Coastal Neurological
Medical Group, Inc.

Ten Most Recent Important Advances In Parkinson's Disease
BY DEE E. SILVER M.D.

These are ten areas of increased knowledge and understanding in IPD. They are important because we are now recognizing them and/or making major advances in the understanding or treatment in the areas. We need to practice medicine based on evidence that our treatment formats will have benefit yet be safe and tolerable. We also have to look for patterns that are developing in treatments so as to give our patients cutting edge therapeutic management. We need to make a determination and decision using our knowledge, discretion, fairness to all and do so in good faith.

ETIOLOGY. Genetics and environment play a major role in the etiology of Idiopathic Parkinson's Disease (IPD),even though age is the greatest risk factor of IPD. Knowing that IPD is a heterogeneous syndrome, we realize that everyone has their own clinical picture and the pathology varies for each group or person. Now with 13 different genetic locations (loci) for IPD, we are just seeing the tip of the iceberg for discovery of genetic causes. Most, so far, are for younger autosomal recessive (AR) or autosomal dominant (AD) types, but the last one discovered, (LRRK2 on chromosome 12-AD) involves older patients. Genetics and environmental influences and mutations allows proteins to be miss folded or aggregated and they, in turn, become toxic to the cell and become inclusions which maybe protective or toxic, i.e. the Lewy body which is made up of the protein alpha- synuclein. Other neurodegenerative disease's such as Alzheimer's Disease (AD), anterior horn cell disease (ALS) and Myotonic Dystrophy have proteins that are abnormal and aggregated. As we understand more about genetics and protein abnormalities, new treatments will be found. Most will deal with blocking the development of the abnormal proteins, their misfolding or their aggregation.

NON-MOTOR SYMPTOMS AND FLUCTUATIONS. Over the last few years we have become aware of the non-motor symptoms in IPD. These are anxiety, mood changes, panic attacks, slow thinking, pain, sweating, numbness and even diplopia. They can occur anytime, but are often associated with the "off" period. It is important to be aware of there non-motor symptoms for at least two reasons. First, they are very common and disturbing clinically and must be recognized so they can be treated. Secondly, if they are associated with an "off" time or anticipate an "off" period they can be treated just like managing the "off" time. Increasing the frequency of the l-dopa dose, increasing the dopamine agonist dose, adding entacapone or the 3 in 1 pill (Stalevo), or using apomorphine (Apokyn). Entacapone or Stalevo can reduce "off" time by 1.2 to 1.7 hours per day. Apomorphine is a rescue drug that can be given by a subcutaneous injection and has an onset of action in 10 minutes and lasts for 30 to 60 minutes. It can be used up to 8 times a day. The side effects are usually easily tolerated with correction titration. Sarizotan and Istradefylline are being studied by us and several other centers for improvement in Parkinson's signs and symptoms and possibly for reduction in dyskinesias. There will also be clinical trials for consideration of neuro- protection. Levetiracetam (Keppra) is being looked at also for reduction of dyskinesias.

DEEP BRAIN STIMULATION (DBS). There have been about 30,000 patients in the world that have had DBS. In patients with IPD, with a robust response to l-dopa, without cognitive impairment , neuropsychiatic symptoms, or limiting medical conditions, this nonablative (nondestructive) surgery can be very beneficial clinically. The patient should have had optimized pharmalogical treatment prior to DBS and evaluated by a movement disorder specialist. Results vary in various centers, but patient selection, skill in electrode placement, and programming are all important. The number of cases done and experience are crucial, both for the neurosurgeon and the neurologist. The sub thalamic nucleus seems to the preferred site in most cases but a few may benefit more by putting the electrode in the globus pallidus interna. Our experience (Dr. Silver & Dr. Ott at SMH La Jolla) is consistent with the reviews. 80% or more of the patients will have a significant clinical benefit with appropriate patient selection a major key factor. The DBS can be done unilaterally or bilaterally, the latter most common and gives the best results. 30 to 50% reduction in l-dopa dose can be accomplished with time. There is a 50 to 65% reduction in "off" score testing and 20 to 30% reduction in "on" score testing. Tremor and dyskinesias can both be improved by the DBS. "Off"dystonia and "off" time can be reduced. Gait may be somewhat improved as well as speech. Possible side effects are intracerebrel hemorrhage, infections, fractured wires, worsening dyskinesias, apathy, and behavior changes. All are very uncommon in our experience. New targets are in the future as are multiple targets. We have found this to be a safe and very beneficial treatment in our hands and we are doing the surgery sooner than later in many cases. More on deep brain stimulation ยป

EXCESSIVE DAYTIME SLEEPINESS (EDS). EDS occurs in 80% of patients with IPD and is a major cause for the reduction in the quality of life (QOL) as are other sleep disorders. Sleep disorders are common in IPD and are due to the disease itself (rigidity, tremor, akinesia at night), medication (dopaminergic medication), depression , dementia , psychiatrics symptoms, restless leg syndrome (RLS), periodic leg movement disorders (PLMD), sleep apnea (OSA), and REM behavior disorders (RBD). Patients with IPD should be screened for EDS by giving the Epworth Sleep Scale test. RLS and PLMD can be treated with dopamine agonist and RBD treated with klonopin. 20% of IPD patients have RLS as compared to 15% of the population. 15% of IPD patients have PLMD but 80% of patients with RLS have PLMD. 38% of patients with RBD will develop IPD in 4 years, 60% in 10 years. Iron deficiency must be looked for in patients with RLS because 5% will have iron deficiency and iron supplements will generally be of benefit. Of patients with iron deficiency, 20 % will have RLS. 70 to 90% of patients with RLS will benefit from dopamine agonists or gabapentin.

