PARKINSON DISEASE

PARKINSON DISEASE BRADYKINETIC VARIANT — Bradykinetic movement disorders consist predominantly of conditions with features of parkinsonism, of which Parkinson disease (PD) is the most prominent example. Characteristic findings include rigidity, akinesia, and gait disturbance.

Clinical features — PD typically presents in middle and late life. However, early-onset disease can occur before age 40 years, and a juvenile form presents before age 20. Most affected children have a rigid, akinetic disorder, although many have a typical resting tremor. Dystonia often involving the legs, levodopa-induced dyskinesias, and levodopa-related motor fluctuations (eg, "wearing off" and "on-off" responses several hours following a dose) are common in the juvenile form.

Genetics — Most cases of PD are sporadic, but genetic loci (PARK1 through PARK13) with causative mutations in six nuclear genes have been associated with autosomal dominant or recessive Parkinson disease or parkinsonism. These genes encode the following proteins: Alpha synuclein Ubiquitin carboxyl-terminal hydrolase-1 (UCHL1)Parkin DJ1  PTEN-induced putative kinase 1 (PINK1)  Leucine rich repeat kinase 2 (LRRK2), also called dardarin.

Most sporadic cases of PD do not show clear familial aggregation, but genetic factors likely contribute to PD susceptibility. One genetic locus (PARK10) on chromosome 1p has been associated with late onset idiopathic PD, and mutations in the glucocerebrosidase gene (GBA) in Ashkenazi Jews have been associated with a significantly increased risk of PD compared with healthy controls.

The pathogenesis of autosomal dominant or recessive Parkinson disease is not completely understood. A speculative unifying model suggested by genetic analysis proposes the following mechanisms: Abnormal aggregation and misfolding of alpha synuclein leads to Lewy body formation, triggering cellular oxidative stress and energy depletion. Mutations in parkin and UCHL1 may interfere with proteosome degradation of abnormal proteins such as alpha synuclein. Mutations in DJ1 may enhance misfolding and aggregation of alpha synuclein. Mutations in DJ1 and PINK1 may contribute to increased oxidative stress and decreased cellular resistance to stress imposed by misfolded and abnormally aggregated proteins. Mutations in GBA may lead to reduced lipid binding of alpha synuclein and thus an increased pool available for misfolding and aggregation.

Phenotypic variability — Some have argued that it is premature to claim that all of these gene mutations cause true Parkinson's disease, since Lewy bodies are not clearly associated with either DJ1 or PINK1 mutations. In addition, there is phenotypic variability between these different mutations. Alpha synuclein mutations (PARK1 and PARK4) are associated with an autosomal dominant inheritance mode; the phenotype varies from classic Parkinson's disease to dementia with Lewy bodies. Many patients with early-onset autosomal recessive familial PD and isolated juvenile-onset disease have mutations in the parkin gene (PARK2), located on chromosome 6q25.2-27. In one series, mutations occurred more frequently in patients with isolated disease when the age of onset was before 20 than after 30 years (77 versus 3 percent). In the patients who died, neuropathologic examination of the brains showed depigmentation of the substantia nigra pars compacta. However, the neurons did not contain the eosinophilic cytoplasmic inclusions (Lewy bodies) typically seen in PD.

However, the parkin-associated phenotype can be indistinguishable from idiopathic Parkinson's disease in some individuals, as evidenced by detailed evaluation of a large pedigree of parkin mutation carriers from northern Italy. Among the 77 parkin mutation carriers, 25 had levodopa-responsive parkinsonism, and five of them met criteria for definite Parkinson's disease. Neuropathologic examination of one 73 year old patient who carried two mutant parkin alleles demonstrated Lewy bodies in substantia nigra and locus ceruleus. Mutations of DJ1 (PARK7) are associated with autosomal recessive inheritance, age younger than 40 at onset, slow progression, and good response to levodopa. Mutations of PINK1 (PARK6) are associated with autosomal recessive inheritance, age younger than 50 at onset, slow progression, and excellent response to levodopa, similar to parkin and DJ1. PARK6 has been found worldwide. Although preliminary evidence suggested that PINK1 was not associated with sporadic forms of PD, a subsequent report from Italy found that PINK1 was responsible for some sporadic cases of early onset PD. The LRRK2 gene (PARK8 locus) maps to chromosome 12p11.2-q13.1 and codes for dardarin, a protein of unknown function whose structure suggests it may be a cytoplasmic protein kinase. Mutations in LRRK2 are associated with parkinsonism characterized by typical clinical features of PD, including levodopa responsiveness. However, the age of onset is highly variable (range 35 to 78 years). Furthermore, the neuropathologic features may be variable even within the same family; these include abnormalities consistent with Lewy body PD, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and tau pathology suggestive of progressive supranuclear palsy.

