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  In this Article
 »  Abstract
 »  Early DBS, What ...
 »  GPi v/s STN Targ...
 »  Newer Targets fo...
 »  Redressal of Non...
 »  Deep Brain Stimu...
 »  Technological In...
 »  Long-Term Effect...
 » Conclusion
 »  References
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Table of Contents    
SYMPOSIUM
Year : 2020  |  Volume : 68  |  Issue : 8  |  Page : 179-186

Deep Brain Stimulation for Parkinson's Disease: Currents Status and Emerging Concepts


Jaslok Hospital and Research Center, 15 Dr. G. Deshmukh Marg, Mumbai, Maharashtra, India

Date of Web Publication5-Dec-2020

Correspondence Address:
Dr. Paresh K Doshi
Jaslok Hospital and Research Center, 15 Dr. G. Deshmukh Marg, Mumbai - 400 026, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.302466

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 » Abstract 


The clinical application of DBS has become manifold and there has been a tremendous growth in DBS technology in the last few decades making it safer and user friendly. The earlier concept of its delayed application in motor fluctuations of Parkinson's disease has been replaced by Class-I evidence of EARLY-STIM trial in 2013, leading to its FDA approval to be used in early-stage despite criticism. Various studies have provided evidence of beneficial effects of bilateral STN-DBS on both motor as well as nonmotor symptoms and different new targets such as the pedunculopontine nucleus, posterior subthalamic area or caudal zona incerta, centromedian-parafascicular complex, and substantia nigra pars reticulata have now become a new area of interest in addition to the subthalamic nucleus and globus pallidus internus for the alleviation of both motor and nonmotor symptoms of Parkinson's disease. New data has confirmed that the DBS is clinically as effective and safe in elderly patients as it is in younger ones. Technological advances like current steering, directional leads, and closed-loop DBS are directed towards reducing the stimulation-induced adverse effects and preservation of the battery life for a longer period. Results of the long-term efficacy of DBS on Parkinson's disease are now available. These have shown that as the motor benefit continues, the clinical progression of Parkinson's disease also continues. We plan to discuss all these in this paper.


Keywords: Deep Brain Stimulation, DBS, indications for DBS, Early DBS, DBS in elderly, dbs outcome
Key Message: The understanding and indications of DBS for Parkinson′s disease have changed from those that were initially described. Several questions, still remain unanswered; e.g. role of Early DBS, Long term effects of DBS or its effect on non-motor function, which is the ideal target, GPi or STN, etc. We have discussed these in this paper. Recent technological advancements, like directional lead and constant current stimulation, have helped in improving the efficacy and therapeutic window of DBS, whlist, others like closed loop stimulation are just being introduced. This will change the way we offer DBS. The current paper sheds some light on this.


How to cite this article:
Doshi PK, Das D. Deep Brain Stimulation for Parkinson's Disease: Currents Status and Emerging Concepts. Neurol India 2020;68, Suppl S2:179-86

How to cite this URL:
Doshi PK, Das D. Deep Brain Stimulation for Parkinson's Disease: Currents Status and Emerging Concepts. Neurol India [serial online] 2020 [cited 2021 Feb 24];68, Suppl S2:179-86. Available from: https://www.neurologyindia.com/text.asp?2020/68/8/179/302466




The evolution of deep brain stimulation (DBS) has come a long way since its discovery and successful application by Benabid, initially for tremor and later for Parkinson's disease (PD).[1],[2] The reversibility and titrability qualities, in comparison to lesioning surgery, led to its rapid growth in the field of treatment of movement disorder in the following decades. The subsequent developments have led to the expansion of its use for several indications, besides movement disorders.[3] PD, however, remains the most common application of DBS. Most of the aspects e.g., selection of the patients, techniques, and outcome are now standardized and uniform across centers. Increased experience and advances in technology have refined the application of DBS for PD. We plan to discuss these in this paper.