SITE OF FIRST PATHOLOCIAL CHANGES IN IPD. Braak and Braak have done postmortem studies on patients with IPD and have found six subgroups of pathology that have different locations and seem to have a progression of advancement that seems to imply that the disease progresses in most IPD patients in the same way and starts in the olfactory nucleus (smell) and vagus nucleus (swallow). The pathological changes then advance to lower brain stem nuclei in stage 2, and in stage 3 involves the forebrain, amygdala and the substantia nigra (main site of dopamine neuronal loss in IPD). The disease changes then progress in stage 4 to the temporal lobe and in stages 5 and 6 is in the cortex. These findings if confirmed give us a possible pattern of progression of the disease and may offer a chance to make a diagnosis very early. This will be very important if we find drugs that allow for disease modification or neuroprotection. 50 to 60% of patients now have loss of smell as one the first signs of their disease even before any motor signs. We do know however that there is a great deal of heterogeneity to IPD so the advancement of the pathology may vary somewhat in patients.

DISEASE MODIFICATION (DM). DM is the ability to reduce the progression of the disease or its signs and symptoms by some therapeutic method. DM maybe gaining support from data in clinical trials. The dopamine agonist (DA) (ropinirole and pramipexole) when compared to l-dopa showed delay in development of motor complications (MC). These were motor fluctuations ("off" time, end dose failure) and dyskinesias, i.e. MC. There are three reasons for the development of MC; progressive cell loss with disease progression (increasing degree of substantia nigra denervation means less ability to buffer fluctuating levels of striatial dopamine), short half of the medication, and hence pulsatile stimulation rather than continuous stimulation. The ability to delay these complications is a clinical benefit to the patient, but if this is DM is uncertain. To complicate the picture the imaging studies showed reduction in the loss of uptake on the beta CIT and PET scan in patients on the DA as compared to l-dopa. This reduction in loss of uptake suggested that patients on DA had less neuronal loss as compared to patients on l-dopa. Some experts however felt that this reduction was a drug effect on the imaging and not a true reduction in neuronal loss. More testing needs to be done to clarify this however. None the less DA monotherapy allows a delay in the development of MC as compared to l-dopa. The ELLDOPA study used three doses of l-dopa (150mg, 300mg, and 600mg per day) and placebo and monitored patients for 9 months and showed by clinical standards that l-dopa is not toxic. The 600mg group after stopping the l-dopa did better (had better rating scores) than any of the other l-dopa dose groups or the placebo. However, the beta CIT imaging showed that the 600mg group had a great reduction in the uptake which suggested greater neuronal loss that the placebo group. Studies with rasagiline, an MAO-B inhibitor, in a staggered start study, show that rasagiline when given early to patients allows the patients to do better clinically at one year than the group where placebo is given for 6 months, then switched to rasagiline. The rasagiline always treated group always did better clinically (scores where better) suggesting that delaying the rasagiline was clinically detrimental, i.e. DM. 50% of the patients on rasagiline at 2 years were on monotherapy. At 6.5 years the annual decline for the rasagiline was 2 UPDRS units where as the placebo average decline is 8 to 14 units (decline would be worsening). More studies are however needed to document a DM benefit of rasagiline or any other drug.

THE UBIQUITIN-PROTEASOME SYSTEM (UPS).Recently two scientists have received the Nobel prize for advances in understanding the UPS. IPD like AD is a protein disposition disease. Hence understanding the way abnormal proteins are handled or miss handled is very important in understanding the pathology and treatment of these diseases. This system or pathway is complex and involves a series of metabolic changes where abnormal proteins (misfolded or aggregrated) are chaperoned by a protein (ubiqutin) to a formation of protosomes (enzymes) arranged like a barrel. Here the abnormal proteins enter the top of this enzymatic protosome structure (barrel) and a when the UPS is functioning normally, exit from the bottom as amino acids that can be reentered into the normal workings of the cell. If this system is not working properly, then abnormal proteins accumulate and they maybe toxic. As aggregated or misfolded proteins diffused in the cell they may be toxic or they may become deposited in a formation like the Lewy Body, which in IPD is present as an inclusion body made up of deposited alpha synuclein. It is uncertain if this inclusion body is protective ( isolating) the proteins or if it is toxic it self. An environmental insult or a genetic mutation may alter this pathway or process. There are already known genetic mutations to this UPS pathway that is connected to the development of parkinsonism (UCH-L1). Dr. Warren Olanow has in mice altered this pathway and developed a mouse with Parkinson features. He has shown that environmental substances from bacteria and fungus in mice can result in dysfunction of the pathway leading to parkinsonism. They are currently working on medications that can result in a more normal functioning pathway, hence resulting in reduction in the misfolded or aggregated proteins. This will be a very exciting area since there are other diseases that have protein deposition. This also would be a different mechanism for treatment in IPD.

