Dr. Maria Knöbel, MBBS BSc (hons) ARCS

Abstract

Parkinson’s disease is a debilitating and slow progressing neurological disorder, in which the regions of the brain that control bodily movement are damaged. Cells in the brain that produce a chemical called dopamine begin to die. Dopamine is essential for producing movements of the body, and with the loss of nerve cells, Parkinson’s symptoms begin to appear.  It is characterised by stiffness, tremor, and slowness in movement, alongside other afflictions such as depression, pain, tiredness, and constipation. Parkinson’s does not directly result in death, but symptoms will get worse over time. There is currently no cure, and much of its causes remain elusive. Today, the mainstay treatments are to replace the dopamine that the body cannot produce itself, in the form of drugs. Occasionally, in advanced Parkinson’s surgery is performed, of which the newest kind is deep brain stimulation.  Probes are surgically inserted into the brain to send an electrical signal into areas that are implicated in Parkinson’s. This study follows a group of patients who had received this kind of surgery for 5-6 years to determine whether it remains effective in the long-term. It finds that while the electrical stimulation is not as effective as they were shortly after surgery, the results remain impressive and provide a great improvement to patients’ quality of life.^{1, 2}

Background and Rationale for Work

Parkinson’s Disease (PD) is a disabling chronic neurodegenerative disorder affecting over 6.3 million people world-wide, with ever-increasing prevalence. ³ Currently, it is one of the most common neurodegenerative disorders, second only to Alzheimer’s disease.⁴ The condition was first described by James Parkinson in 1817 in his famous An Essay on the Shaking Palsy based on observation of six cases in his practice and neighbourhood.⁵  His name was later made eponymous by the prominent French neurologist Charcot, who called the condition ‘la maladie de Parkinson’ 60 years after the original publication.⁵  The condition is characterised by degeneration of dopaminergic neurons of the substantia nigra produces brady- and akinesia, postural instability, tremor, rigidity, and a myriad of other motor as well as non-motor symptoms that greatly debilitate daily life.^{6, 7} Treatments used in PD to date are palliative and aim to alleviate symptoms, rather than slow disease progression. Levodopa and various dopamine agonists are used in dopamine-replacement therapy to relieve motor symptoms in the early stages of PD. However, the increasing development of motor complications on these medications, such as wearing-off, on-off effects, and unpleasant hyperkinesias greatly limit the use of these treatments as the disease progresses. ⁸ The 50s was an era of often experimental surgical lesion procedures such as pallidotomies and thalamotomies for treatment of symptoms, with varying success, but almost always with irreversible and severe side effects such as hemiparesis and dysarthria.⁹ The high complication rates of bilateral surgeries caused it to lose favour to dopamine-based treatments and are now rarely performed.¹⁰  It became clear that new methods to manage PD were necessary, and so in 1986 deep brain stimulation (DBS) of the motor thalamus and ventral intermedius nucleus was first performed for the treatment of PD.¹¹ DBS quickly became the next success story of PD therapeutics. Table 1 shows how interest in DBS has sky-rocketed over the decades in a simple Pub Med search of citations.  

In PD, DBS of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) were found to be safe and effective targets compared with surgical lesioning procedures as they lead to little or no tissue damage.¹² Various randomised control trials have demonstrated DBS provides a good functional outcome with fewer side effects, however, being a relatively new intervention few long-term studies exist. Only in the last decade has DBS been implemented on a large enough scale to allow for studies with large enough sample sizes. Significant improvements in motor function and quality of life have been demonstrated in both STN and GPi DBS. However, short-term follow-up studies have revealed trends to less motor improvement with GPi-DBS but continued benefit from STN-DBS. These observations emphasise the need for a long-term follow-up study such as this one for both targets. Even more research into the long-term effects of DBS is absolutely warranted as even now we may not yet know what the possible future sequelae may be.

Approach to Question and Key Results

The purpose of this study was to evaluate the long-term effects of bilateral GPi- and STN-DBS in patients with advanced PD and followed for 5-6 years.  One hundred and five patients (of 134) from eight surgical centres who received bilateral STN- or GPi-DBS implantation as part of an original separate nonrandomized multicentre study between 1996 and 1998 agreed to participate in this extended study.  At 3-4 yrs 69 patients were available and at 5-6 years 41 patients were available for follow-up. Table 2 summarises the steps and reasons for drop outs.

Of the patients that died between the 3/4 yr and 5/6 year evaluation none were directly attributable to DBS: 1 was of a stroke, 1 after a fracture, and 8 more for unknown reasons.  At 5-6 yrs the STN- and GPi-DBS groups were compared in a double-blind cross-over evaluation comparing  1) UPDRS motor scores (see Appendix for details on the UPDRS) in stimulation on and off conditions, as well as 2) an unblinded evaluation comparing motor UPDRS scores in stimulation on and off while on medication and stimulation on/off while off medication.

