Spotlight on Parkinson’s Disease: Report of the Movement Disorder Society’s 5th International Congress of Parkinson’s Disease and Movement Disorders
conference update
The 5th international congress of parkinson’s disease and Movement Disorders was held in New York, N.Y., Oct. 10-14, 1998. Organized by Stanley Fahn, MD, the meeting produced several new and important pieces of information. In the field of genetics, abnormalities of at least four independent gene loci are now known to cause familial Parkinson’s disease. M. Polymeropoulos of Washington DC described the discovery of the Contursi kindred, an Italian family afflicted with early-onset autosomal dominant levodopa-responsive Parkinson’s disease (Science 1997;276:2045-2047). A mutation in alpha-synuclein, a protein encodes on chromosome 4q, is responsible for the family’s phenotype. The biology of alpha-synuclein is intriguing. It genetically induces the non-A-beta component of Alzheimer plaques, is preferentially expressed in dopamine neurons, is abundant in Lewy bodies (the pathologic marker of Parkinson’s disease), and is even amyloidogenic (Burke R. Trends Neurosci 1998;21:249-254). One investigator described his discovery of a gene on chromosome 6q, named "parkin," that is responsible for autosomal recessive juvenile Parkinson’s disease (Mizuno Y. Nature 1998;392:605-608). This cohort differs from the Contursi kindred: their symptoms began at an earlier age, they developed early dyskinesias and motor fluctuations, and their brains lack Lewy bodies in the substantia nigra.
Two investigators from Boston together amplified their recent publications on the molecular biology of the DYT-1 gene, responsible for early-onset dystonia. The DYT-1 gene, located on chromosome 9q, encodes torsinA, a protein homologous to heat shock proteins (Ozelius L, Penney J. Nat Genet 1997;17:40-48). It is expressed in many tissues and abundantly expressed within hippocampus, putamen, cerebellum, and substantia nigra. A deletion of a single amino acid engenders all cases of DYT-1 dystonia. At least six additional loci described by another investigator from New York have also been linked to inherited forms of dystonia, most of which begin in adulthood (Bressman S. Ann Neurol 1997;42:670-673). Pandolfo, of Montreal, Canada, Klockgether, of Bonn, Germany, Tsuji, of Niigata and Patchek, Salt Lake City, UT, reviewed the enormous strides made in the past decade to map the genes responsible for Friedrich’s ataxia, autosomal dominant cerebellar ataxias, DRPLA, and episodic ataxias. These markers for rare diseases—most now commercially available for testing suspected patients—offer unique opportunities to construct transgenic mouse models of disease. Currently, their phenotypes express a spectrum of neurologic presentations that are wider than previously suspected. Commercially available markers (via Athena Neurosciences) include SCA-1, 3, and DRPLA.
New Therapy. In the last 16 months, two new dopamine agonists, Mirapex and Requip, and one catechol-O-methyltransferase (COMT) inhibitor (Tasmar), have been released in the United States. Another COMT inhibitor (Entacapone) may be released next year. Two investigators reviewed the role of the new dopamine agonists and COMT inhibitors in the treatment of Parkinson’s disease (Rascol O. Clin Neuropharmacol 1998;21:169-175; Nutt J. Lancet 1998;351:1221-1221). Mirapex and Requip, both non-ergot dopamine agonists, act at the D2 and D3 receptors, as opposed to Permax and Requip, which also have D1 activity. Despite the assertions of the pharmaceutical companies, no evidence supports the newer agonists superiority to older agonists as add-on therapy to levodopa in fluctuating Parkinson patients. Both new agonists are effective as monotherapy in levodopa-naïve early Parkinson patients. Unfortunately, they also possess the same side effect profile as the ergot agonists (Parlodel, Permax, and Cabergoline), namely hallucinations, orthostasis, and somnolence. Tolcapone, the only currently available COMT inhibitor, decreases the elimination of levodopa and, thus, increases the amount of levodopa that crosses the blood-brain barrier. It is effective in patients with wearing-off phenomena, increasing "on" time. However, the drug is not without side effects. It may occasionally induce diarrhea severe enough to force discontinuation of the drug. More concerning, a small percentage of patients develop abnormalities in liver function. Three patients have died from acute hepatic failure after taking Tasmar. Before starting the drug, physicians must obtain a written informed consent and must check liver function tests on all patients. Liver function tests must then be followed every two weeks for the first year of therapy, every four weeks for the next six months, and then every eight weeks thereafter. Before increasing the dose to 200 mg three times per day, liver function tests should always be checked.
Invasive Therapy. The last five years have seen an explosion of interest and renewed experience with neurosurgical interventions for advanced Parkinson’s disease (Obeso J, et al. Mov Disord 1998;13(1):73-82). Two central questions pervade the use of these approaches: which target should be chosen, and should a lesion be performed or a permanent stimulator implanted? Lesions (thalamotomy or pallidotomy) are less expensive and simpler to perform. However, they are permanent, not titratable, and carry unacceptable risks of neurologic sequelae when performed bilaterally. Stimulators are more expensive (currently only approved in the United States for unilateral V.i.m. stimulation for intractable tremor from Parkinson’s disease or Essential Tremor) and carry a risk of infection or hardware failure. Nevertheless, they can be implanted bilaterally, do not damage tissue, and can be titrated to achieve optimal response. Both procedures carry an unavoidable 1-2% risk of operative hemorrhage, stroke, or visual field cut. Pallidotomy remains an effective technique for reducing contralateral levodopa-induced dyskinesias. The anatomy of the pallidum is so complex, however, that many centers are abandoning the pallidum as a site for stimulation. Instead, groups in Grenoble, Paris, and Toronto have implanted bilateral subthalamic nucleus (STN) stimulators. Bilateral STN stimulation is extremely effective in alleviating virtually all of the levodopa-responsive signs of Parkinson’s disease, including tremor (N Engl J Med 1998;339:1105-1111). Motor scores and videotapes of selected patients with bilateral STN stimulators show remarkable improvement: they can often reduce and sometimes eliminate levodopa altogether. Although these techniques remain experimental and are currently available in the United States only in research protocols or to patients who can afford the operation, the data and clinical opinions suggest a dominant role for bilateral STN stimulation for intractable Parkinson patients in the next decade.
