Acute disseminated encephalomyelitis (ADEM) is a neuroinflammatory disorder characterised by central nervous system demyelination. Whereas the exact pathomechanisms remain elusive, the thalamus and the basal ganglia are commonly affected (1). Involvement of pathways within these motor circuits may result in complex secondary movement disorders (2), which necessitate tailored treatments according to individual clinical characteristics. Meanwhile deep brain stimulation (DBS) targeting these pathological network dynamics may also provide valuable insights into symptom-specific structural correlates, given its efficacy to a plethora of movement disorders such as dystonia (3) and hereditary myoclonus-dystonia (4). However, due to clinical heterogeneity and limited systematic analyses, accurately predicting outcomes of DBS for secondary dystonia syndromes is challenging. This uncertainty in prediction may lead to the cautious application of DBS beyond routine clinical practise, potentially resulting in the withholding of this effective treatment from certain patients (5). This report presents a case of secondary myoclonus-dystonia syndrome following ADEM in childhood, alleviated by DBS surgery at the internal part of the globus pallidus (GPi). We used a patient-specific connectome analysis to investigate the fibres and circuits modulated by stimulation.

We evaluated a 20-year-old male patient with a history of progressive dystonia, myoclonic jerks, speech difficulties, and impaired concentration. He was diagnosed with ADEM at the age of 10 in November 2009 and underwent several weeks of intensive medical therapy followed by months of rehabilitation. While initial symptoms (meningismus, encephalopathy, and cranial neuropathy) resolved, dystonic symptoms first appeared in December 2009, manifesting as involuntary movements in his right index finger while writing. Over the course of 3 years, the patient’s motor symptoms progressed beyond dystonia to myoclonic gestures.

On initial examination, the patient presented with involuntary movements of the right arm and face, which were characterised by focal dysrhythmic jerks that were exacerbated by certain postures, movements, and stimuli. He also presented with multifocal dystonia of the right arm and foot. Brain MRI revealed lesions in the pons, cerebellum, thalamus, and periventricular white matter around the lateral ventricles (Figure 1).

Despite the often self-limiting nature of ADEM, we hypothesised an association between focal demyelination in the thalamus (6–8) and brainstem (7, 8) and delayed onset of symptoms (Figures 1B,C). Especially in secondary dystonia, the time between structural lesions and the onset of symptoms can be several months or even years (7). In addition, there was no family history of neurological disorders in the entire family.

The patient was thus diagnosed with a secondary multifocal myoclonus-dystonia syndrome following ADEM. Dystonia and myoclonus had remained refractory to anticonvulsants (Piracetam, Levetiracetam) and anticholinergics (Trihexyphenidyl). Following thorough multidisciplinary evaluation, the patient decided to undergo unilateral lead placement in the left GPi using directional leads (Vercise Cartesia™ 2202-02 leads, Boston Scientific Neuromodulation Corporation, Valencia, United States). DBS programming according to monopolar review revealed the largest therapeutic window when the current was steered in the anterior direction of the distal three-segmented ring contact. Using a top-down approach, we gradually increased the stimulation amplitudes to the maximum tolerated voltage while maintaining a frequency of 130 Hz and a pulse width of 60 μs. The patient was allowed to adapt DBS settings according to his preferences and was informed about the known long-term effects in dystonia. He deliberately chose programme 2 [C+ 1−(30%), 2−(35%), 3−(35%), 4 mA, 60 μs, 130 Hz] because it provided the most significant relief of motor symptoms (Table 1).

During 3 years of follow-up, the patient reported worsening of dystonia and myoclonic jerks. To address these issues, we introduced four new stimulation programmes. In view of reports indicating efficacy of higher stimulation frequencies and pulse widths in the treatment of dystonia (9), increased pulse width (90 μs) was used in programme 6, higher frequency (185 Hz) in programme 7, and a combination of increased pulse width and frequency in programme 8, allowing the patient to adjust the settings prospectively. In addition, we used an imaging-guided optimisation of DBS parameters (programme 5) by directing the volume of tissue activated (VTA) towards proximal contacts moving from [C+, 1−(30%), 2−(35%), 3−(35%)] to [C+, 2−(10%), 4−(10%), 5−(40%), 7−(40%); avoiding contacts 3 and 6, respectively] in order to maximise the intersection between VTA and the ventral parts of the GPi, which are in close anatomical proximity to the pallidothalamic tract (PTT) (10). For dystonia, modulation of the PTT has been demonstrated to improve symptoms after pallidal DBS (11), while relief of myoclonus has been reported after contralateral pallidothalamic tractotomy (12). For this programme, we set the pulse width to 90 μs and the frequency to 185 Hz. A figure illustrating the changes in active DBS contacts after imaging-guided programming is provided as Supplementary material.

We assessed motor symptoms employing the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Myoclonus Rating Scale (UMRS) with DBS turned off and on. This resulted in predominant improvement in dystonia (OFF: 26, ON: 4) relative to myoclonus (OFF: 85, ON: 60) after imaging-guided adjustments of DBS parameters. See Figure 2 for a timeline of the patient’s medical history.

To the best of our knowledge, this is the first published case of secondary myoclonus-dystonia syndrome after ADEM successfully treated with unilateral GPi DBS. Adjustments of DBS parameters according to connectomic data for a modulation of distributed brain networks (24) has been used to identify stimulation sweet spots in patients suffering from movement disorders such as Parkinson’s disease (25, 26) and paediatric dystonia (27). In our patient, predominant improvement of dystonia relative to myoclonus was observed when the VTA was steered to overlap prefrontal and sensorimotor subregions of the GPi. This is consistent with recent findings suggesting that pallidal DBS effectively normalises dystonia-associated sensorimotor and prefrontal hyperactivity, which have been implicated in the pathophysiology of dystonia (28).

For secondary movement disorders, growing evidence highlights a key role of alterations in multiple anatomical pathways (29). For dystonia and myoclonus in particular, desynchronisation of the cortico-basal ganglia-cerebellar network has been put forward as an underlying mechanism (30). Our results indicate an alleviation of both symptoms upon modulation of basal ganglia circuits with fibre tracts intersecting the DRT and projecting to the SFG. The interpretation of a complex multinetwork model seems to be corroborated by findings indicating a synchronicity of pallidal oscillations and myoclonic jerks (31), whereas secondary myoclonus may also result from lesions in the cerebellum (32).

While DBS targeting the posterior part of the ventrolateral thalamic nucleus (VLp) can effectively address myoclonus (33, 34), in our patient, right-sided dystonic features were the predominant symptom, causing significant difficulties with activities of daily-living and severely affecting the patient’s quality of life. This led us to choose the left GPi as the most appropriate target for DBS treatment, given its widely demonstrated efficacy for ameliorating dystonia (3). While this case highlights the importance of a thorough clinical assessment as the basis for selecting stimulation targets, future insights from patient-specific connectivity profiles could improve our understanding of the underlying neural dynamics and provide insights into the precise target for DBS leads in rare movement disorders.

The datasets presented in this article are not readily available because of ethical and privacy restrictions. Requests to access the datasets should be directed to the corresponding author.

Ethical review and approval was not required for this case report in accordance with the local legislation and institution requirements. The patient provided written informed consent for the use of anonymized data for research purposes and for publication of any potentially identifiable images or data included in this article.

AC and LB collected the clinical data and co-wrote the manuscript. AC performed the image analysis. MG, MB, and CN contributed to the data curation. LT and DP confirmed the diagnosis of the case and supervised the study. All authors contributed to the article and approved the submitted version.