 » Early DBS, What do we know? Top


DBS of the subthalamic nucleus (STN) and the globus pallidus internus (GPi) has been demonstrated to improve motor fluctuations and reduce OFF duration in PD patients.[4],[5] Conventionally, DBS is offered at a mean age of 11 to 12 years after diagnosis.[6],[7],[8] In 2013, results of the EARLY-STIM study, a large-scale multicenter trial to evaluate DBS in PD with early motor fluctuations, revealed the superiority of STN-DBS for treating PD patients with early motor complications compared to the best oral medications (BOM).[9] The quality of life (QoL) measured by PD questionnaire (PDQ-39) score after DBS improved by 7.8 points vs 0.2 points worsened by BOM alone. Medication dose reduced by 39% in the neurostimulation group vs 21% increase in the BOM group. Nearly 53% improvement was noted in unified Parkinson's disease rating scale (UPDRS)-III scores in the neurostimulation group vs 4% in the BOM group. No significant cognitive changes were found between both groups. Serious adverse events occurred in 54.8% of the patients in the neurostimulation group vs 44.1% of those in the BOM group. Depression was more persistent in the neurostimulation group. This crucial study demonstrated Class I evidence of sustained motor and QoL improvement after 2 years of DBS compared to BOM alone. Following this, the Food and Drug Administration (FDA) approved DBS for PD with early motor fluctuation. A decision analysis model of early vs delayed bilateral DBS implantation exhibited early intervention results in superior cost-effectiveness due to a greater quality-adjusted life expectancy by a reduction in pharmaceutical cost, therapy, and specialist consultations.[10] Recently, results of a prospective single-blinded randomized pilot clinical trial studying 5-year outcomes from the STN-DBS in early-stage PD patients (Hoehn & Yahr II off medications) who received bilateral STN-DBS plus optimal drug therapy (ODT) vs ODT alone have been published.[9] At the end of 5 years, the early STN-DBS + ODT subjects required lower levodopa-equivalent daily doses (LEDDs) and had 0.06 times the odds of requiring polypharmacy compared to early ODT subjects. The odds of having worse rest tremor for early STN-DBS + ODT subjects were 0.21 times those of early ODT subjects. The safety profile was similar between both groups. They concluded early DBS reduces the need for the complexity of PD medications while providing long-term motor benefit over standard medical therapy.

However, people have raised concerns and advised caution for implementing this criterion of early intervention based on the EARLY-STIM criteria. There have been extensive ethical discussion interpreting this data.[11] Despite a strong design, the inclusion criteria excluded patients older than 60 years, an age group that has a high risk of the rapid development of motor complications, and this data may not apply to elderly patients who have other issues.[12] The 2-year follow-up limits the long-term expectations from the procedure. The probability of a placebo and lessebo effect, that would prevail for a long time given the natural history of disease progression, had not been factored in the results.[13],[14] Mestre et al. enumerated five important risk factors to be considered before recommending early STN-DBS in the course of PD when motor complications are still mild.[15] First, undesired inclusion of patients with atypical  Parkinsonism More Details may occur, as they are operated earlier than 5 years after the onset of symptoms. Second, the benefit-to-risk ratio in patients undergoing STN-DBS just after the onset of motor complications could be much lesser than in PD patients with greater preoperative disability from motor complications since the baseline disability at the time of surgery is mild. Third, motor complications developing after a few years remain minimally disabling for a long period, and in older patients more than 60 years, there is an important risk of the more rapid development of symptoms that do not respond well to either dopaminergic treatment or DBS. Fourth, not all centers have an expert multidisciplinary team involving a movement disorder neurologist, a neurosurgeon, a neuropsychologist, and a psychiatrist to manage relatively young patients who present with a higher risk of suicide. Fifth, there is a higher probability of lead fractures or malfunctioning and a greater number of implanted pulse generators (IPGs) that will require additional surgeries as patients operated at younger age will live for many years with the implanted material. Though some of these points are worth considering, our personal experience suggests that a multidisciplinary center with a low complication rate should be willing to offer early DBS. The question should be, not when? but to whom? early DBS should be offered. In our practice, we offer it to patients presenting with tremor, rigidity, and dyskinesia as disabilities affecting either their work or profession. It is important to offer the option of DBS with proper counseling to such patients and make an informed decision.[16]


