Demystifying SWEDD syndrome: scans without evidence of dopaminergic deficit

The term SWEDD was first introduced to describe patients who had been entered into therapeutic trials on the basis that they were thought to have Parkinson’s disease by their clinicians, but were found to have normal presynaptic nigrostriatal dopaminergic imaging.

Introduction

The clinical diagnosis of Parkinson’s disease (PD) can be challenging in the early stage and when patients present with subtle or ambiguous signs. One of these diagnostic challenges is SWEDD syndrome. The term SWEDD is relatively recent in usage and has originated from clinical trials literature referring to PD mimics where the parkinsonism is not of a presynaptic, dopaminergic deficiency origin.

The term SWEDD stands for Scans Without Evidence of Dopaminergic Deficit (SWEDD). SWEDD syndrome is a non-degenerative variant of the parkinsonian syndromes (PS) which mainly include presynaptic degeneration syndromes, such as idiopathic Parkinson’s disease.¹ Thus, SWEDD can be levelled at any patient that looks clinically as if the patient has PD, but subsequent functional imaging assessments, such as single-photon emission computed tomography (SPECT) or dopamine transporter (DaT) scans, do not confirm this.

Further reading

• Apathy: the known but ignored symptom of Parkinson’s disease
• Mental health problems in Parkinson’s disease
• Management of Parkinson’s disease symptoms in the last days of life

The term SWEDD was first introduced to describe patients who had been entered into therapeutic trials on the basis that they were thought to have PD by their clinicians, but were found to have normal presynaptic nigrostriatal dopaminergic imaging.

Early and accurate identification of these variants is important for effective patient management as the course, therapy and prognosis differ substantially between the two groups.¹

Approximately 10% of patients clinically diagnosed with early Parkinson’s disease subsequently have normal dopaminergic functional imaging.² In the ELLDOPA study, SWEDD subjects lacked clinical responsiveness to levodopa, and follow-up dopamine transporter (DAT) scans after four years remained normal.³

Epidemiology and pathophysiology

The prevalence of SWEDD in general practice is currently unknown, and the significance of normal imaging in patients with a clinical diagnosis of PD is still debated.² However, there is growing evidence that these patients suffer from conditions not affecting the nigrostriatal dopaminergic system and may therefore have different pathophysiology, prognosis, and treatment requirements.

About 4-15% of subjects €“ clinically thought to have PD – scanned in several studies, did have normal dopaminergic functional imaging, SWEDD².

The aetiology and pathophysiology of SWEDD syndrome remain unknown. Recently, it was shown that abnormality in cortical plasticity, assessed by paired associative stimulation, was markedly different in PD and tremulous subtype of SWEDD.⁴ In addition, some recent olfaction studies have shown near normal olfaction scores in SWEDD patients whereas PD patients were notable for impaired olfactory function.⁵

Clinical features of SWEDD syndrome

Generally, SWEDD patients can be subdivided into two broad phenotypes, in the same way as in PD. These are the tremor dominant and non-tremor dominant (or tremor absent) subtypes.⁶ The clinical distinction of tremulous SWEDD from PD remains difficult in some cases.²

However, certain clinical features point toward a diagnosis of tremulous SWEDD, such as lack of true bradykinesia, normal olfaction, and presence of dystonia or head tremor, whereas re-emergent tremor, true fatiguing or decremental, good response to dopaminergic drugs, and the presence of non-motor symptoms favour a diagnosis of PD.⁴

The tremulous SWEDD cases are not uncommon and SWEDD patients of this subtype are the really troublesome diagnostic conundrums and to emphasise clinical diagnostic error rate.⁶

SWEDD patients with asymmetric rest tremor present bilateral action tremor during specific motor task of handwriting and drawing contrary to PD patients.¹³ In addition, SWEDD are at greater risk (30 %) of having cognitive decline than PD patients at early stages (15 %).¹⁴

Alternative diagnoses should always be considered, such as essential tremor (ET), depression, vascular or psychogenic parkinsonism, dopa-responsive dystonia, supra-nigral parkinsonism, and primary adult-onset dystonic tremor⁷ (table 1).

Alternative diagnosis for non-tremor dominant SWEDD phenotype	Alternative diagnosis for tremor-dominant SWEDD phenotype
Vascular Parkinsonism Tardive (neuroleptic- induced) Dyskinesia Brain Neoplasm Huntington’s disease	Adult-onset Dystonic Tremor Valproate Toxicity Essential Tremor Psychogenic Tremor

Table 1. Possible alternative diagnoses for SWEDD syndrome

Diagnosis and investigations

About 10% of patients clinically diagnosed with early PD will have normal dopaminergic functional imaging,² and this group could be the non-degenerative variant of the parkinsonian syndrome, SWEDD.