The LRRK2 gene may account for a significant proportion of PD cases. Genetic screening studies suggest that the Gly2019Ser mutation in the LRRK2 gene accounts for 3 to 13 percent of autosomal dominant PD in Europe, and 41 percent of autosomal dominant PD in families from North Africa. The Gly2019Ser mutation has been identified in asymptomatic carriers, suggesting reduced or age-dependent penetrance. LRRK2 mutations have been found in 0.4 to 1.6 percent of patients with idiopathic PD, although such cases could also be explained by reduced penetrance in familial disease.

Diagnosis — The diagnosis of juvenile parkinsonism is based on clinical signs. Patients have gradual onset of slowness of movement, tremors in the hands or legs (but not the head), rigidity of muscles, shuffling gait, and postural instability. Other signs include lack of facial expression (hypomimia), drooling, dysarthria, and dystonia (involuntary spasms and abnormal postures of hands and feet).

Treatment — Levodopa is the most effective drug in the treatment of PD. However, most patients develop abnormal involuntary movements (dyskinesias) and unpredictable fluctuations in motor functioning within three years of treatment. Patients with onset before age 20 years are most likely to be affected. As a result, therapy is initiated with other drugs that will control the symptoms and delay the need for levodopa. They include anticholinergic drugs (eg, trihexyphenidyl, amantadine) and dopamine agonists (eg, pramipexole, ropinirole, and pergolide).

Complications of levodopa are managed by adjusting the dosage and frequency of administration. If these changes do not alleviate symptoms, surgical treatment, such as high frequency stimulation of the subthalamic nucleus or globus pallidus, is considered.

Motor fluctuations and dyskinesia in Parkinson's disease

INTRODUCTION — As many as 50 percent of patients on levodopa for five years experience motor fluctuations (MF) and dyskinesia. These symptoms are especially common in patients with young-onset (eg, under the age of 50) Parkinson's disease (PD); they are unique to levodopa and are not produced by the other antiparkinson drugs. Patients typically experience a smooth and even response to the early stages of levodopa treatment. As the disease advances, however, the effect of levodopa begins to wear off approximately four hours after each dose, leaving patients anticipating the need for their next dose. This phenomenon may be explained by the observation that dopamine nerve terminals are able to store and release dopamine early in the course of disease but, with more advanced disease and increasing degeneration of dopamine terminals, the concentration of dopamine in the basal ganglia is much more dependent upon plasma levodopa levels. Plasma levels may fluctuate erratically because of the 90 minute half-life of levodopa and the frequently unpredictable intestinal absorption of this medication. Motor fluctuations (MF) are alterations between periods of being "on," during which the patient enjoys a good response to medication, and being "off" during which the patient experiences symptoms of their underlying parkinsonism.

Dyskinesia consists of abnormal involuntary movements that are usually choreic or dystonic but, when more severe, may be ballistic or myoclonic. Dyskinesia usually appears when the patient is "on." It may occasionally occur in the form of painful dystonia when the patient is "off," especially in the morning on awakening, when dystonic intorsion of a foot (usually on the side of greater parkinsonian involvement) occurs as a withdrawal reaction because of the long interval without medication overnight. 

Surgery for advanced PD is another therapeutic option, as bilateral deep brain stimulation of the subthalamic nucleus or globus pallidus appears to improve motor function in selected patients with advanced typical PD and MF, whose condition cannot be further improved by medical therapy. The surgical management of advanced PD is discussed elsewhere.

WEARING-OFF PHENOMENON — Patients with advanced Parkinson's disease (PD) begin to be aware of a wearing "off" or end-of-dose effect less than four hours following a dose of levodopa.

Alteration of levodopa dosing — Wearing "off" can initially be managed by increasing the dose of levodopa, if the patient is not having side effects and is taking a relatively low dose. However, increasing the dose often increases side effects without effectively increasing the dose duration.