 » GPi v/s STN Target for PD Top


The globus pallidus internus (GPi) and the STN are commonly targeted in DBS for PD. The initial liking for the STN as the preferred target, with several prominent studies[17],[18] backing its superiority, has been questioned as more and more information about the impact of STN-DBS on cognitive, behavioral, and other side effects have come to light. The smaller size of STN requiring much lower charge density and stimulation parameters compared to the GPi has a distinct advantage for longer battery life.[19] Several studies have been conducted to evaluate the advantage of one target over the other. The COMPARE trial investigated unilateral GPi or STN-DBS in 45 patients and showed a similar improvement of motor function and mood in both groups but QoL improved more in the GPi group than in the STN group.[20] Another randomized control trial by Follett et al. comparing 24-month outcomes for patients who underwent GPi or STN stimulation did not show any significant difference in the motor outcome. However, patients with STN-DBS required a lower dose of dopaminergic agents than those with GPi DBS. The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation but no significant difference in adverse events was found between these groups.[21] The veteran's group conducted a randomized trial to compare DBS between the two targets and concluded that, the motor improvements with off medications and on stimulation showed no statistical difference between the effects of DBS at either target at 36 months. The study provided Class III evidence showing that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical targets between GPi vs STN.[22] The randomized control trial by Netherlands Subthalamic and Pallidal Stimulation (NSTAPS) group showed a greater change in motor scores in the medication off phase with STN-DBS vs GPi. STN may be the preferred target for DBS in PD due to more substantial improvement of symptoms and disability in the off phase, in combination with the need for fewer drugs and lower battery consumption.[23] Randomized trials have not been able to prove that GPi is more effective in controlling dyskinesias. Acute changes like delirium, confusion, hypomania, and apathetic mood have been noted after STN-DBS, and GPi DBS is associated with lesser long-term cognitive deterioration.[24] A meta-analysis of randomized controlled trials, of GPi V/s STN, by Tan et al., concluded that DBS of GPi and STN significantly improve symptoms, functionality, and QoL in advanced PD patients.[25] GPi DBS allowed greater recovery of verbal fluency and provided greater relief of depression symptoms as well as better QoL. However, GPi DBS was associated with an increased dosage of LEDD. The question regarding which target is superior remained open for discussion and finally, an understanding of the target selection depends on individual symptoms, neurocognitive/mood status, therapeutic goals of DBS (e.g., levodopa reduction), and surgical expertise [Table 1].
Table 1: Comparison between the outcomes of STN and GPi targets for PD

Click here to view



 » Newer Targets for Motor Symptoms Top


In a subset of PD patients (including advanced PD), there are certain axial and NMS that cannot be addressed by medicine or GPi/STN stimulation.[27] Efforts have been made to address these using alternative targets or multiple targets. The pedunculopontine nucleus (PPN), caudal zona incerta (cZi), thalamic centromedian-parafascicular complex (CM-Pf), and substantia nigra pars reticulate (SNr) are now being evaluated as new experimental brain targets for PD.

The Pedunculopontine Nucleus (PPN) is part of the functional area of the mesencephalon which exerts a crucial role in locomotion.[28] The PPN is divided into two parts: the pars dissipata, located at the rostrocaudal axis contains cholinergic, glutamatergic neuron subtypes, and the pars compacta (PPNc), located dorsolaterally containing mainly cholinergic neurons.[29] In PD patients with freezing of gait, there is increased activation of the mesencephalic locomotor region compared to PD patients without freezing.[30] Degeneration of nearly 50% of the PPNc cholinergic neurons is found in neuropathological studies in PD patients.[31],[32] PD patients with postural instability have a more pronounced cholinergic loss within the PPN compared to those without postural instability.[33] These observations have led to the investigation of PPN as a potential target for improving gait and balance in PD patients.

PPN is a heterogeneous nucleus, with boundaries not well defined, it lacks clear neurophysiological activity and acute clinical benefit during surgery, which has led to the variability in targeting by several authors [Figure 1] and [Figure 2].[27],[34],[35] A double-blind study by Moro et al. did not show any significant improvement in the motor scores by unilateral PPN stimulation in six PD patients at 3 and 12 months of follow-up but there was a significant reduction in falls 1 year after surgery.[36] Thevathasan et al. reported an improvement of gait and falls with bilateral PPN stimulation 2 years after surgery.[37] Mazzone et al. in their studies of PPN-DBS in 24 patients of PD and four patients of PSP with follow-up of 3.8 years, reported an improvement in UPDRS III scores and axial symptoms (UPDRS items 27–30) (off levodopa therapy).[38],[39] PPN, thus, is a promising target that needs further evaluation.
Figure 1: Targeting the PPN area. Various groups have slightly different targeting

