Surgical Outcomes in Rare Movement Disorders: A Report of Seventeen Patients from India and Review of Literature

Background: Rare movement disorders (RMDs) throw remarkable challenges to their appropriate management particularly when they are medically refractory. We studied the outcome of functional neurosurgery among patients with RMDs. Methods: Retrospective chart-review from 2006 to 2021 of patients with RMDs who underwent either Deep brain Stimulation (DBS) or lesional surgeries in the department of Neurology and Neurosurgery at a tertiary care centre. Results: Seventeen patients were included. Generalized dystonia (11 patients, 64.7%) and tremor (5 patients, 29.4%) were the most common indication for surgery whereas, Wilson’s disease (8 patients, 47.1%) and Neurodegeneration with brain iron accumulation (5 patients, 29.4%) were the most common aetiology. Sixteen patients (94.1%) had objective clinical improvement. Significant improvement was noted in the dystonia motor scores both at 6-months and 12-months follow-up (n = 11, p-value of <0.01 and 0.01 respectively). Comparison between DBS and lesional surgery showed no significant difference in the outcomes (p = 0.95 at 6-months and p = 0.53 at 12-months), with slight worsening of scores in the DBS arm at 12-months. Among five patients of refractory tremor with Wilson’s disease, there was remarkable improvement in the tremor scores by 85.0 ± 7.8% at the last follow-up. Speech impairment was the main complication observed with most of the other adverse events either transient or reversible. Discussion: Surgical options should be contemplated among patients with disabling medically refractory RMDs irrespective of the aetiology. Key to success lies in appropriate patient selection. In situations when DBS is not feasible, lesional surgeries can offer an excellent alternative with comparable efficacy and safety.


INTRODUCTION
Rare diseases (RD) are defined as those with a prevalence of less 200,000 people in United States [1]. On the contrary, the European Union under the jurisdiction of the European Medical Agency considers RDs as prevalence of less than or equal to 50 people per 100,000 population. As of now, 6000 to 8000 rare diseases have been discovered so far which has been estimated to affect 6-8% of the global population [1]. Collectively, they add up to significant burden of disease in the overall population. RDs pose remarkable challenges to the formulation of management strategies. Many of them are life-threatening or disabling which raises ethical concerns with regards to the conduct of controlled or randomised clinical trials. Thus, in most of these situations, treatment decisions are guided by evidence-limited medicine and principles of good clinical practice.
As per European Reference Network (ERN) for rare neurologic disorders (RND), neurologic manifestations are widely prevalent among RDs [2]. Movement disorders constitute one of the most important phenotypes in rare neurological disorders [2], treatment of which is often challenging with definite medical therapy available in only a handful of conditions. Often, the associated movement disorder responds unsatisfactorily to the standard medical management [3]. Since the definitive therapies for majority of the RMDs are still lacking, symptomatic management by means of surgical interventions in these often disabling and intractable movement disorders can play an immense role in improving the quality of living. With the refinement of surgical techniques, the past few decades have witnessed a significant upsurge in the role of surgical interventions as a part of treatment protocol in medically refractory movement disorders of various aetiologies. The evolution of Deep Brain Stimulation (DBS) technology has led to a decline in the number of publications related to ablative surgeries in recent times because of several advantages in the former such as reversibility, programmability, and bilateral targeting ability. Studies have also shown persistent beneficial effects of bilateral GPi DBS in patients with dystonia in long-term follow-up [4,5]. Younger age at surgery, higher BFMDRS motor and disability scores were associated with better clinical response to DBS [4]. GPi stimulation were associated with a greater clinical benefit compared to posterior ventro-lateral (VLp) thalamic stimulation [6]. The reversibility of DBS and its modulatory effects on neural plasticity in patients with dystonia after prolonged stimulation has been robustly demonstrated by means of transcranial magnetic stimulation [7]. Experience of DBS in Parkinson's disease has shown the large economic burden of DBS. However, in the long run, it successfully reduces the financial burden of pharmacotherapy and indirectly the social costs bu improving the quality of life [8]. Robust cost-effectiveness studies of DBS in movement disorders are still lacking, and remains an area of further research [9]. There has been significant improvement of health-related quality of life (HRQoL) in patients with dystonia post-DBS, particularly with primary dystonia [10]. Nevertheless, lesional surgeries still constitute a very crucial part of the armamentarium in the management [11,12]. This modality of management is particularly important in patients with financial constraints, poor compliance to follow-up visits and those at prone for infections.
Outcomes of surgical interventions in RMDs are less well-known in the literature. There is a dearth of studies on the impact of lesional surgeries and DBS among patients with RMDs. We aimed to discuss our experience over a period of past 15 years on the various surgical interventions performed among patients with RMDs with drug refractory dystonia, tremors, chorea and tics. demographic parameters and clinical profile. Repeatedmeasures ANOVA was used to compare the BFMDRS scores between the independent groups comprising lesioning and DBS as well as overall study population, at baseline, 6-months and 12-months post-surgery with post-hoc analysis wherever applicable. Independent samples T-test was applied between the two groups, lesional surgery and DBS, at each of the time frames. Surgical outcomes were also compared between the two disease groups, WD and NBIA at 6-months and 12-months post-surgical intervention. These tests were corrected using Bonferroni correction. Statistical analyses were applied only on patients with dystonia. A p-value of less than 0.05 was taken as statistically significant. Statistics were performed using IBM SPSS version 23. Graphpad Prism 8 was used for synthesis of figures.