Shortening the interdose interval while administering lower doses is usually a more effective approach. However, it is often difficult to titrate the dose precisely, and some patients begin to exhibit an "all or none" response whereby individual lower doses produce no evident clinical response. This occurs because the pharmacologic response threshold is higher in advanced disease than it is in earlier disease.

Liquid Sinemet (carbidopa/levodopa) is occasionally used for patients when titration of the dose and dose interval using tablets is difficult. However, this approach is not typically practical since Sinemet is insoluble in water and no commercial preparation of liquid Sinemet is available. Instructions for preparation of a daily supply of liquid Sinemet are available, but use of this approach is best left to the specialist.

The sustained-release forms of levodopa preparations (eg, Sinemet CR) may be useful in the early stages of the wearing "off" phenomenon and may add up to 90 additional minutes throughout the day to levodopa's duration of effect. However, Sinemet CR is less well absorbed than immediate release Sinemet; thus, an individual dose increase of approximately 30 percent may be required to achieve the same clinical response. A practice parameter from the American Academy of Neurology (AAN) issued in 2006 concluded that sustained-release carbidopa/levodopa does not decrease "off" time compared with immediate release formulations.

Addition of a second drug — Addition of a second drug is indicated if the adjustments cited above are not successful.

1. Dopamine agonists — Dopamine agonists are commonly used to reduce the amount of "off" time in patients with advanced PD and may also allow for the dose of levodopa to be reduced. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), and apomorphine (Apokyn). Cabergoline is approved by the FDA only for the treatment of hyperprolactinemic disorders, and its use for advanced PD is off label.

Studies comparing the efficacy of various dopamine agonists have found either no significant difference or only mild superiority of one agent over another. The dopamine agonist apomorphine administered subcutaneously can be used for rapid onset (usually within 10 minutes) rescue therapy when patients suddenly turn "off". In a randomized, double-blind, placebo-controlled study of 29 patients with advanced PD and two hours or more of "off" time despite aggressive oral therapy, administration of subcutaneous apomorphine (2 to 10 mg) resulted in successful amelioration of "off" state events following 95 percent of injections compared with 23 percent receiving placebo injection. One review concluded that the magnitude and pattern of the motor response to a single subcutaneous dose of apomorphine is qualitatively comparable to that of oral levodopa; a 4 mg dose achieved a clinically significant improvement in 75 percent of patients.

Cabergoline may have some utility for reduction of "off" time in patients with advanced PD, but data are limited. In a single center, 24-week study of 37 patients (19 active, 18 placebo), treatment with cabergoline (mean dose 5.4 mg/day) was associated with a significant decrease in daily "off" time compared with placebo (2 versus 0.7 hours [40 versus 18 percent]). However, these results are limited by a potentially confounding baseline difference in "off" time duration between the treatment groups. In another single center, 24-week study of 27 patients (17 active, 10 placebo), patients treated with cabergoline (mean dose 4.9 mg/day) had an increase in "on" time (2.7 hours [30 percent]) and a decrease in "off" time (3.3 hours [59 percent]), but no information was provided for the placebo group about these parameters.

Cabergoline treatment was not associated with increased dyskinesia in these trials. However, a retrospective case control study of 210 patients with PD found that high cumulative dose and long-term treatment with cabergoline was associated with an increased risk of cardiac valvulopathy detected on transthoracic echocardiography. In a randomized controlled trial, bromocriptine decreased "off" time compared with placebo (8 versus 3 percent, respectively), but the difference was not statistically significant.

2. COMT inhibitors — Catechol-O-methyl transferase (COMT) inhibitors such as tolcapone (Tasmar) and entacapone (Comtan) may prolong and potentiate the levodopa effect and reduce the "off" time when given with a dose of levodopa. The net result is an increased levodopa effect in fluctuating patients. These medications may allow a reduction in the total daily levodopa dose by as much as 30 percent.

The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.

The most common side effects of these drugs are due to increased dopaminergic stimulation and include dyskinesia, psychiatric effects (mainly visual hallucinations), nausea, diarrhea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone or entacapone. Both drugs may also cause a brown-orange urine discoloration.

In clinical trials, tolcapone was associated with transient, asymptomatic elevations of transaminases (AST and ALT) in 1 to 3 percent of subjects exposed to the drug. Three reported deaths from hepatotoxicity in patients using tolcapone prompted its removal from the market in Canada and Europe, although it is still available in the United States with the recommendation that it be used for treatment of motor fluctuations only after other methods have been exhausted and with monitoring of ALT and AST levels for the first six months of therapy. Entacapone has thus far not been associated with hepatotoxicity.

