loss, both of which differ from idiopathic Parkinson's disease were identified, indicating that vascular lesions may disrupt the dopaminergic system to produce parkinsonian features. In summary, a simple visual inspection of 123I-FP-CIT SPECT scans helps in differentiating parkinsonian syndromes from essential tremor and detecting changes in the dopaminergic system in patients with unilateral parkinsonism, even in patients not fulfilling diagnostic criteria for iPD. However there are limitations in using this technique in differentiating iPD from MSA or PSP. A reduction in striatal uptake was shown in vascular parkinsonism patients supporting a dopaminergic source of symptoms in this group. The correlation of disease staging, severity and duration with striatal 123I-FP-CIT uptake indicates the potential usefulness of SPECT in monitoring disease progression and the effects of putative neuroprotective therapy. In conclusion, this new technique represents a significant advance in medical diagnosis of movement disorders.