Movement Disorders

Winter 1998-1999
Volume 9, Number 2

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Introduction. It has been 4 years since the CNI Review has presented a discussion of movement disorders. This issue will cover what is new in the most common clinical problems. New understanding of pathophysiology, genetics, and diagnostic tools have led to more effective therapies and, indeed, a marked increase in clinical and research activities at the CNI Movement Disorders Center. With this growth, and the addition of personnel to the program, we are optimistic about the future for patients seeking help for Parkinson’s disease, tremor, dystonia, and other movement disorders.

Parkinson’s Disease. Society and medicine have been aware of the shaking palsy now known as Parkinson’s disease (PD) for hundreds of years. What has dramatically changed in the last decade and indeed since the last CNI Review devoted to Movement Disorders in 1994, is the emerging knowledge of the interplay between genetics and environment along with a host of new treatment options. This state of affairs reflects the combined efforts of dedicated basic scientists, clinicians, PD research networks, and the pharmaceutical industry. In this section of the CNI Review, the disease process and treatment will be discussed.

Epidemiology. Once relegated to “a disease of the very old”, PD is becoming more common. This is due to 2 major factors; we are living longer, and the baby boom generation is getting closer to the average age at onset of PD. Data collected over the past 30 years has shown a prevalence of PD of 300/150 000. This varies by geography, and of course, when stratified by decade. The greatest incidence of PD occurs during the 6th decade with a mean age at onset of 59 years. It is estimated that there are close to 1.5 million people currently afflicted with parkinsonism in North America.

There may be 2 other contributions to the increase of PD. The diagnosis of young-onset PD is now more accurately made. For many years, young individuals with signs of neurologic dysfunction suggestive of PD were told “you are too young for PD.” We now appreciate that classic histologic changes may be found in patients with parkinsonism beginning in their 20’s and 30’s. It is not unusual for PD to begin in the 40’s and early 50’s. We distinguish between juvenile parkinsonism (under age 20) and young onset PD because of the recognized genetic, clinical, and histology differences between these 2 groups of patients.

Clinical Manifestations. The astute reader will have noticed that the term “parkinsonism” is used at times. This is not interchangeable with Parkinson’s disease, a diagnostic term with more precise and restrictive criteria. Idiopathic PD reflects loss of dopamine cells in the substansia nigra accompanied by the proteinaceous cellular inclusion known as Lewy Bodies. The typical clinical features include gradual onset of asymmetric resting tremor, slowly progressive rigidity, and bradykinesia. As the disease progresses, postural instability becomes problematic. Symptoms are typically responsive to dopaminergic medications for several years. This is quite in contrast to parkinsonism from other causes. Indeed, there are nearly 50 different causes of parkinsonism, most are listed in Table 1. Accurate diagnosis is important as the prognosis and treatment differs among these various conditions.The term Parkinson’s Plus refers to patients with parkinsonism and additional signs and symptoms. The most common Parkinson’s Plus syndromes include the multisystem atrophy disorders, such as Shy-Drager syndrome (parkinsonism and antoronic failure), striato-nigral syndrome (parkinsonism unresponsive to levodopa) and olivoponto cerebellar atrophy (parkinsonism and cerebellar dysfunction). Atypical parkinsonism patients have predominantly akinetic rigidity which is poorly responsive to dopaminergic medication and associated with more rapid disease progression. One variant is the so-called Dopa Responsive Dystonia (DRD) due to a mutation in the gene for GTP cyclohydrolase causing dopamine deficiency. These patients come from families with a mix of dystonia, mild parkinsonism, or a cerebral palsy-like illness that respond exquisitely to low doses of levodopa.

The reader is referred to one of the recent movement disorders texts for a more in-depth discussion of these various syndromes (see for example, Jankovik and Tolosa 1998 or Koller and Watts 1997).

Biology and Genetics. While the neurochemical abnormalities of PD are reasonably well understood, the process which triggers dopamine cell loss and progressive degeneration remains only partially sorted out. Several important discoveries have occurred in the past 2 years. A genetic basis for PD has been found for several families with PD in multiple generations. In fact, several different genetic mutations have been found for different families on chromosome 4.

The other important factors of cellular change seem to be related to the process of apoptosis. This term refers to programmed cell death, akin to “built-in obsolescence.” It appears that dopamine cells somehow lose the capacity to regulate normal repair and upkeep.