Monitoring of liver enzymes with liver function tests (LFTs) must be done at baseline and then every two weeks for the first year of tolcapone therapy, then every four weeks for the next six months, then every eight weeks thereafter. Monitoring of LFTs should be resumed at the previous frequency if the tolcapone dose is increased to 200 mg three times a day. Tolcapone should be discontinued if the ALT or AST exceeds the upper limit of normal or if the clinical signs and symptoms suggest the onset of liver failure.

3. MAO B inhibitors — Rasagiline is a selective monoamine oxidase (MAO) B inhibitor. It has potential long-term effects on dopamine transmission because it acts irreversibly on MAO B receptors. Rasagiline appears to be effective for motor complications in PD as demonstrated in randomized clinical trials. One of these, the 18-week multicenter LARGO trial, evaluated 687 patients with PD who had motor fluctuations (MF) for at least one hour every day despite optimum levodopa/dopa decarboxylase therapy. Patients were randomly assigned to adjunct therapy with either rasagiline 1 mg daily, entacapone 200 mg with every levodopa dose, or placebo. Both rasagiline and entacapone reduced mean daily "off" time (the primary outcome measure) by about one hour compared with placebo, and both increased daily "on" time without troublesome dyskinesia compared with placebo. The beneficial effect of rasagiline was independent of age (<70 versus 70 years) and of adjunct use of dopamine agonists. Rasagiline was well tolerated in these studies. The frequency of dopaminergic adverse events in the LARGO trial was similar to that seen in the entacapone and placebo groups. Rasagiline is approved by the European Commission as initial monotherapy in patients with early PD and as adjunct treatment in moderate to advanced PD. It received similar approval by the United States Food and Drug Administration in May 2006.

Selegiline is another selective MAO B inhibitor. Unlike rasagiline, selegiline is metabolized to amphetamine derivatives. Although selegiline may extend the levodopa effect, the clinical benefit this produces is usually relatively mild. Results from a small randomized controlled trial suggest that orally disintegrating selegiline may also be beneficial, although the study did not report change in levodopa dose.

Other strategies — Anticholinergic drugs and amantadine are not very effective in managing the wearing "off" effect and are rarely indicated for this purpose, given the other more effective options. Early studies of adenosine A2A antagonists as adjunctive therapy in PD have yielded promising results, and clinical trials are ongoing.

Preliminary studies suggest that eradication of Helicobacter colonization, which is present in about half of the population, may be a useful method for improving levodopa absorption and reducing motor fluctuations in patients with PD. These require confirmation in larger clinical trials before routine testing for H. pylori and antibiotic eradication can be recommended.

Guideline recommendations for treating "off" time — An evidenced-based practice parameter from the AAN issued in 2006 made the following recommendations for the treatment of "off" time in patients with PD and motor fluctuations: Entacapone and rasagiline are established as effective and should be offered to reduce "off" time. Pergolide, pramipexole, ropinirole, and tolcapone are probably effective and should be considered to reduce "off" time, with the stipulation that the adverse effects of tolcapone (hepatotoxicity) and pergolide (valvular fibrosis) require that they be used with caution and monitoring. Apomorphine, cabergoline, and selegiline are possibly effective and may be considered to reduce "off" time. Sustained release carbidopa/levodopa does not decrease "off" time compared with immediate release carbidopa/levodopa; bromocriptine does not reduce "off" time compared with placebo; both may be disregarded to reduce "off" time.

UNPREDICTABLE OFF PERIODS — Transitions from being "on" to being "off" can be sudden and unpredictable in some patients. Unlike the wearing "off" phenomenon at the end of a levodopa dose cycle, there is sometimes no obvious relationship between the time of levodopa administration and the appearance of "off" episodes in patients with unpredictable "off" periods. These periods typically occur in patients with advanced Parkinson's disease (PD) who are also experiencing motor fluctuations (MF) and severe dyskinesia.

Management of these individuals is similar to that for patients who are having problems with wearing "off," although it typically is much more difficult. Direct observation of the patient during a prolonged outpatient visit as he or she cycles through such episodes is useful to determine the relationship of levodopa doses to "off" episodes. In some cases, these episodes occur at times of peak levodopa effect due to excessive rather than insufficient dopaminergic stimulation; such patients are best treated by reducing rather than raising the levodopa dose.

