Treatment Options for Parkinson’s Disease

Introduction to Parkinson’s Disease

India is witnessing a great deal of advancements in medical services on par with the Western world in many domains. Our population is now living longer. With longevity, we now have certain challenges to cater to. Diseases that have an incidence in the ageing brain are now becoming more prevalent. Rising awareness (thanks to the digital world) and more urbanisation make these disorders come into the spotlight at an earlier time than before. Our priorities have changed and we are marching towards the concept of “quality of living” from the yesteryear thoughts of “making people live”. Now, this is where a condition like Parkinson’s disease poses a huge challenge, both to the medical service and to the carer. With some advanced treatment options available, we now can confidently give hope to persons with Parkinson’s disease for a peaceful and gratified life.

A Primer on Parkinson’s Disease:

Parkinson’s disease is a degenerative neurological disorder known to occur in the 6th decade of life. The earliest symptoms of Parkinson’s disease are anosmia (loss or reduced perception of smell), dream enacting behaviour during sleep, and autonomic disturbances including postural giddiness and constipation. These symptoms are either ignored or thought to be due to old age and treated as individual symptoms. The disease comes to light only when the motor symptoms start to hit the patient. These include tremors in the hands, slowness in walking or while doing activities and stiffness. A rare group of patients present with a balance disorder.

Stages of Parkinson’s Disease:

Early Stage:

Every person with Parkinson’s disease goes through three phases. The early stage where the symptoms are predominantly due to lack of dopamine (a chemical responsible for enhancing the motor activities, and feeling good) in the brain circuits leading to what clinicians call the ‘off’ state. Put simply, the ‘off’ state can be any or a combination of tremors, slowness and stiffness. This stage is often thought to be the honeymoon state as there is a marked response to the treatment. The affected population feel a dramatic change on taking medications like levodopa or dopamine agonists like pramipexole, ropinirole, etc. and in most instances this stage lasts for a period of 5-7 years followed by mid-stage.

Mid-Stage:

The mid-stage of Parkinson’s disease creates greater challenges for the neurologists. This stage is marked by motor complications. Here, the ‘off’ state becomes complicated as rapid and unpredictable off stage (when patients experience sudden slowness and stiffness without a gradual phase), freezing of gait (a feeling of getting stuck to the ground when any movement is desired) and delayed and shorter effects with medications. On the other end, dyskinesia (abnormal involuntary movements of neck, legs and arms) tends to occur at peak dose. These symptoms may interfere with fine motor functioning and walking leading to extreme fatigue and this inhibits the confidence to lead a social life. Despite such difficulties, patients would still prefer to be in dyskinetic state than in the off state. To establish a dosing regimen that maintains the affected persons in the ‘on’ state (the desired normal functioning state) as they used to be in the early stages will become close to impossible at the peak of the mid stages. This is because of the constant loss of brain cells leading to a very narrow therapeutic range to work with. Adding to the misery are the gastric motility issues that affect the absorption and delivery of the drug to the brain cells.

Late Stage:

The late stage of Parkinson’s disease is characterised by the disappearance of the dyskinetic symptoms and refractoriness of the motor symptoms to dopaminergic medications. By this stage, associated dementia could also markedly affect the quality of life. For most patients, ambulation is greatly affected. This may slowly lead to dependency for all activities and later bed-bound stage.

Guiding the Patients for a Better Quality of Life:

A clinician is the best judge to utilise his armamentarium of Parkinsonian drugs to keep his Parkinson’s patients in the best on stage possible. This could be achieved with ease in the early stage.

The most important step in clinical practice is to keep the patients well-educated on the natural progression of the disease and make them participate in the selection of the drugs. This can be done by asking the patients to fill in their Parkinson’s disease chart before they attend to each clinic. The neurologist, affected person and their caregivers should be on the same page. Medications are meant to give the best possible quality of life and not cure. This message could be blunt yet will make the patients get more involved and realistic. Evidences are ripe to suggest that aerobic exercises have a great impact on prolonging the natural course of the disease. This must be emphasised. Parkinson’s patients have to be convinced to use the more affected arm for their daily activities.

Advanced Parkinson Therapeutics:

The neurologist has the responsibility to prepare the patient and his/her family for the advanced stages when they are first diagnosed. It is recommended to throw some light on the advanced therapeutic options while the patient is in the late phase of early stage. These options come handy when the motor fluctuations start to kick in and the oral medications are themselves not able to achieve the desired effects without causing side-effects. To date, there are 3 available options to choose from:

• Deep brain stimulation of subthalamic/globus pallidus interna nucleus
• Apomorphine subcutaneous pump
• Duodopa continuous intestinal gel infusion

The principle of all these options remains the same. To deliver a sustained and continuous dopaminergic activity either chemically or electrically. Choosing the right therapy for a given patient requires a lot of understanding and experience in each of these advancements.

Deep Brain Stimulation:

Deep brain stimulation (DBS) is an advanced Parkinson therapy that has the highest efficacy to provide a quality of life in carefully selected Parkinsonian patients. DBS is a surgical procedure. The entire DBS process is classified into 3 stages:

• Preoperative stage
• Intraoperative stage
• Postoperative stage

Preoperative Stage:

The preoperative stage involves careful selection of patients who can achieve the best results with the DBS surgery. This includes:

• Identifying patients who exhibit features of classic idiopathic Parkinson’s disease for at least 4 years duration.
• Making sure that such Parkinsonian patients do not have red flags symptoms and signs that argue for other Parkinsonian syndromes like Parkinson plus syndromes, secondary Parkinsonian syndromes, etc.
• Performing a Levodopa Challenge Test: The selected subject is examined and scored on a standard Parkinson’s disease scale before and after a supranormal dose of levodopa medication is administered. Those who demonstrate a score difference of >30% are ideal for the procedure.
• Cognitive and Psychological Assessment: Patients with dementia (memory loss and other cognitive issues) and psychological disorders have a a poor post-surgical outcomes. This requires a careful evaluation by both neurologist and a psychiatrist. Only those patients with acceptable cognitive and psychological functioning will qualify for the procedure.
• Anaesthetic assessment.
• Once a patient is selected, he or she undergoes an MRI imaging of the brain for surgical planning.