RESULTS
Seventeen patients (11 males, 64.7%) were included in the study ( Table 1). The mean age at onset was 13.7 ± 8.9 years with the mean duration of illness prior to the surgery of 5.9 ± 3.7 years. The mean age at the time of the surgery was 19.8 ± 9.7 years, with a range of 6 years to 32 years. The most common underlying aetiology was WD (8 patients, 47.1%) followed by NBIA (5 patients, 29.4%), and the predominant phenomenology at the time of surgeries was dystonia in 11 patients (64.7%) and tremor in 5 patients (29.4%). Among patients with dystonia, 6-month follow-up data of BFMDRS motor severity scores were available in all and 12-month follow-up scores were available for 9 patients. Lack of data of these two patients was attributable to the unfortunate demise of one patient of WD from hepatic failure and the absence of follow-up of the patient with DYT-TOR1A (Table 1, Figure  1). Genetic testing was performed in 3 cases. Patient DYT1 had previously reported heterozygous 3-bp deletion (c.907_909del) in exon-5 of TOR1A gene, patient NPC had novel homozygous likely pathogenic missense variant (c.2473T > C;p.Tr825His) in exon-16 of NPC1 gene, and patient NAC had novel homozygous pathogenic nonsense variant (c.9477G < > A;p.Trp3159Ter) in exon-72 of VPS13A gene. Clinical vignette is provided for patient NBIA4, WD8, DYT1, and NBIA2 along with videos for patient NBIA4 (Video e1), WD8 (Video e2), and DYT1 (Video e3).

TREATMENT PRIOR TO THE SURGERY
The patients were tried on symptomatic medical therapy which included clonazepam, baclofen, tetrabenazine, trihexyphenidyl and decoppering agents for a mean duration of 4.6 ± 2.6 years. In patients with WD, the mean daily dose of D-Penicillamine was 937.5 ± 320.0 mg while for Zinc, it was 632.5 ± 341.6 mg. Among patients with primary and secondary dystonia, the mean daily dosage of trihexyphenidyl, tetrabenazine, baclofen, clonazepam and diazepam were 13.6 ± 5.3 mg, 87.5 ± 19.8 mg, 26.8 ± 13.1 mg, 1.5 ± 0.9 mg and 8.8 ± 1.8 mg respectively. Patients with severely disabling movement disorders and suboptimal response to the maximal therapeutic and tolerated dosage of the drugs were considered for the surgical intervention after a detailed discussion with patient and the caregivers.