Addition of a COMT inhibitor or a dopamine agonist can be helpful; marked reduction of the levodopa dose together with the addition of high doses of a dopamine agonist may be required. Controlled release levodopa preparations (eg, Sinemet CR) are usually not helpful and occasionally exacerbate the situation.

Competition with neutral amino acids for transport across the gut and into the brain may be responsible for "offs" that appear following meals. A protein redistribution diet in which most protein intake is reserved for the evening was useful in approximately two-thirds of such patients in small studies, although this type of diet tends to be impractical for long-term use.

Episodic freezing is a special form of unpredictable "off" in which patients suddenly become immobilized for seconds to minutes at a time. This complication usually occurs while walking when it may cause falls; it is often not medication related and is very resistant to treatment. When freezing is more prolonged and accompanied by the emergence of other parkinsonian signs, treatment is similar to patients with other forms of the wearing "off" effect.

ACUTE AKINESIA — Acute akinesia is a sudden exacerbation of Parkinson's disease (PD) characterized by an akinetic state that lasts for several days and does not respond to treatment with antiparkinson medication. This phenomenon is different from wearing "off" effects and may occur in patients not previously treated with levodopa.

Acute akinesia should prompt a search for systemic infection or other intercurrent medical problems that are capable of causing a sudden worsening of parkinsonism. In a review of this problem in 26 patients, acute akinesia appeared after a flu-like syndrome in six patients, hip joint surgery or bone fractures in eight patients, gastrointestinal disturbances in three patients, and various medication manipulations in the remaining patients. Four patients died in spite of treatment. Episodes of acute akinesia may therefore have serious consequences and usually warrant acute hospitalization in order to identify and correct the underlying cause.

FAILURE OF ON-RESPONSE — Patients with motor fluctuations (MF) sometimes fail to turn "on" following a dose of levodopa. This has been called the "no-on" response. In some cases, this is due to delayed gastric motility, which results in inadequate plasma concentrations in advanced patients who have a narrow therapeutic window. A common reason for the "no-on" phenomenon is an excessively prolonged or severe "off" period occurring before the "no-on." This is best managed by avoiding "offs."

The prokinetic agent cisapride increases gastrointestinal motility and may be helpful in such patients, but the drug has been associated with a number of drug interactions and fatal cardiac arrhythmias, prompting the manufacturer to severely restrict its availability in the United States. The prokinetic drug metoclopramide is a dopamine receptor blocker that should be avoided. Patients should be encouraged to take levodopa on an empty stomach and avoid protein at the time of drug administration.

Domperidone is a D2-blocker with selective peripheral activity in the upper gastrointestinal tract; it does not cross the blood-brain barrier and therefore lacks the neurologic side effects of metoclopramide. It is currently not available in the United States but is available in Canada and other countries. Although data are limited, domperidone (starting at 20 mg four times daily) may be useful as a prokinetic agent to treat delayed gastric emptying in patients with PD. However, animal studies suggest that, like cisapride, domperidone may increase the risk of cardiac arrhythmias.

DYSKINESIA — Dyskinesia refers to a variety of involuntary movements, which occur as a direct effect of levodopa. Other antiparkinson drugs are much less likely to produce these motor abnormalities but may exacerbate them once they have appeared following treatment with levodopa. Dyskinesia is sometimes mistaken for manifestations of progressive Parkinson's disease (PD) or confused with tremor by patients and their families, rather than recognized as reversible consequences of treatment.

Dyskinesia occurs in 30 to 40 percent of patients treated with levodopa by five years and nearly 60 percent by ten years, but not all dyskinesia requires treatment. A retrospective study suggests that the rate of dyskinesia requiring medication adjustment at five and ten years after levodopa treatment is 17 and 43 percent, respectively.

Dyskinesia is usually choreiform in type, manifested by continuous, restless appearing movements of the extremities, head, face, trunk, and respiratory muscles. These dyskinetic movements are remarkably well tolerated by most patients since patients feel entirely relieved of their parkinsonism while dyskinesia is present. However, severe dyskinesia may take the form of large amplitude, ballistic movements that interfere with function and become very disturbing to patients and their families.

Levodopa was given in relatively high doses when it was first used as therapy for PD. As a result, dyskinesia was often seen early in treatment, especially in those with advanced disease who were being treated for the first time. The subsequent use of more modest doses resulted in its later appearance, months to years after initiating levodopa. Dyskinesia is especially common in patients with young-onset PD.