In both GPi and STN cases pre-operative L-dopa response was positively correlated with the motor improvement at 5-6 yrs stimulation (p = 0.0098 for both)

Both the double-blind and unblinded assessment of bilateral STN-DBS showed significant treatment effect on motor scores in off medication condition. All UPDRS motor subscores except speech, early morning dystonia and dyskinesias, and off-medication ADL were greatly improved while L-dopa equivalent daily dose was markedly reduced. There was some decline in STN-DBS clinical benefit between 3-4 and 5-6 year follow-ups as expected, most likely due to the natural progression of PD and simultaneous reduction of the L-DOPA response.

Similarly in the GPi group DBS was also effective at improving motor PD signs in both blinded and unblended evaluations, especially tremor, rigidity, ADL and dyskinesia subscores which were significantly improved by off medication stimulation.  However, in the GPi-DBS group there was no reduction in the L-DOPA equivalent daily dose needed at 5-6 yrs compared with before surgery.

Nonetheless, since both STN and GPi patients showed deterioration in L-DOPA response over the years suggests it is a result of PD progression.  There was one GPi-DBS patient who lost stimulation benefit (as reported in table 2) and subsequently underwent STN DBS surgery.  A possible explanation for this loss of benefit was cited as suboptimal placement of the original electrodes, which highlights the importance of possible skill difference between individual surgeons for this kind of surgical trial which could represent a confounding factor. However, as this is a large multicentre trial it is both impractical and unfeasible to have all DBS surgeries performed by one surgeon. This also invites caution over individual variability in postoperative behavioural and cognitive outcomes, which may relate to pre-existing psychiatric illness, changes in medication, surgery-related stresses, and alterations in social life associated with mismatch between motor improvement, adverse effects, and patients’ own expectations.^{13, 14}

Adverse effects (AEs) (see Table 3) and deaths were proportionally more common in the STN group compared with the GPi group. No reasons for this difference in mortality rates were suggested, however, it has been previously reported that there is no difference in mortality rates between PD patients with and without STN-DBS¹⁵.

Table 3.  Adverse Effects present at 5-6 year follow-up in both STN and GPi patients

	STN (n=35)	GPi (n=16)
No Patients with AEs	26	8
Total no of AEs	47	11
Cognitive decline	8	2
Depression/Anxiety	7	2
Speech difficulties	10	2
Gait disorders	9	1
Hypersexuality	1	2
Balance disturbances	5	1
Motor Fluctuations	3
Sleep disorders	4

Ultimately, while both STN and GPi DBS have been effective in improving motor PD signs with sustained benefit at 5-6 years, STN group patients received greater benefit as measured by quality of motor and ADL improvement, while GPi patients suffered fewer AEs. However in light of these results, it should be borne in mind that this study was not designed to compare between STN and GPi DBS, but to evaluate their respective success long-term. In addition, previous studies comparing STN- and GPi-DBS did not discover significant differences in motor outcome between these targets.^{16, 17}  Based on this single study alone, it can be concluded that DBS of either the STN or GPi still provides significant improvement to PD symptoms as measured by UPDRS scores at 5-6 yrs post implantation.

Likely Impact of Research Outcome

This long-term follow up of bilateral DBS in patients with advanced PD confirms the effectives of both STN and GPi DBS in improving L-dopa induced dyskinesias and L-dopa responsive PD signs.  It’s findings are also consistent with previous studies indicating that pre-operative response to dopaminergic medication has the highest predictive value for persistent motor benefit with DBS.¹⁸

One limitation of this study is that the original target site (STN or GPi) were not randomised and therefore prevents any direct comparison between the two groups. However, while no direct comparisons can be made, it has provided us with valuable information on the long-term effectiveness of DBS. Overall, the data has indicated that both GPi and STN DBS are efficatious methods to improve parkinsonian symptoms and allow long-lasting reduction of dopaminergic treatment for at least 5-6 years.

Up until the publication of this paper, many studies have analysed 2 to 3 year follow up of bilateral DBS but as little as three had considered 5 years or longer duration follow-up. ^19-21  Even more research into the long-term effects of DBS was absolutely and still is warranted as even now we may not yet know what the possible future and even more long-term sequelae may be. But these kinds of studies will only come with time, and now that more similar multicentre studies such as this one are underway, and it is the consensus that DBS continues to provide benefit past the 5-6 year mark, it is only natural to continue to follow-up cohorts into the future.