SURGICAL INTERVENTION: DEEP BRAIN STIMULATION
Nine patients (52.9%) underwent DBS with the mean duration of illness prior to DBS of 4.8 ± 1.8 years (Tables  1, 2). Seven patients (77.8%) underwent DBS for dystonia with underlying aetiology of NBIA spectrum disorders in three patients (33.3%), WD in two patients (22.2%), and Niemann-Pick Type C (NPC) and DYT-TOR1A in one patient each (11.1%). Other indications were chorea due to Neuroacanthocytosis in one patient and complex motor and vocal tics in Tourette syndrome in one patient. All these patients underwent bilateral Globus Pallidus interna (GPi) DBS.

SURGICAL INTERVENTION: LESIONAL SURGERIES
Eight patients (47.1%) underwent lesioning surgery after a mean duration of illness of 6.5 ± 5.2 years prior to surgery. The primary indication was tremor in four patients (57.1%), all of whom had WD (n = 4). Three patients with dystonia (37.5%), two with WD and one with NBIA underwent lesioning. A single patient with combined tremor and dystonia who underwent lesioning had NBIA as underlying etiology. Among patients with tremor, three patients underwent unilateral ventralis intermediate nucleus (ViM) thalamotomy (left-2, right-1) whereas one patient underwent bilateral ViM thalamotomy in 2 stages 6-months apart. All patients with dystonia underwent bilateral pallidotomy. The patient with tremor and dystonia (patient NBIA2) underwent left ViM thalamotomy as the tremor was more disabling (Tables 1, 2).

SURGICAL OUTCOMES OF PATIENTS WITH DYSTONIA
Total eleven patients had significant dystonia in our cohort of which ten patients underwent surgeries primarily for dystonia (DBS-7, pallidotomy-3). Irrespective of the type of surgical intervention, statistically significant improvement was noted in the BFMDRS motor scores at 6-months(p < 0.001) and 12-months interval (p = 0.02) compared to the baseline. Lesioning surgery led to a reduction of BFMDRS score by 26.9 ± 19.5% (p = 0.11) at 6 months and 17.4

VARIABLES(N,% OR MEAN ± S.D) TOTAL LESIONING DBS REMARKS
Number of patients 17 8 9 Mean age at onset (y) 13     and anxiety respectively. OCD scores (YBOCSS) remained 0 at follow up. This patient was tried on several drugs for varying intervals upto four years and repetitive transcranial magnetic stimulation (rTMS) before he underwent DBS (Table 2). The infection subsequently subsided with no residual complications and patient continued to have sustained improvement even after lead removal. Transient imbalance was seen in two of the patients. Both these patients also had post-surgical pneumocephalus. (Tables 1, 2).

CASE VIGNETTES Patient NBIA4
This 4-year-old girl presented with generalized dystonia of one year duration. The clinical presentation of pediatric dystonia, significant bulbar involvement and opisthotonus and MRI brain finding of eye-of-tiger appearance suggested a diagnosis of NBIA-pantothenate kinaseassociated neurodegeneration (NBIA-PKAN). She was started on medical management which was escalated to tetrabenazine, trihexyphenidyl, clonazepam over a period of next 3 years. She responded unsatisfactorily to medical management and was subsequently taken for DBS. Her BFMDRS score at presentation was 56 which worsened to 92 pre-operatively. She made significant clinical improvement. Her BFMDRS scores improved to 64 and 59 at 6-months and 12-months follow-up respectively (Video e1). Unfortunately, during the follow-up at 2 years, she developed surgical site infection of the cranial wound which mandated removal of leads and intravenous antibiotics after which the infection was controlled. However, she continued to have beneficial effects probably due to the lesional effect. Thereafter, she was lost to follow up. Later, DBS leads were re-implanted at outside centre. Unfortunately, she passed away following chest infection.

Patient WD8
This 20-year-old lady, diagnosed patient of WD on treatment, presented to us with severely disabling and medically refractory tremors of 4 years duration. The patient had FTM score of 82 at presentation which did not improve significantly over next two years despite being on penicillamine, zinc, clonazepam, levodopa-carbidopa and propranolol. Subsequently, she underwent left ViM thalamotomy and had a remarkable improvement (93%) in tremors to a score of 5 at 1 year of follow-up (Video e2).