New Treatment Options. New Medications. While dopamine replacement via precursor loading with levodopa remains the “gold standard” for symptom control, complications of moderate or advanced PD have led to adjunctive therapies and alternatives to the widely used combination of carbidopa/levodopa. As PD progress, the nigro-striatal system loses its capacity to buffer, store, and release dopamine. This translates clinically into a wearing-off phenomena, on/off fluctuation, freezing, and dyskinesia. The 2 main strategies for treatment include use of dopamine agonists and catechol-O-methyl transferase (COMT) inhibitors. Direct stimulation of the dopamine receptors by an agonist bypasses the nigral dopamine cell and the short pharmacological half-life of levodopa. This often results in longer duration response to a given dose an increase in “on” time for the patient. We now know that monotherapy with an agonist can provide good symptom control in early stages of PD and combined agonist/levodopa treatment affords smooth motor response in moderate and later stages of PD. There is preliminary but compelling data that suggest such an approach may be valuable, especially in young-onset PD patients. Table 2 lists the 4 agonists currently in use in the United States. The 2 newer agents, pramipexole and ropinerole have the potential advantage of being non-ergot based, pergolide has an advantage of the longest half-life. All agonists must be started at a low dose and titrated gradually.

The availability of levodopa for the brain may be increased and its effect prolonged by inhibiting its metabolism in the periphery. The carbidopa in carbidopa/levodopa inhibits the decarboxylation of levodopa, but there is another degradation pathway via the enzyme COMT. Inhibition of this enzyme system is possible with 2 drugs. Tolcopone was released in the spring of 1998 and another is in Phase III clinical trials (entacapone). They act as carbidopa/levodopa extenders and may be useful for patients with wearing off phenomena. Tolcopone requires monitoring of ALT and AST as there is a small risk of hepatotoxicity.

New Surgical Interventions. One of the most dramatic treatment strategies to win FDA approval in the past year is thalamic stimulation, also described as Deep Brain Stimulation (DBS). The basic concept is simple. The neuronal circuits responsible for generation of tremor are located via stereotactic and electrophysiologic guidance in the ventralis intermedius (VIM) of the thalamus. The circuit may be “turned off” with high-frequency electrical stimulation. Once located, the stimulating electrode is left in place and an extension lead is tunneled under the scalp down to an impulse generator implanted subcutaneously, just like a cardiac pacemaker. The stimulation parameters may be adjusted via radio telemetry for optimal tremor control. The patient may activate the stimulator with a remote control magnet instantly suppressing the tremor. Even more exciting is the clinical improvement in other PD symptoms when the electrode is placed a short distance away from the VIM into the sub-thalamic nucleus (STN). This alternative location is still considered investigational, but appears close to FDA approval. The CNI Movement Disorders Center has worked with DBS for several years and is pleased to welcome Dr. Rajeev Kumar to our staff as of August 1998. Dr. Kumar has been instrumental in pioneering the precise electrophysiologic mapping of motor control circuitry while at the University of Toronto.

We look forward to expansion of our DBS program and clinical research protocols under his direction.

Re-thinking Rehabilitation. Tradition dictates that physical therapy (PT), occupational therapy (OT), and speech therapy (ST) have little long term value for PD. Indeed, standard musculo-skeletal rehabilitation techniques have little lasting value in the setting of a chronic progressive condition. Recently our understanding of how best to work with PD has changed allowing for effective intervention in an outpatient setting. Primarily through the auspices of the Nation Parkinson Foundation Rehabilitation effort and guidance from the Parkinson Outreach Program (POP), patients with a decline in function have enrolled in an intensive course of therapy which appears to improve activities of daily living, safety, and quality of life. Over 40 POP centers have been operational in 10 states over the past few years. In addition to specialized PT, OT, and ST, the program now includes social services that address coping strategies, patient/care partner communication, and resource information. The treatment comprises new therapies demonstrating efficacy for PD, such as voice therapy based upon the Lee Silverman Voice Treatment pioneered by Lori Ramig, PhD. The program is for several hours a day, 3 days per week for 2 to 12 weeks. Long-term outcome studies are currently underway here in Colorado, Philadelphia, and other centers.

Hope for a Cure. Update on Neuro- transplantation. In the 1994 CNI Review, neuro-transplantation was discussed by Curt Freed, MD. Since that time, a large, controlled clinical trial has been carried out with funding by the National Institutes of Health. The data is still being collected and analyzed. We do know that several recipients of transplants who died of unrelated causes show histologic evidence of transplant survival, synaptic outgrowth, and dopamine production. At the same time, transplantation of porcine tissue and cloned bovine tissue capable of producing dopamine is undergoing study. The preliminary results are encouraging, although all neuro-transplantation remains investigational.

