Volume 61, Number 1 - Winter 2010

 

By Lynne Love, MD

The most important news in the diagnosis and treatment of Parkinson’s disease is that we may have seen the holy grail: a disease-modifying treatment. Although not a boarded subspecialist in movement disorders, I see many patients with parkinsonism and Parkinson’s disease, as do all general neurologists. There is satisfaction in accompanying patients with this neurodegenerative disorder because in almost every case we can improve symptoms and quality of life with our interventions. However, we have essentially been treating the condition symptomatically while searching for a disease-modifying treatment. 

A study published in the New England Journal of Medicine in September 2009 found that the MAO-B inhibitor rasagiline (brand name Azilect) slowed the progression of Parkinson’s disease.[1] The title of the study (ADAGIO, for Attenuation of Disease progression with Azilect GIven Once daily) hints at the slower pace of disease progression. An earlier study (TEMPO), had already suggested benefits of rasagiline.[2] The latest study may move us along the continuum from recommending to requiring that patients with Parkinson’s get disease-modifying treatment.

The double-blind, placebo-controlled ADAGIO trial used a delayed-start study design to differentiate symptomatic from “neuroprotective” or disease-modifying effects of rasagiline. In laboratory work, neuroprotective means that a tally of neurons in experimental animals determines that nerve cells have been saved.[3] Many previous studies of rasagiline and another MAO-B inhibitor, selegiline, used various models of cell damage, including dexamethasone, ubiquitin-proteasome system dysfunction, and MPTP.[4-6] Rasagiline was found to be more potent in some studies, but both medications demonstrated neuroprotective effects. 

Risk managers and others are busily trying to find alternative explanations for rasagiline’s success.[7,8] The main argument is that effects that appear to be disease modifying may actually be due to other metabolic pathways. The skeptics are right that research needs to continue so we can better understand neurodegenerative processes. Still, many movement-disorder experts have already started using rasagiline for their patients, are saying they would start themselves on it, and have finally convinced me that it is time to work to get all patients with Parkinson’s disease on these medications if reasonably possible.

The work required to start disease-modifying treatment in Parkinson’s patients is comparable to the work needed for adequately treating patients’ blood pressure. In both cases, symptoms are not often helpful in motivating the patient to take the medications. Moreover, getting blood pressure under control should probably be a prerequisite to getting the patient on an MAO-B inhibitor, for multiple reasons. For one, the incidence of parkinsonism secondary to microvascular disease is necessarily underestimated since Parkinson’s disease is a clinical diagnosis and we usually do not get a brain scan. In one study, three autopsy cases out of 24 had been misdiagnosed by neurologists as regular idiopathic Parkinson’s disease during life, whereas autopsy revealed evidence of small-vessel strokes without Parkinson’s pathology.[9,10] 

Another reason for getting blood pressure under control is the all-too-common “microvascular disease” (also called “periventricular white matter disease” or “small vessel ischemic changes”) that appears on our patients’ brain scans. Even if this condition is not causing symptoms, it is additive brain damage that is likely at least partially due to hypertension. Finally, hypertension is one of the theoretical side effects of MAO-B inhibitors.

The work of getting patients on MAO-B inhibitors continues with the need to counsel patients to avoid excessive tyramine (aged and fermented foods) in their diets. Although nonselective MAO inhibitors have been used for decades in psychiatry, they have been relegated to a third- or fourth-line choice of treatment because of the dietary restrictions. A 2009 study of 32 depressed patients on one of these medications (tranylcypromine) concluded that it is still clinically feasible to use the medication with a good benefit-risk ratio.11 Failure of the diet was thought to have resulted in headache in a couple of patients and hypertension in one. 

The selective MAO-B inhibitors used for Parkinson’s disease (selegiline and rasagiline) still bear all the same warnings and dietary restrictions as their nonselective cousins, although evidence increasingly suggests that selective inhibitors may be safe in the recommended dosages without dietary restriction.[12-14] Apparently the most that may have actually happened was a 30-point blood pressure elevation after a tyramine load when the selective inhibitors were used in addition to carbidopa-levodopa, and even that increase was not convincingly pegged to the medication.

I prefer to speak more in terms of “parkinsonism” than Parkinson’s disease. Parkinson’s disease by definition is idiopathic parkinsonism. The symptoms of parkinsonism are bradykinesia, lead-pipe rigidity, parkinsonian tremor and postural instability, although patients with Parkinson’s disease have multiple types of tremors. Symptomatic orthostatic hypotension and dementia will develop about 20% and 30-60% of the time respectively but are not part of the diagnostic criteria.[15,16] 

When the symptoms are not due to one of the Parkinson’s Plus syndromes or secondary (including to medications, toxicity or vascular disease) then the diagnosis is Parkinson’s disease. In terms of starting treatment, these diagnostic categories do not much matter unless there are potentially offending substances that first should be removed in an attempt to improve symptoms before trying the medications for Parkinson’s disease.

The term “parkinsonism” acknowledges the possibility that time will tell whether a patient actually has one of the Parkinson’s Plus syndromes and perhaps most importantly helps make the link for patients that their underlying health is important. Daily, if not hourly, we see people who need help or encouragement to stop bad habits, start good ones and understand what they can do to improve their health. Our society seems to have lulled us to ignore the type and amount of calories we consume while obesity and metabolic syndrome mount around us. 

In a condition as compromising as parkinsonism, obesity added to the parkinsonian tendency against movement makes life harder. Vascular risk factors are important to control, at least to prevent additive brain damage, strokes and heart attacks, if not frankly to prevent the progression of parkinsonism where small vessel disease may be contributing.

I have been asked about surgical intervention for Parkinson’s. Outcomes are much more positive in patients younger than 55, a tiny minority of Parkinson’s patients.[17] Nonetheless, surgery is becoming increasingly available, together with associated quality control concerns.[18] Eligibility requirements try to ensure that the patient has regular idiopathic Parkinson’s disease, including manifestation of symptoms for at least 18 to 24 months, which allows some time for Parkinson’s Plus syndromes to become apparent. There must be response to carbidopa-levodopa for the same reason. The patient cannot be demented or depressed, and selection criteria narrow down the candidates to 4.5% or less of patients.[19] 

Unlike what patients may hope, there are many visits required for programming after surgery. While they are not expected to need as much medication after surgery, they still have to use some. Even in studies showing patients doing better with surgery plus medication, as many as a third of the patients did better on medication alone.[20] Powerful placebo effects of brain surgery are being increasingly noted.[21] Most significantly, this is brain surgery, with possible infections, acute surgical complications and cognitive complications.[18-23]

Where are we going? What is the vision of this holy grail of a disease-modifying medication for Parkinson’s disease? We may still be decades or centuries in advance of understanding and curing Parkinson’s disease. Nonetheless, if we have good disease-modifying therapies, we may have as much success with Parkinson’s as we have had recently in glaucoma: if you treat it well, it will not become disabling. In Parkinson’s disease, that is an extremely worthy vision.