Patient DYT1
A13-year-old boy presented with progressive isolated generalized dystonia of 4-years duration, with the onset from right lower limb. At the time of admission, the patient was severely disabled BFMDRS motor score for dystonia of 64. MRI brain with spine was normal except for scoliosis. Genetic testing revealed a previously reported heterozygous 3-bp deletion (c.907_909del) in exon-5 of TOR1A gene confirming the diagnosis as DYT-TOR1A. Patient was on medical management with tetrabenazine (75 mg/day), trihexyphenidyl (12 mg/day) and levodopa 400 mg but showed unsatisfactory clinical response over the next one year. Subsequently, he underwent bilateral GPi-DBS. At 6-months follow up, patient reported significant clinical improvement with reduction in BFMDRS scores to 23. Postsurgery tetrabenazine and levodopa was stopped and was maintaining well on trihexyphenidyl 12 mg during last follow up at 9 months (Video e3).

Patient NBIA2
This 30-year-old gentleman, diagnosed case of NBIA, presented with features suggestive of early childhood onset generalized combined dystonia with associated tremors from the age of 13 years. Patient was severely disabled due to medical refractoriness of his symptoms. He was on trihexyphenidyl (18 mg/day) and baclofen (30 mg/ day). Examination revealed BFMDRS motor scores of 92.5 and FTM score of 54. Patient underwent left ViM thalamotomy. There was notable improvement in dystonia to BFMDRS score of 54 at 6 months follow up, which however was not sustained as the score dropped off to a score of 74 at 12 months and 84 at 3 years. However, tremors showed a sustained improvement to a score of 12 at 3 years follow up. Post-operatively, patient developed blepharospasm, which subsequently improved. There was no response in his lingual dystonia, hence botulinum toxin was administered, in addition of continuation of medical therapy.

DISCUSSION
In this retrospective chart review, we report a series of patients with RMDs who underwent functional neurosurgery for various medically refractory disabling movement disorders. Dystonia was the most common phenomenological indication with WD being the most common aetiology. Overall, the outcome was modest in both DBS and lesioning groups and was better in the first six months compared to the one year follow up. There was no significant difference in the outcome either with respect to the surgery (DBS versus lesioning) or the aetiology (WD versus NBIA). However, patients with tremor who underwent ViM thalamotomy had excellent and sustained response over long follow-up. Speech impairment was the most common post-surgical complication and life-threatening complications were observed in two patients; post-operative status dystonicus requiring intensive care in one patient and infection of DBS lead requiring lead removal in the other.

OUTCOMES BASED ON PHENOMENOLOGY
Generalized dystonia is often a highly disabling syndrome and usually has unsatisfactory response to medications further limited by side effects at the high doses required for control of dystonia. Functional surgical treatment options either in the form of DBS or lesioning surgeries can up to a certain extent fill this therapeutic gap. However, the response may not be uniform and depend on various factors such as the underlying aetiology, duration of illness before surgery, nature of progression, underlying disability, and other associated neurological and systemic features. Whereas primary isolated dystonia, lower preoperative score, early surgery predicted a better outcome, combined and progressive dystonia tend to do worse with DBS [16,17]. In our report as well, among dystonia, patient with DYT-TOR1A, an isolated dystonia had the maximum improvement. The other patients with dystonia were secondary to WD, NBIA or NPC and had mild to moderate response and often were not sustained at one year follow up. Even though effective, in some patients, DBS may not be feasible due to lack of accessibility and affordability. In such patients, bilateral pallidotomy can be an effective treatment alternative [18]. In addition, pallidotomy is devoid of hardware related adverse effects and need of long-term programming. However, bulbar adverse effects can be more in pallidotomy. In patients with affordability and accessibility issues, having contraindication to DBS, and in those in whom severity of dystonia outweighs the risk of permanent speech disorders, one may consider pallidotomy. In our cohort, three patients underwent bilateral pallidotomy for dystonia due to affordability issues and had modest response. In line with previous studies, both DBS and pallidotomy had similar overall response in our cohort. However, the sample size was too small [19].
Similarly, thalamotomy can be a good alternative to DBS in patients with medically refractory tremor. Often it is done unilaterally, opposite to the most affected side owing to the increased risk of adverse events with bilateral thalamotomy. All patients underwent ViM thalamotomy for refractory tremor in this study and all had moderate to excellent response that was sustained in the majority. Tremor of various aetiologies respond to thalamotomy with minimal side effects and should be considered in patient having predominantly unilateral tremor or in those not affordable for DBS especially so, when it is the dominant and disabling symptom irrespective of the underlying aetiology [14].