Nerve Growth Factors. Major progress has been made towards the identification of substances that trigger cellular growth and regeneration. Two specific agents hold promise for PD. Glial Derived Neurotrophic Factor (GDNF) has been shown to reverse clinical symptoms of PD in monkeys, and histologic examination reveals apparent recovery and sprouting of nigral dopamine neurons. The results in monkeys have led to Phase I and II clinical trials with humans. CNI is participating in a multi-center, double-blind, placebo-controlled trial of GDNF infusion into the cerebral ventricles of PD patients. At the time of this writing, we are just now entering the dose range that might be effective in humans. Preliminary results should be available in 1999. Another group of compounds appears to induce regeneration in injured or sick neurons. These are oral medications known as neuro-immunopholins. They resemble, in part, cyclosporin A without the immunosuppressive effects.

One agent in particular, GPI 1046, has shown promise in mice and rats. If the trials in monkeys result in similar improvements, Phase I trials should begin in humans in the year 2000 or 2001 using drugs similar to GPI 1046.

Huntington’s Disease. Please refer to the article by Dr Lauren Seeberger in this issue. 

Tic Disorders and Tourette’s Syndrome. Perhaps the most interesting findings regarding tic disorders in the past 5 years are the high prevalence of the clinical phenomena and a possible link, in some cases, to the immune system. Recently published epidemiological data suggest that Tourette’s Syndrome (the presence of noise tics and movement tics for more than 1 year) is quite common, especially in mild forms. Such individuals typically do not seek medical evaluation nor do they require specific treatment. Indeed, even if the tics are quite prominent, it is the consensus of most patients (and specialists) that medical treatment is not necessary.

Following observations of tics emerging after streptococcal pharyngitis, researchers began to explore the possible relationship between neuronal antibodies and the neurologic phenomena. A spectrum of signs and symptoms are under investigation including tics, obsessive thinking, compulsive behaviors, and attention deficits. The model is similar to that of Sydenham’s Chorea. The challenge for researchers is to some how document cause and effect between two very common problems (i.e., streptococcal infection and tics) along with difficult to measure neuronal antibodies. To this end, the CNI Movement Disorders Center is participating in a NIMH sponsored multi-center trial as part of the Tourette’s Syndrome Study Group.

Dystonia. Abnormal posture of body parts due to co-contraction of antagonist muscles is the clinical feature of dystonia. The term may refer to the formal diagnosis (as seen with the DYT 1 gene in patients with autosomal dominant inheritance of the chromosome 9 mutation) or as a description in patients with other known neurologic illness such as stroke or multiple sclerosis. In the past 2 years, a new understanding of the pathophysiology is emerging. We now know that disruption of the sensory input or motor output pathways of the basal ganglia may result in dystonic contractions of muscles. This includes injury to peripheral sensory nerves, thalamic relay neurons and projections from the putamen and globus pallidum nuclei. Treatment strategies include alteration of neurochemistry (as we have done for years with oral agents), increased proficiency in botulinum toxin injections and stereotactic surgical intervention (preliminary pallidotomy). The explosion of genetic mapping has already revealed several new genes causing dystonia and we may come to appreciate that the clinical phenomena is best seen as the result of genetic predisposition and environmental trigger.

Tremor. The reduction of severe tremor following DBS is nothing short of amazing. New electrophysiologic mapping techniques and improvement in implantation technology have had profound impact on the lives of patients with Essential Tremor (ET) and PD tremor. In addition, recent genetic linkage studies have revealed 2 genes responsible for ET in two different families. This may allow us to sort out the biochemistry of this relatively common problem.

Spasticity. With improved survival following stroke, spinal cord injury, and traumatic brain injury, patients are often afflicted with spasticity. Spasticity is a brain disorder of defective descending inhibition due to loss of cortical, subcortical and brain stem pathways. The result is inappropriate over activity of spinal interneurons and several reflex loops. Clinically, patients suffer involuntary muscle spasms, clonus and abnormal muscle inhibition (“increased muscle tone”). Recent research from the CNI Movement Disorders Center and other centers has demonstrated efficacy of botulinum toxin injections for certain forms of spasticity.

The best results seem to be for patients with subacute spasticity in which focal areas of muscle contraction interfere with rehabilitation. For a comprehensive review, see Supplement 6 of Muscle and Nerve, 1997, entitled, “Spasticity: Etiology, Evaluation, and Management of the Role of Botulinum Toxin Type A.”

Conclusion. As 1998 came to a close, advances in the diagnosis and treatment of movement disorders have led to the improvement in quality of life for patients with PD, ET, HD, TS, dystonia and spasticity. We look forward to the rapid development of new treatment options over the next few years while continuing our strong commitment to patient education and compassionate care.

Address comments and questions to:

Christopher F O’Brien, MD
CNI Movement Disorders Center
701 East Hampden Avenue
Suite 530
Englewood, CO 80113

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