The positive results of studies such as this one will give surgeons, neurologists, as well as patients’ and their families assurance that DBS (both GPi and STN) is a relatively safe and successful treatment pathway that improves patients’ quality of life for at least half a decade, and holds even further promise. For a debilitating condition such as Parkinson’s, a treatment success of this scale is a great milestone. The late Professor David Marsden, a prominent British neurologist, once said he saw two miracles in PD in his career: the first being the introduction of levodopa and the second the development of DBS.²²

Future Work & Conclusion

DBS has come a long way from when early experiments by groups in Baltimore and Manchester showed that over-activity of the GPi and STN could be neutralised by precise lesioning.²³  Now DBS has almost eliminated the practise of ablative procedures in PD and provided dramatic improvements for many patients with advanced PD suffering from complications of drug therapy.²² In direct comparison with the best medications currently available, DBS has improved “off” time in PD by 5-6 hours compared with just 1-2 hours offered by medications.²²  

As mentioned above, DBS is currently primarily only used to treat PD with severe motor fluctuations in advanced stages, and at this stage most patients show great impairment in quality of life and have experienced psychosocial decline.  It has been shown that once deprived, even restoration of mobility does not always result in a return of independence.²⁴ The same author also presents evidence²⁵ suggesting that outcome of motor function and complications are better when DBS is performed at an earlier stage. A larger clinical trial investigating this would be highly warranted.

Now that the success of DBS is widely reported by studies such as this one and almost universally accepted by neurologists to be suitable treatment for advanced PD, a key question to tackle next is when is the optimal time for implantation? Currently the mean disease duration before DBS surgery is 13 years.²⁶ If DBS continues to be so effective at improving PD symptoms, should it be offered at an earlier disease stage to prevent psychosocial decline and improve quality of life for a longer period of time?

With an ever aging population, Parkinson’s disease will only become ever more relevant to many.²⁷ Already now, every hour someone in the UK is diagnosed with Parkinson’s.²⁷ As a slow progressing neurodegenerative condition, improving quality of life for those suffering with PD must become a key focus in future research.  While DBS and other therapeutics become ever more successful in controlling PD symptoms, there must also be a change in the direction of research from palliative to curative—tackling neurodegeneration and not just the symptoms that result thereof. But Rome was not built in a day, and international research effort, of which this study is just one, is already leaning towards the right way.

APPENDIX.   UNIFIED PARKINSON’S DISEASE RATING SCALE (UPDRS)²⁸

The UPDRS is a rating tool to follow the longitudinal course of Parkinson’s Disease. It is made up of the 1) Mentation, Behavior, and Mood, 2) ADL and 3) Motor sections. These are evaluated by interview. Some sections require multiple grades assigned to each extremity. A total of 199 points are possible. 199 represents the worst (total) disability), 0–no disability.

I. Mentation, Behavior, Mood

• Intellectual Impairment
• Thought Disorder
• Depression
• Motivation/Initiative

II. Activities of Daily Living

• Speech
• Salivation
• Swallowing
• Handwriting
• Cutting Food/Handing Utensils
• Dressing
• Hygiene
• Turning in Bed/ Adjusting Bed Clothes
• Falling-Unrelated to Freezing
• Freezing When Walking
• Walking
• Tremor
• Sensory Complaints Related to Parkinsonism

III. Motor Exam

• Speech
• Facial Expression
• Tremor at Rest
• Action or Postural Tremor
• Rigidity
• Finger taps
• Hand Movements (open and close hands in rapid succession)
• Rapid Alternating Movements (pronate and supinate hands)
• Leg Agility (tap heel on ground, amp should be 3 inches)
• Arising From Chair (pt. arises with arms folded across chest)
• Posture
• Gait
• Postural Stability (retropulsion test)
• Body Bradykinesia/ Hypokinesia

IV. Hoehn and Yahr staging of Parkinson’s disease

Stage One

1. Signs and symptoms on one side only

2. Symptoms mild

3. Symptoms inconvenient but not disabling

4. Usually presents with tremor of one limb

5. Friends have noticed changes in posture, locomotion and facial expression

Stage Two

1. Symptoms are bilateral

2. Minimal disability

3. Posture and gait affected

Stage Three

1. Significant slowing of body movements

2. Early impairment of equilibrium on walking or standing

3. Generalized dysfunction that is moderately severe

Stage Four

1. Severe symptoms

2. Can still walk to a limited extent

3. Rigidity and bradykinesia

4. No longer able to live alone

5. Tremor may be less than earlier stages

Stage Five

1. Cachectic stage

2. Invalidism complete

3. Cannot stand or walk

4. Requires constant nursing care

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