Scans without evidence of dopamine deficiency: The triumph of careful clinical assessment

Ten years ago, the two main differentials considered in the diagnosis of Parkinson’s disease (PD) were essential tremor and other akinetic-rigid syndromes such as multiple system atrophy and progressive supranuclear palsy. However, in the last decade, there has been increased recognition that some patients who may appear to have mild PD may in fact have intact dopamine pathways on functional imaging. This problem has been fairly consistently reported in 10 to 15% of patients entered into clinical trials of neuroprotection for PD. Although the differential diagnosis of conditions resulting in bradykinesia and rigidity may be challenging to the best clinicians, especially in early stages, the combination of asymmetric rest tremor, bradykinesia, and rigidity is widely accepted as supportive of a diagnosis of PD. Potential explanations for this unexpected prevalence of normal dopaminergic function in people diagnosed with PD hinged on three possibilities: (i) that not all apparent PD is associated with loss of presynaptic dopamine function, (ii) the imaging findings were incorrect, and (iii) that the rate of misdiagnosis, even in apparently expert hands, was relatively high. The last consideration was somewhat mitigated by the appearance of this phenomenon in patients with early disease and the possibility that investigators overzealous to enter subjects in clinical trials were loosening their criteria and including patients presumed in retrospect to have essential tremor. Initial anxiety about this phenomenon soon gave way to genuine uncertainty, as the diagnosis of PD appeared to be confirmed, at least in some cases, upon independent assessment by experts reviewing blinded videotapes. Eventually, given the consistency with which this rate of false diagnosis was identified in clinical trials, the problem was assigned a name: Scans Without Evidence of Dopamine Deficiency (SWEDD). Clinical follow-up of patients diagnosed with SWEDD revealed (i) inconsistent response to dopaminergic medication, (ii) lack of clinical progression, and (iii) when specifically assessed, preservation of olfactory function, commonly impaired in PD. Follow-up imaging studies revealed that dopamine deficiency did not emerge over time, nor did subjects develop the metabolic fingerprint (hypermetabolism in the basal ganglia, with hypometabolism in premotor and posterior parietal cortex) characteristic of PD. Two years ago, Schneider et al. reported here that a number of SWEDD patients might have dystonic tremor. This conjecture now appears to be supported by a much more extensive analysis reported in the current issue of the journal, in which the authors have compared clinical features in 25 patients with SWEDD versus 25 with tremor-predominant PD. Patients with SWEDD were carefully selected to have asymmetric rest tremor, and the diagnosis of SWEDD versus PD was supported by dopamine transporter imaging. Although clinical and accelerometric features were similar in the two groups, the presence of certain clinical findings, particularly true fatiguability and decrement (which had a sensitivity of 84% and specificity of 96% for the diagnosis of PD), re-emergent tremor on change in posture, and the presence of nonmotor abnormalities helped support a diagnosis of PD, whereas others (lack of true bradykinesia, head tremor, and dystonia) were more suggestive of SWEDD. Furthermore, transcranial magnetic stimulation studies of cortical plasticity demonstrated enhanced facilitation and loss of spatial specificity typical of dystonia in a subset of SWEDD patients, whereas a subnormal response was seen in the PD subjects. How could we have missed this phenomenon for so many years? Why should it matter? How should we act on this information? Review of clinical and videotape data from Schwingenschuh et al. and the earlier article by Schneider et al. from the same group demonstrate how readily one might confuse the two diagnoses, but also reinforce the irreplaceable benefits of thoughtful clinical evaluation. In retrospect, the clinical differentiators may seem obvious. However, the careful analysis of the current article helps formalize key points that clinicians should look for in their examination. It should also be emphasized that isolated slowness or low amplitude of repetitive movements is insufficient to differentiate PD from SWEDD, nor are hypomimia and reduced armswing, seen in 1/2 and 2/ 3 of SWEDD patients, respectively, adequately specific. Although SWEDD patients are generally unresponsive to dopaminergic medication, more than 80% of patients with tremor-predominant PD responded to dopaminergic medication. This interesting observation, upon which the authors do not expand, attacks another common misperception about PD. Although tremor may correlate better with serotonergic than dopaminergic abnormalities, the current report reinforces the benefits of dopaminergic replacement therapy for all the primary features of PD, including the tremor. However, many dopaminergic therapies, particularly the dopamine agonists, may be expensive, and their use may be associated with unwanted side effects, including disabling impulse control disorders. Thus, as the authors point out, accurate differentiation of SWEDD from PD may spare patients (and drug plans) from unnecessary and potentially harmful therapies. A diagnosis of SWEDD is also associated with a better prognosis than PD, and it may be advantageous to disclose this, although it is likely to become apparent over repeated clinical assessments. A major importance of identifying SWEDD, not discussed by the authors, is for inclusion in clinical trials of putative disease-modifying therapies. If randomization is adequate, one might expect that patients with SWEDD would be equally distributed in placebo and active treatment arms of such trials, but if the SWEDD patients could be excluded from the outset, there might be a substantial gain in power. Should functional imaging studies with SPECT or PET be performed in all cases where there is diagnostic uncertainty? In routine clinical practice, this may not be an option and even if available, the testing may not affect treatment to a meaningful degree. For patients with relatively mild features, careful clinical evaluation with examinations repeated every several months should suffice to clarify the diagnosis, and there should be no need to initiate symptomatic therapy. On the other hand, if a convincing neuroprotective therapy should become available, early diagnostic clarity would clearly be advantageous. Published online in Wiley InterScience (www.interscience. wiley.com). DOI: 10.1002/mds.23138