OUTCOME BASED ON AETIOLOGY Wilson's disease
Prior studies in the field investigating the impact of surgical interventions among patients of WD with medically refractory movement disorder have shown variable results. For instance, in a study on 27 patients of WD, 17 of them reported clinical improvement after stereotactic destruction of ventrolateral nucleus of thalamus and subthalamus (  complications. They concluded significant improvement in hyperkinesia and greater appropriateness of unilateral surgery compared to bilateral ones [20]. Another study reported clinically significant benefit in dystonic symptoms along with improvement in functional activity following bilateral GPi stimulation [21]. Posterior subthalamic area DBS led to significant benefits in controlling refractory tremors (Fahn-Tolosa-Martin tremor rating scale, FTMTS 4/144 with neurostimulator ON and 74/144 in OFF state) in a patient of proven WD. There was significant albeit slower improvement in dystonia as well [22]. Our study which comprised 8 patients of WD, projected similar results with significant improvement in tremors in all 4 cases but much lesser benefit in dystonia.

NBIA
Despite limited number of studies, the surgical outcomes among patients with NBIA have been promising. In a study of 6 patients of PKAN, the largest series so far, sustained improvement in the BFMDRS motor scores was noted ranging from 46% to 91.5%. Compared to pallidal stimulation, DBS of subthalamic nucleus was found to be less beneficial [23]. Case reports prior and subsequent to this series have provided evidence on the favourable effects of surgical intervention on PKAN patients [24][25][26].
In one of the case reports, the patient with proven PKAN had gradual decline in the motor scores following initial dramatic benefits with bilateral GPi DBS. Authors attributed this to the natural course of disease in which the dystonia gradually gets converted to fixed deformities, rather than fall in DBS efficacy. The functional outcome at five years was still better compared to that of pre-operative state despite the deterioration [27]. In another report, a patient of early onset PKAN demonstrated initial significant benefit following bilateral GPi-DBS but worsened after removal of device due to infection. While the event was unfortunate, it has served to emphasise on the clinically meaningful impact of DBS in these patients [28]. De Vloo et al. in their meta-analysis on 99 patients of NBIA revealed level 4 evidence on the role of GPi DBS in improving dystonia [29]. Our current study, comprising five patients of NBIA, showed initial improvement at 6 months follow up followed by deterioration of dystonia, although severity was lesser compared to pre-surgical state, corroborating with previous studies. Patients continued to be on anti-dystonic therapy.

Neuroacanthocytosis
Anecdotal reports have revealed significant benefits of DBS among patients with chorea-acanthocytosis with improvements in truncal spasms, chorea and dystonia following DBS [30]. However, the rarity of the disease has precluded large scale studies. A case report on two patients with intractable chorea demonstrated definite improvements at low frequency stimulation (40 Hz) of GPi-DBS [31]. On the contrary, improvement in dystonia and chorea were exhibited on high frequency stimulation in other case reports, whereas in another report there was no clinically significant outcome [32][33][34]. Our experience with single patient revealed persistence of choreiform movements although of reduced severity at 4 year follow up.