Click here to view
Figure 2: Proton density MRI showing PPN targeting by author

Click here to view


The posterior subthalamic area (PSA) has been suggested as an alternative DBS target for the control of tremor.[40] Plaha et al. refer to this area as cZi and suggest that the stimulation of this area can provide optimal control of tremor, rigidity, and to some extent of bradykinesia, as well.[41] However, these findings should be taken cautiously since the little experience with cZi DBS and the number of patients included is small and no randomized studies are available. Recent studies have shown that stimulation within the STN increased voice intensity, but stimulation within the cZi worsened it as well as the articulation of speech.[42],[43] Khan et al. investigated the combined effects of bilateral PPN-DBS and caudal cZi-DBS and suggested that PPN stimulation alone was insufficient in improving “on” medication and resistant axial symptoms and that costimulation of cZi could provide an additive, beneficial role.[44]

The Centromedian-parafascicular Complex (CM-Pf) has been studied for its critical role in arousal, sensory awareness, pain control, behavior, and cognition.[45] Some clinical data in humans have also pointed out its possible role in dyskinesias and the stimulation of this region for pain control showed additional improvement in involuntary movements.[46],[47] The CM-Pf complex has got important connections with basal ganglia and undergoes partial neurodegeneration in PD. Multitarget strategy with STN or GPi and CM-Pf stimulation have been tried. CM-Pf stimulation improves tremor and dyskinesias but less than GPi. CM-Pf stimulation slightly reduces bradykinesia and rigidity, but less than STN or GPi stimulation.[48] Further studies are required to evaluate these preliminary observations obtained. Another study with a small sample size of six patients demonstrated that CM-Pf stimulation alone led to significantly reduced freezing of gait, better than GPi stimulation alone but CM-Pf stimulation alone may not control PD motor symptoms adequately leading to the possibility of a multiple-target stimulation strategy to optimize axial symptoms and overall motor control in PD.[49]

The Substantia Nigra Pars Reticulata (SNr) lies ventrolateral to the STN. Axial motor symptomatology, including gait impairment and postural instability, in PD patients, has shown a favorable response to SNr stimulation in different studies.[50] UPDRS III axial motor subscores and braking capacity have shown significant improvements but distal motor symptoms like segmental akinesia, limb rigidity, and tremor have not shown good recovery with SNr-DBS. A double-blind, randomized controlled trial with combined STN and SNr stimulation has shown significant improvement in freezing of gait, but not in other axial symptoms when compared to STN-DBS alone. SNr represents an area of preference in the studies evaluating its potential as a DBS target. The outcome has been variable, as some studies of SNr-DBS have shown improvement in axial motor symptoms, but the incidence of acute mania, hypomania, and depression limit its utility as a target in alleviating PD symptoms.[51],[52]