RECOGNIZING, TREATING AND MANAGING MEMORY AND BEHAVIOR CHANGES IN IPD. In primary care in the USA 95% of mild memory loss is undiagnosed and 50% of moderate memory loss is undiagnosed. Many neurologists do not recognize the 30 to 40% of the cases of IPD that have dementia. In the first 10 years of IPD 20 to 30% of the IPD patients will have dementia, and in the second 10 years up to 80% have dementia. Age is the greatest risk factor for the occurrence of dementia and for IPD. There is an overlap in these cases with DAT. The acetyl choline esterase inhibitor (ACEI) rivastigmine (Exelon) has now been shown to be effective in the treatment of memory impairment in IPD in a 3 year clinical trial. There was also significant benefit in behavior symptoms. Probably all ACEI's are of benefit however, but the only trial that was done was with rivastigmine. It has been known for 15 years that ACEI's help memory and behavior in Alzheimer's disease ( DAT). For 14 years I have treated dementia in IPD but for the last 10 years very aggressively. Many of the IPD patients dementia is DAT, likely 80 to 90%, the remaining cases of dementia is related to Lewy Bodies, i.e. Lewy Body Dementia (LBD). LBD is robustly response to ACEI's. The ACEI's should be the foundation for the treatment of the behavior disorders (depression, apathy, agitation, combativeness, hallucination, and delusions) seen in IPD. Atypical neuroleptics such as quetiapine (Seraquel) are probably of benefit for behavior disturbance in IPD and this drug does not make the parkinsonism worse. The one clinical trial with quetiapine however did not show a clinically significant benefit for behavior improvement. In my clinical experience it has been of benefit however, most notably when used with the ACEI's. Risperidone (Risperadol) another atypical neuroleptic is also used for behavior symptoms however it often will increase the parkinsonism. All atypical neuroleptics have recently been noted by the FDA to increase stroke and death. Mild cognitive impairment (MCI) occurs in IPD just like it does in the rest of the population. MCI is isolated memory loss where there is just recall difficulty (amnestic type) without other features of dementia. 15% of these patients per year will develop DAT, 60% in 4 years. Recently it has been shown that using donepezil (Aricept) early in patients with MCI the donepezil delays the onset of DAT in the first 12 months as compared to the placebo group. There is however no documented delay when comparing donepezil to placebo at 3 years. Hence you must treat early to get the drug benefit.

BOTOX® AND IPD. BOTOX® injections are being used today in many diseases. Its first use was for movement disorders such as dystonia associated with the neck (spasmodic torticollis) and for blepharospasm of the eyes seen by itself or with IPD or other Parkinson diseases. Even though I have injected it frequently for 15 years with little or no side effects it is probably being over used. In my opinion it is being used with out much scientific evidence for headache, neck and back pain and often before other less expensive treatments that have been shown to be of benefit. However in the last few years many of us have found that in IPD patients with focal, medication adjustment refractory dystonias it is very beneficial and the results last for 3 to 4 months. Blepharospasm has always responded to BOTOX® when carefully done and consistently improves the QOL of the patient whose eyes often remain too often closed. One fairly new use is for drooling that is excessive and very annoying. Several studies have been carried out and they confirm my experience in a series of well over 30 cases that I have done, that when carefully injected into the parotid gland bilaterally and sometime the submandibular gland, significant reduction in drooling can be obtained.

NEUROTROPHIC FACTORS (NTF'S). These are substances that we have in and around our brain cells that help keep the cells functioning and healthy. It is one way our own body helps us with neuroprotection. IPD and other neurodegenerative disease's are a failure of endogenous (inside) neuroprotection. There are many NTF's but one recently investigated is glial derived neurotrophic factor (GDNF). It has been known for many years to be necessary for cell growth and survival. This NTF has been studied extensively for and with dopamine cells. A clinical trial using GDNF in IPD patients and injecting it in the brain was halted by Amgen because of side effects that occurred. Other than significant side effects there was no clinical benefit. There are now others ways being investigated to use NTF's. One very interesting and practical way to increase GDNF is to exercise. It has been shown that exercise stimulates NTF's. GDNF activates ERK 1,2,and 5 and these are essential for survival of dopamine cells in a culture and in animals. ERK's are substances that at various doses either help the cell survive or cause the cell to die or become dysfunctional. GDNF at low levels activates the ERK's and gives a neuroprotective response and in animal models exercise has been able to increase GDNF. This has been shown in elaborate mice studies. The clinical and practical application of this is that exercise in patients with IPD may be of benefit and may give some NP benefit. The physiological event called pre-conditioning may play a role in this NP. In my 35 years of experience with IPD patients the ones who exercise regularly and aggressively have always seemed to have done better.

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