(Dr. Steven Frucht is Post-Doctoral Clinical Fellow, Movement Disorders Division, The Neurological Institute, Columbia University, New York, NY.)
Spotlight on Parkinson’s Disease
Source: Lang AE, Lozano AM. Medical progress: Parkinson’s disease. Parts 1 and 2. N Engl J Med 1998;339:1130-1143;1044-1053.
Supplementing in detail frucht’s congress report, Lang and Lozano of Toronto have provided an excellent review article in the New England Journal of Medicine. Starting with the announcement that underdiagnosis of Parkinson’s disease (PD) may affect as many as 24% of cases, they emphasize the accuracy of careful clinical diagnosis and consider brain imaging as "rarely helpful." The review indicates as many as 45% of PD patients develop a variety of dementia. Pathogenic processes, including mitochondrial dysfunction and oxidative metabolism, are skillfully described to the reader. Excitotoxins, neurotrophic factors, and immune processes receive reasonable attention, as do genetic and other factors in the disorder’s development.
Some interesting points are that Asians and African blacks have a lower incidence compared to American blacks and, especially, whites. Remarkably, PD risk declines among those who smoke(d) sometime during their life. A full page deals with the genetic forms of PD and their various biochemical defects that might resemble exogenous factors that may cause the illness. This latter item may particularly indicate that even non-genetic mitocondrial errors may contribute to PD’s incidence.
Part two of the review starts with pathophysiology emphasizing that the brain’s dopa-deficient state inherently is reciprocated by increased, inhibitory GABA circuits resulting in the disease’s cortical motor system. For example, both thalamectomy and pallidotomy are considered to reduce inhibitory outflow and both improve unwanted motor activity in PD. Treatment is fully discussed in three categories: protective-preventive, symptomatic, and restorative-regenerative.
No known agent or behavior protects against PD. Early treatment invites disparity because of a paucity of well-designed and completed controlled studies. Lang and Lozano debunk the concept that levodopa is either toxic or accelerates the course of PD if started at onset of diagnosis. Selegeline and amantidine may provide early, but not late, assistance. Dopamine agonists, such as bromocriptine or pergolide, appear to bring mild, early relief, but levodopa sooner or later becomes necessary to lessen symptoms. Sections on late management along with their associated problems deserve the reader’s attention since they are discussed in relatively helpful detail. Surgical treatment comes in four forms: 1) transcellular exogenous implants, including the present selectively successful transplants of human fetal nigral dopaminergic cells into the striatum; 2) potential future possibilities of transplanting autogenous dopaminergic cells from the individual’s carotid body dopaminergic cells into selected basal ganglia targets (Espego EF, et al. Neuron 1998;20:197-206); 3) intracerebral lesioning of the globus pallidus (pallidotomy) to relieve tremor—a procedure with several potential complications; and 4) bilateral stimulation of the internal segment of the globus pallidus or, even more successful in outcome, the subthalamic nucleus.
Subthalamic Nuclei
Source: Limousin P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s Disease. N Engl J Med 1998;339:1105-1111.
This collaboration of french-based clinical scientists reports the outcomes of 24 patients with severe PD treated by direct stimulation of both subthalamic nuclei (STN). Twenty patients had at least one year of experience with the procedure.
Paradoxically, the STN normally enhances parkinsonian symptoms in monkeys given 1-methyl-4 phenyl- 1, 2, 3, 6-tetrahydropyridine. Nevertheless, high frequency, direct stimulation of the STN also ameliorated the monkey’s signs and did the same in advanced human PD in a preliminary study by Limousin et al (Lancet 1995;345:91-95). For this study, only patients with disabling motor flutuations were chosen. Of the 24 patients, one developed a severe hemiparalysis and aphasia from a hematoma, one subsequently died of unrelated causes, one was geographically inaccessible for follow-up, and one had electrodes removed because of secondary infection.
All patients treated had disabling motor fluctuations despite drug treatment. During off periods, these patients were severely handicapped (19 had painful dystonia) but could perform most daily activities during on periods. All received levodopa + inhibitor, 21 took a dopaminergic agonist, and 12 received apomorphine. Post-implantation electrical connections were adjusted at follow-up according to need. Detected dementia excluded possible candidates.
Stimulation generally reduced signs/symptoms of patients off medication by 60%. During medication-timed continued stimulation, 10% produced improved scores for akinesia, rigidity, tremor, ability to rise from chairs, gait, and postural stability all during off periods of medication. Other mobilities also improved, especially disabilities previously severe in off times. Painful off-period dystonia ceased in 12 patients and improved in four. All changes were highly significant and maintained. Medication was reduced in about half.
COMMENTARY
Parkinson patients and their doctors should consider this success of ameliorating severe, late developed disabilities by subthalamic stimulation. Presently, the disease must be crippling and advanced, pharmacologically resistant, and dementia-free before such stimulation is considered. What will be the cost? No one for sure can set a cost, but, compared to other risky ventures of like approaches, $100,000 sounds like a bottom price.
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