Back to School Part 1
Parkinson’s Disease
We’ve all heard of Parkinson’s Disease but not many of us know much about it. Today we will discover a bit about the condition that is affecting more of us as our population grows older.
Parkinson’s Disease (PD) is a progressive, neurodegenerative condition, resulting from the death of dopamine containing cells of the substantia nigra. The substantia nigra is the area of the brain that sends signals down the spinal cord to control movements. PD is characterised by bradykinesia (slow movements), tremor, rigidity, gait disturbances and postural instability (loss of balance). It is the second most common neurodegenerative disease in the world, affecting 1% of the population over 65 years of age, and rising to 2% for those over 80 years of age. An estimated 4% of people with PD are diagnosed before the age of 50. It is more common in male patients.
Diagnosis
There is no consistently reliable test that can distinguish PD from other conditions that have similar clinical presentations. The diagnosis is primarily a clinical one, based on history, physical signs and examination. Conventional brain imaging is normal initially, but atrophy (deterioration of brain cells) develops over time. Other conditions (e.g. Alzheimer’s Disease, repeated head injury, hypothyroidism, certain forms of depression) can display symptoms similar to PD, so referral to a specialist to confirm diagnosis is important in patients displaying the symptoms of PD.
Signs and Symptoms
The combination of tremor, rigidity and akinesia (loss of control of voluntary muscle movements) develops slowly, over months to several years, together with a change in posture. Common initial symptoms are tremor and slowness. Limbs and joints feel stiff and they ache. Fine movements become difficult. Slowness causes difficulty rising from a chair, or getting in or out of bed. Writing becomes small and spidery.
Tremor – A characteristic pill-rolling tremor (movements between thumb and forefinger) at rest, typically decreases with action.
Rigidity – Stiffness develops throughout movements.
Akinesia – Slowing of movements is an additional sign of PD, as distinct from muscle rigidity. There is difficulty initiating movement. Rapid fine finger movements, such as playing piano become indistinct, slow and tremulous. Facial immobility gives a mask-like appearance. Frequency of blinking reduces.
Postural and gait changes – Stooping is characteristic. Gait becomes unsteady, with shuffling and poor arm swinging. Balance deteriorates, and falls are common in later stages.
Speech – Pronunciation is initially a monotone, and progresses to tremulous, slurring speech, that is difficult to understand. Eventually, speech may be lost.
Cognitive changes – Cognitive decline may occur early in the condition and is rarely absent in advanced disease. Depression is common.
Gastrointestinal and other symptoms – These include constipation, heartburn, dribbling, dysphagia (difficulty swallowing), and weight loss. Urinary incontinence is common, especially in men. Skin can be greasy and prone to excessive sweating.
Implications of PD
In the short term, the prospect for good symptom control with minimal impact upon lifestyle is good for the majority of patients. In the long term however, patients and their carers may face a number of problems. Generally, for the first four or five years post diagnosis, there is typically a period of good symptom control using medication. At this point, however, it is common for the patient to begin noticing a wearing off of the medication effect before the next dose is due. Increasing the medication can lead to fidgety movements, or more sustained abnormal muscle contractions and postures. As PD progresses, the patient can experience more profound effects on their movement, and can fluctuate between dyskinesia (abnormal voluntary muscle movement) and periods of complete immobility (known as freezing episodes, which can occur suddenly and unpredictably). Falls become more frequent as the disease progresses. Depression can have a significant impact on daily life, but is eminently treatable.
Treatment
Medication therapy does not prevent disease progression, but improves most patients’ quality of life. Because PD is a progressive, neurodegenerative condition, resulting from the death of dopamine containing cells of the substantia nigra, treatment focuses on supplying an alternative to dopamine i.e. Levodopa, or by using Dopamine Receptor Agonists or MAO-B Inhibitors.
Levodopa replaces the body’s natural dopamine and is the gold standard treatment for PD since it was introduced in the 1960s. Patients experience rapid improvement in their symptoms and quality of life. It can be given with Carbidopa (Sinemet®) to help prevent the nausea that can be caused by Levodopa alone. Over time – months or years depending on the patient – decreased efficacy and dyskinesias (abnormal muscle movements) can occur. For this reason, many clinicians reserve the use of levodopa for later in the course of the disease.
Dopamine receptor agonists e.g. Pramipexole (Mirapexin®), Ropinirole (Requip®), Rotigotine (Neupro Transdermal Patch®), are commonly used in the initial treatment of the disease or in combination with Levodopa in later PD. Dopamine agonists are less effective than Levodopa, but are considerably less likely to cause dyskinesia. The combination of dopamine receptor agonists and Levodopa can lead to impulse control disorders such as gambling, binge eating and hypersexual urges. If this occurs, one of the medications should be withdrawn, or the dose reduced until the symptoms resolve.
MAO-B Inhibitors e.g. Rasagiline (Azilect®), Selegiline (Eldepryl®), increase the amount of dopamine at receptors by preventing its metabolism (the break-down of dopamine by the body). They are used as initial therapy, particularly if dopamine receptor agonists should be avoided, or as Levodopa sparing agents later in the disease. They have the potential to interact with other medicines.
Anti-muscarinic drugs e.g. Procyclidine (Kemadrin®) are not widely used as they are less effective than dopaminergic drugs and are associated with cognitive impairment.
Other Non-Motor Symptoms
Patients with PD can develop non-motor symptoms as the disease progresses – these include depression, psychosis, dementia, sleep disturbances and autonomic dysfunction e.g. postural hypotension, urinary dysfunction or constipation. These non-motor symptoms can be treated using appropriate conventional medication.
Later-Stage Disease
Over time, a patient’s response to initial treatments will decline. When this occurs, patients experience “switching off” or “off time”. After taking their medication, the level of the drug in the patient’s plasma initially peaks (which can cause dyskinesia – abnormal voluntary movement), then, as the plasma drug levels fall, the patient can experience akinesia (lack of voluntary movement) and rigidity. The patient can fluctuate rapidly and erratically between these two states – this is known as the “on-off” phenomenon. This can be addressed by increasing the dose of medication (which can lead to more side effects) or shortening the time between doses. Eventually combinations of drugs will be necessary, including the introduction of Entacapone (Comtess®) alone or in a combination product with Levodopa/Carbidopa (Stalevo®), which prevents the peripheral breakdown of Levodopa, allowing more Levodopa to reach the brain.
For some patients, as their disease progresses, their dyskinesia and “off” periods become unmanageable with conventional treatments. For such patients, the use of Apomorphine or Levodopa intestinal gel may be an option to consider.
Apomorphine is a powerful dopamine receptor agonist. It is administered via a subcutaneous infusion pump that the patient attaches to the abdomen area. It is non-invasive and is reversible. Following patient selection and pre-treatment safety checks, a one day treatment initiation process in a hospital setting occurs. Then, if successful, dose optimisation and reduction of other PD medications can occur over time.
Levodopa intestinal gel is the continuous administration of Levodopa/carbidopa (Duodopa®) by infusion into the duodenum/jejunum (small intestine). It requires a gastronomy procedure for the placement of the infusion tube. Because of its expense and the invasive route of administration it is limited to those with severe motor fluctuations that are not managed by other drug therapies.
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