The clinical distinction of tremulous SWEDD from PD remains challenging in some cases.² A focal, task-specific tremor, with irregular frequency and amplitude, and static or fluctuating parkinsonism, spontaneously remittent, with mild severity are characteristic of tremulous SWEDD.^6,8 Furthermore, clinical features such as asymmetric resting tremor, rigidity, chin tremor appear to be less specific of idiopathic PD than it is commonly accepted.⁸

Most of tremulous SWEDDs patients would have dystonic tremor, psychogenic tremor and less frequently, essential tremor.^6,8 Neuroimaging using presynaptic nigro-striatal dopaminergic scans are essential for establishing the diagnosis of SWEDD syndrome and differentiating it from early PD.

Recent clinical trials using [¹²³I] β-CIT single-photon emission computed tomography (SPECT) and [¹⁸F]-dopa PET as surrogate markers for disease progression have found that 5.7% to 14.7% of cases clinically diagnosed as early Parkinson’s disease have normal scans, SWEDD syndrome.⁹

Midbrain hyperechogenic alterations, particularly in the subthalamic nucleus (SN), have been consistently found in up to 90% of patients with PD in a variety of studies using transcranial sonography (TCS).²

Midbrain hyper-echogenicity has also been observed in approximately 10% of the healthy population.² TCS has been shown to detect midbrain hyper-echogenicity in approximately 90% of Parkinson’s disease.² Moreover, midbrain hyper-echogenicity has been associated with the development of PD in patients with idiopathic REM sleep behaviour disorder.¹⁰

In one study, there was a significantly increased area of echogenicity in a group 0f 19 PD patients (0.24 ± 0.06 cm²), compared to the group of 14 patients with SWEDD (0.13 ± 0.06 cm²; P < 0.001) ².

TCS could be used to distinguish PD patients from patients with suspected parkinsonism and SWEDD, but the technique is operator dependent. Investigations illustrating different striatal specific binding ratios and striatal asymmetry indices among SWEDD and PD patients may indicate different disease entities.¹⁵  Although autonomic dysfunction is common among SWEDD patients, its severity does not correlate with the severity of parkinsonism.¹⁶

Management of SWEDD syndrome

In several drug trials that led to the discovery of the syndrome, patients with SWEDD had no benefit from active medications.¹¹ In addition, follow-up presynaptic dopaminergic system imaging demonstrated that the scans continued to be normal up to four years later, with negligible deterioration in clinical features, thus casting considerable doubt on the diagnosis of Parkinson’s disease.¹¹

Some SWEDD patients could be treated as patients with dystonic tremor syndrome. In their report, Schneider et al stated that dystonic tremor can masquerade as Parkinson’s disease and this suggests that some SWEDDs patients in these clinical trials may have had a dystonic tremor syndrome rather than PD.¹²

The severity of parkinsonism is an important marker for response to L-dopa. SWEDD patients with advanced parkinsonism score on the Modified Hoehn and Yahr score (HYS) may have higher response to L-dopa.¹⁶ In general, the treatment of dystonic tremor matches the treatment of dystonia and there are no specific therapeutic trials evaluating the treatment efficacy. Dystonic limb tremor may respond to anticholinergics and may be successfully treated by injecting botulinum toxin.³

Conclusion

The acronym SWEDD stands for Scans Without Evidence of Dopaminergic Deficit. The SWEDD syndrome has originated from clinical trials literature referring to PD mimics who had presynaptic functional neuroimaging. The syndrome is considered as a non-degenerative variant of the parkinsonian syndromes and its prevalence in general practice is currently not well known. However, about 10% of patients clinically diagnosed with early PD will have normal dopaminergic functional imaging.

The clinical distinction of tremulous SWEDD from early PD remains difficult in some cases, but presynaptic functional neuroimaging is essential for the differentiation between the two entities. SWEDD subjects in several clinical trials had no benefit from active medications. Furthermore, follow-up presynaptic neuroimaging demonstrated that the scans continued to be normal up to four years later, with negligible deterioration in clinical features.

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Nabil Aly, Consultant physician, Southport District General Hospital

Malek Al Moutlak, Specialist Registrar in Acute and General Medicine, Southport District General Hospital

[email protected]

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