Primary dystonia
Beneficial effects of DBS in cases of primary dystonia is evident based on various studies [35][36][37][38][39][40][41]. Long term experience with DBS has been satisfactory as shown in a limited number of studies till date, not only with respect to motor benefits but also in terms of disability and safety profile [42][43][44]. Significant improvement of 39-47% in the DBS group in comparison to the sham group (5-22%) was demonstrated in a 3-month randomised controlled trial of pallidal DBS in primary dystonia [45]. The current study showed remarkable benefits at 9 months follow up after bilateral GPi DBS in a single case of TOR1A mutation associated primary dystonia, re-emphasising the evidence based literature.

Tourette syndrome
While grey areas are still persistent with regards to the role of surgical intervention in medically refractory Tourette's syndrome, results from a randomised cross-over trial have been promising with significant improvement in YGTSS scores post DBS [46][47]. The results from the multinational study on medically refractory tic disorder among patients with Tourette syndrome by the International Deep Brain Stimulation Database and Registry showed significant symptomatic improvement after DBS implantation (from mean YGTSS of 70.01 at baseline to 41.19 at 1-year followup) [48]. The common sites for implantation of electrodes were chosen as centro-median region of Thalamus followed by anterior and posterior GPi, and anterior limb of internal capsule [48]. However, the data didn't reveal any significant difference in clinical outcomes depending on location of stimulation at 1-year follow-up. Other studies have also corroborated the positive impact of DBS on the tic severity scales amongst these patients [49]. Our experience with a single patient has shown significant initial improvement but there was relapse of motor symptoms at 1 year and mild improvement in behavioural symptoms at 3 years follow up.

COMPLICATIONS OF SURGERY
Complications of DBS can be operation, hardware or stimulation related [50]. While there were no intra-operative complications in our study, one of the patients who had undergone DBS suffered from surgical site infection which mandated surgical removal of leads. Among post-operative complications, speech impairment was the single most common complication. A recent meta-analysis showed a significant risk of speech and language related adverse effects following thalamotomy amounting to 10.3% in the unilateral dystonia subgroup which increased to 56.3% in the bilateral dystonia group [51]. The same study estimated the risk of stimulation induced dysarthria after thalamic DBS to be 24.2% with unilateral procedures and 39.2% with bilateral procedures. Status dystonicus post DBS was reported in a single patient. Although a rare complication, there are scanty reports of the same developing after an uneventful DBS surgery [52]. While sudden failure of DBS device is one of the mechanisms, it has been postulated that just like any other surgery, DBS itself can act as a trigger for worsening dystonia [53]. Blepharospasm and apraxia of eyelid opening are other known complications with DBS, which were also reported by some of our patients [54].

LIMITATIONS
The present study has some obvious limitations such as retrospective nature, small study population, heterogenous study group, lack of a control group and non-blinded assessment. In the context of small sample size, the tests of statistical significance should be interpreted with caution. However, the rarity of such disorders and the phenotypic heterogeneity in each of them is a challenge and makes it difficult to plan a large controlled study. The present study is an attempt to report our experience and the outcome of functional neurosurgery in various rare movement disorders in order to add to the existing knowledge and to benefit the future patients.

CONCLUSION
To conclude, when optimal medical therapy fails to provide a reasonable improvement in the quality of life, functional neurosurgery can be considered on a case-to-case basis. Even though the overall response is significant compared to the baseline, it is often modest and temporary. However, in patients with predominant tremor, primary dystonia, and Tourette syndrome, an excellent and lasting response can be expected and surgery should be contemplated in such cases. It is important to counsel regarding the realistic expectations of benefits and risks associated before going ahead with surgery. Management of rare movement disorders pose a significant challenge due to the rarity of the disorder, dearth of published evidence and practical limitations to perform a planned systematic trial. In this background, it is important to report such cases irrespective of the nature of the outcome to improve the overall understanding. It will help in future, in better patient selection, avoiding unnecessary invasive procedures, provide a realistic expectation and to plan a better and appropriate target. A worldwide registry of patient who have undergone functional neurosurgery for various rare movement disorder may be a right step forward in this regard.