The Intraoperative Stage:

DBS is an awake surgery! Yes, you heard it right. Patients will only get a local anaesthetic that blocks the scalp. Once this is done, the patient will have a few screws placed on the scalp and then a frame is mounted. After this step, the patient is taken to the CT room from the operating theatre (OT) and a CT brain is performed. This is matched with the MRI brain done previously and a trajectory is plotted.

The patient is brought back to the OT. Then the functional neurosurgeon performs surgery by opening the scalp skin with a small incision. A burr hole is drilled into the skull bone all while the patient is awake without any pain. After the skull is penetrated, the surgeon will insert the microelectrodes. The microelectrode position can be traced with microelectrode recording that gives a characteristic sound for the different brain tissues that it enters. Once the target (the subthalamic nucleus – situated deep in the brain – hence the name deep brain stimulation) is reached, the best position to place the final electrode is done using macrostimulation. This is when the neurologist (who stands on the other side of the table) will examine the patient for tremors, slowness and stiffness. The patient is purposefully awake for this step. The position at which the neurologist feels most comfortable based on his clinical examination is finally set up for the placement of electrodes. A similar procedure is done for the other side and finally cross checked with a CT brain after surgery. After the placement of electrodes, general anaesthesia is given and an implantable pulse generator (IPG) (similar to pace maker) is placed under the skin situated below the collar bone. The wires from the DBS electrodes are connected to this IPG and all surgical sites are closed and sutured.

The Postoperative Stage:

After a successful DBS surgery starts the main process of stimulating the electrodes. This can start the day after surgery. Some centres start it after 2 weeks depending upon the patient’s response to surgery (lesioning effect). The IPG is set to deliver current through an IR operated programmer. The programming is a mathematical process where a balance is struck between the current delivered through the DBS and the medications taken by the patient. The aim of the programming is to achieve a steady ‘on’ state without dyskinesia. It can involve 3-6 sittings in a span of 3-6 months to achieve the ideal settings. Once the ideal settings are achieved, a 3 monthly follow-up is required to keep a constant pace with the disease through fine adjustments of the IPG.

Apomorphine Subcutaneous Pump:

Apomorphine is a drug that is given subcutaneously like insulin. It is 10 times more potent yet very short acting compared to levodopa. Another way to constantly stimulate the dopamine receptors of the brain is by administering the apomorphine through a continuous subcutaneous infusion using a pump device. This is easier for patients as it can be worn like a pager or cellular phone in the trouser belt loop. The patients are in full command of their dose and can administer bolus (large dose) whenever they feel the need. The infusion set can be safely removed before the patient retires to bed and can be restarted the next day. The efficacy of continuous apomorphine is better than oral medications as it bypasses the stomach route and delivers constant drug dose. But it can be lesser than DBS for a longer run. Patients who hesitate to go for DBS surgery can use apomorphine therapy to feel the effect of continuous dopaminergic activity which in-turn leads to less fluctuations and better quality of life. The oral medications are adjusted similar to DBS based on the apomorphine efficacy. The initial dose titration requires the patient to get admitted in the ward for 2-3 days and then follow-up weekly as OPD. This therapy can also be offered to patients who are not fit for DBS surgery during evaluation.

Duodopa Continuous Intestinal Gel Infusion:

Duodopa is a combination of levodopa and carbidopa (similar to the tablet). However, it is in a gel form that gets administered through a permanent tube (PEG-J) that passes through the abdominal wall into the small intestine. The principle of treatment is similar to apomorphine (see above). However, this is slightly more invasive as it involves placement of a tube through the abdominal wall by a surgical procedure into the intestine. It is considered as a suitable option for patients in the late phase of the mid stages and the early phase of the late stages. This procedure is also a suitable option for patients who refuse or are contraindicated for DBS surgery. It offers the similar advantage of patient-driven programming of drug delivery.

Comparative Summary:

Deep brain stimulation scores best in most domains. However, it is an invasive procedure and careful assessment to rule out a Parkinson plus syndrome and other contraindications have to be made before suggesting this option. Duodopa gel can make a cut in very elderly patients with disease moving from mid-stages towards advanced stages. It is by far the most expensive option and can be used for practical purpose in patients with contraindications for deep brain stimulation after carefully ruling out its own contraindications. Apomorphine continuous infusion pump can be cheaper, especially with generic brands. It can be used as a bridge to demonstrate the effects of continuous dopaminergic activity in patients hesitant to go for deep brain stimulation. It can also be an option for very elderly Parkinson disease patients with mid-stage disease and severe motor fluctuations.

Conclusion:

In a nut shell, the art of delivering Parkinson’s disease care starts with a good understanding of the natural course of the disease. Accepting the shortcomings of oral medications and embracing the advanced therapeutic options for patients with longer disease course seems to be the logical choice, when the quality of life becomes the yardstick of measurement. This art is a combination of science woven with the communication skill of the clinician, who has the responsibility to prepare the Parkinsonian patients for their journey ahead after their diagnosis is delivered. With good education and responsible choices, Parkinson’s disease is no longer a disease of misery.