 » Redressal of Nonmotor Symptoms Top


Nonmotor symptoms (NMS) are a constellation of different symptoms e.g., autonomic dysfunction, cognitive abnormalities, sleep disorders, mood disorders, and pain and sensory disorders. They result from multineuropeptide dysfunction including central dopaminergic, cholinergic, noradrenergic, and serotonergic systems and also the peripheral nervous system.[53],[54] Some NMS symptoms like punding and psychosis are also secondary to pharmacotherapy treatment. In addition to being common, NMS has been more disabling than the motor symptoms of tremor and bradykinesia.[55] The role of bilateral STN-DBS in treating motor symptoms is well recognized, but the effect of bilateral STN stimulation on the NMSs in PD is yet to evolve. A study by Zibetti et al. reported that NMS e.g., salivation, swallowing, and sensory complaints were ameliorated to a comparable degree by the medication “On” state, and the “On” state persisted longer postoperatively.[56] Witjas et al. reported NMS-like pain/sensory fluctuations showed the best response to STN-DBS followed by dysautonomic and cognitive fluctuations.[57] EUROPAR, the IPMDS Non-Motor PD study group[54] in a prospective, observational, multicenter, international study including 67 PD patients undergoing bilateral STN-DBS, examined the Non-motor Symptom Scale (NMSS), Non-Motor Symptoms Questionnaire (NMS Q), Parkinson's Disease Questionnaire-8 (PDSQ-8), Scales for Outcomes in Parkinson's Disease-motor examination, -activities of daily living, and -complications (SCOPA-A, -B, -C), and LEDD preoperatively and at 5- and 24-month follow-up. The comparison of baseline with 24-month follow-up showed significant improvements in the NMSS (small effect), SCOPA examination showed a moderate effect, and SCOPA-complications and LEDD showed large effects. This study provided evidence of the beneficial effects of bilateral STN-DBS on NMS and they concluded that the extent of NMSV improvement was directly proportionate to improvements in QoL, activities of daily living, and motor complications. The same group also observed significant improvements of PD-specific sleep scale (PDSS) (small effect), SCOPA-A (moderate effect), SCOPA-C, and LEDD (large effects) after bilateral STN-DBS, and there was a significant relationship between sleep and QoL improvements.[54] A prospective study conducted by Kandadai, et al.[71] among 35 patients with PD who underwent bilateral STN-DBS was assessed by NMS Q and NMSS preoperatively and 6 months postoperatively and concluded that: i) NMSs were seen in all patients, ii) insomnia (66%), nocturia (63%), urgency (49%), and constipation (49%) were the most frequent symptoms in order preoperatively and iii) there was a statistically significant reduction in overall NMSs in both NMS Q (P = 0.008) and NMSS (P = 0.0013) after STN-DBS. There was a significant reduction in cardiovascular symptoms with improvement in sleep, mood, insomnia, and light-headedness but weight gain was more common after STN-DBS.


 » Deep Brain Stimulation in Elderly Top


Age is certainly a critical factor in patient selection criteria for DBS in PD. Some previous studies have shown worsening of activities of daily living scores, as well as axial motor scores in the ON medication state; despite improvement in motor complications, in older patients in contrast to improvement in younger patients, following STN-DBS.[58],[59] However, this has not been the experience of others who have reported uniform benefits from DBS in elderly patients as compared to their younger counterparts.[60],[61],[62],[63] Little difference in postoperative complication rates, length of hospital stay, or mortality rates within 90 days of surgery in older vs younger patients, support an expansion of the therapeutic window greater than the traditional age cutoff proposed by DeLong et al.[60] Vats and Doshi reported that reduction in LEDD was more in the younger PD patients, whereas improvement in the QoL in terms of mobility, the activity of daily living, stigma, and communication was similar in both groups.[62] The complication rates in both groups are similar although the elderly group had a higher incidence of postoperative confusion/psychosis.[62],[63] In a long-term follow-up study by Hanna et al. they found that there was an increased reduction of LEDD in elderly patients (331 mg vs 108 mg) as compared to younger patients, however, the motor outcome was similar.[61] However, Vats and Doshi found the opposite, they had a lesser reduction in LEDD in elderly patients as compared to young patients (45 mg vs 245 mg). The offering of DBS in older age not only stabilizes the QoL but also improves the caretaker burden and should be considered in the overall treatment algorithm.[62] A more careful selection and follow-up of the elderly patients are required as they have a higher risk of surgery-related complications and a higher morbidity rate.[64]


 » Technological Innovations in DBS Top


The technological advances in the DBS are increasingly directed toward a reduction in stimulation-induced adverse effects[65] that uses feedback from the brain itself to fine-tune its signaling, preserving the battery life, and allowing the development of smaller size IPG compared to large pulse generators now in use.[66] Traditionally, DBS for PD is delivered in a constant or “open-loop” manner without real-time adjustments based on the patient's changing signs and symptoms. It is now possible to record the local field potential from the stimulating electrode and use the information to guide the therapy in a “closed-loop” fashion, this method has been named “adaptive” DBS (aDBS).[3] Evidence suggests beta frequency band (13–30 Hz) oscillations in the Local field potential (LFP) can be consistently picked up in the STN of patients with PD and that their level correlates with motor impairment, with or without treatment. Sensing and tailoring the stimulation to attenuate this is the core principle of adaptive DBS.[67] Comparison of the outcome between no stimulation, continuous stimulation (cDBS), and adaptive stimulation (aDBS) in a multicenter study from Britain using adaptive DBS in eight patients of PD reported improvement of motor scores by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (P=0.03) and (P=0.005) better scores than that obtained using cDBS, respectively. These improvements were achieved with a 56% reduction in stimulation time in comparison to cDBS, and a corresponding reduction in the energy requirements (P < 0.001) and aDBS was also more effective than no stimulation and random intermittent stimulation. 83Swann et al. demonstrated adaptive DBS in two patients with PD using a fully implanted neural prosthesis enabled utilizing brain sensing to control stimulation amplitude (Activa PC + S). They used a cortical narrowband gamma (60–90 Hz) oscillation related to dyskinesia to decrease stimulation voltage when gamma oscillatory activity is high (indicating dyskinesia) and increase stimulation voltage when it is low demonstrating substantial energy savings (38–45%) maintaining therapeutic efficacy.[68]

The new directional leads offer a distinct advantage over the traditional leads. The standard leads produce a spherical electric field that diffuses radially from the active contact uniformly in all directions, in contrast, the directional lead helps in fractionating the current and steer it in a particular direction.[69] This helps to minimize the side effects in some patients. Another advancement is the constant current stimulators with independent sources. Passing a current through individual contacts allows current steering along a vector perpendicular to the lead and the smaller size of each contact leads to a greater electric field density at the contact-tissue interface requiring less current to produce a therapeutic effect. This feature may potentially contribute to improved therapeutic efficacy and preserve battery life.[69]

The PROGRESS study demonstrated the utility of directional leads for STN-DBS in which 234 PD patients were implanted with directional leads targeting the STN. The results of this prospective, single-arm crossover study comparing traditional omnidirectional stimulation vs. directional stimulation yielded a significant mean 41% increase in the therapeutic window with directional stimulation and the amount of current required to produce therapeutic effects was reduced by 39%.[70]

Development of automatic target verification algorithms and probabilistic maps to guide target selection will help in neurophysiological mapping in the near future.


 » Long-Term Effect of DBS in PD Top


The efficacy of DBS for short- and medium-term (<5 years) motor outcomes is well documented. Krack et al. reported the results of a 5-year follow-up showing that STN-DBS in 42 patients had marked persistent improvements over 5 years in motor function while off medication and in dyskinesia while on medication. However, they found that there was worsening of akinesia, speech, postural stability, freezing of gait, and cognitive function between the 1st and the 5th year consistent with the natural history of PD.[71] Aviles-Olmos et al. studied long-term outcomes of patients with PD treated with STN-DBS in a cohort of 41 patients who underwent STN-DBS and were followed up for a minimum period of 5 years, with a subgroup of 12 patients being followed up for 8–11 years.[72] They found that STN-DBS significantly improved the off medication UPDRS-III scores compared to baseline. Dyskinesias, motor fluctuations, and dopaminergic medication significantly reduced in the long-term but UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly due to axial and bradykinesia symptoms. QoL, depression, and anxiety scores did not significantly change at long-term follow-up compared with baseline. Severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years, respectively.[72] Mahlknecht et al. evaluated the long-term impact of DBS on PD and compared the key disability milestones (recurrent falls, psychosis, dementia, and institutionalization) and death in PD patients implanted with subthalamic DBS >8 years versus without DBS in a retrospective analysis. A total of 74 DBS-treated and 61 control patients with PD were included in the study period of 14 years, and they found that patients treated with DBS were at lower risk of recurrent falls and psychotic symptoms compared with control patients and there was no significant difference in risk for dementia or death but disease progression as assessed by Hoehn and Yahr scores was not slower in DBS-treated patients. From these observations, they concluded that treatment with chronic subthalamic DBS was associated with a lower risk for recurrent falls, and psychotic symptoms may be mediated through improved motor symptom control and reduction in dopaminergic therapies, respectively but there was no evidence for DBS effects on underlying disease progression.[73] All these studies point towards improvement in motor symptoms in PD patients after STN -DBS whereas non-motor symptoms continue to progress along with the natural course of disease on long-term evaluation.


 » Conclusion Top


DBS for PD is at an exciting juncture. New insights into the disease help us better understand, prognosticate, and tailor the therapy. Technological innovations are promising to make it safer and more efficient. The enigma of this disease and its remedy will continuously stimulate our scientific curiosity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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