Peak-dose dyskinesia is most common. It occurs 60 to 90 minutes following a dose of levodopa. Early in the disease, this complication can be managed by lowering the medication dose, switching to a controlled release preparation, or reducing adjunctive drugs such as dopamine agonists, selegiline, or anticholinergic drugs. However, in more advanced patients with brittle responses, reducing the dose of levodopa may result in complete failure to generate an "on" response. In this situation, the dose of dopamine agonist should be greatly increased and the levodopa dose reduced, since dopamine agonists are much less likely to induce dyskinesia than levodopa.

An unusual pattern sometimes evolves in which dyskinesia peaks twice after each dose (diphasic dyskinesia) - when patients turn "on" and again as they begin to turn "off". In the second phase, dyskinesia in one body part may coexist with the emergence elsewhere of parkinsonian signs such as tremor and dyskinesia. This pattern is often unrecognized and may only be appreciated if the patient is observed during a prolonged outpatient visit.

The diphasic pattern is notoriously difficult to manage and usually requires more frequent levodopa dosing to prevent wearing "off" prior to each dose. However, this strategy often leads to progressively increasing dyskinesia as the day goes on. Addition of a dopamine agonist and a marked reduction in the levodopa dose should be tried in such patients.

Sustained release levodopa is best avoided in patients with severe or complex patterns of dyskinesia since absorption may be delayed and dyskinesia tends to progressively increase into the afternoon and evening.

Amantadine — Amantadine may be useful for treating dyskinesia in advanced PD. Several studies have shown short-term benefit. As an example, a single-center randomized controlled trial found that amantadine administration compared with placebo was associated with a 24 percent reduction in the total dyskinesia score. In addition, a placebo-controlled study involving 17 patients showed that the beneficial effects of amantadine on motor response fluctuations were maintained for at least one year; initial and one-year reductions in dyskinesia scores were 60 and 56 percent, respectively.

In another placebo-controlled study in 40 patients with dyskinesia, amantadine treatment for 15 days resulted in a 45 percent reduction in dyskinesia scores compared with placebo. However, the benefit in this study lasted less than eight months, and amantadine withdrawal resulted in a rebound with increase of dyskinesia in 11 patients. Amantadine was not associated with worsening of parkinsonism symptoms in these studies. The dose of amantadine for dyskinesia is one tablet (100 mg) one to three times a day. Side effects may include peripheral edema, psychosis, and livedo reticularis.

Clozapine — Low doses of the antipsychotic clozapine (30 to 50 mg/day) reduced dyskinesia in several open-label studies, and low dose clozapine (12.5 to 75 mg/day) was significantly more effective than placebo in treating levodopa-induced dyskinesia in a double-blind, randomized controlled trial of 50 patients. The usefulness of clozapine is limited by its potential for inducing bone marrow suppression, but this risk may be acceptably low with monitoring. Clozapine treatment requires obtaining the white blood cell count (WBC) and absolute neutrophil count (ANC) at baseline and weekly for the first six months of continuous treatment, followed by biweekly monitoring thereafter.

The dibenzodiazepine derivative olanzapine has similar properties to clozapine. In a randomized controlled trial of 10 patients with PD, low-dose olanzapine was effective in reducing dyskinesia, but was associated with unacceptable increases in parkinsonism and "off" time.

Guideline recommendations for reducing dyskinesia — An evidenced-based practice parameter from the AAN issued in 2006 made the following recommendations for the treatment of dyskinesia in patients with PD and motor fluctuations: Amantadine is possibly effective and may be considered for reducing dyskinesia. There is insufficient evidence to support or refute the effectiveness of clozapine in reducing dyskinesia.

DYSTONIA — Dystonia is a more sustained abnormal posture than dyskinesia. Dystonic postures usually involve the limbs but can affect the face, neck, or trunk. Dystonia can be a manifestation of early untreated Parkinson's disease (PD) or may appear as a complication of levodopa treatment. A careful history is required since, when due to levodopa, dystonia can occur either as a peak levodopa effect or during "off" periods due to levodopa withdrawal. Withdrawal dystonia most commonly occurs in the early morning when it produces painful flexion and inversion postures of the feet and toes.

Peak dystonia is managed similarly to peak dyskinesia. "Off" period dystonia that occurs early in the morning is managed either by taking sustained release levodopa before retiring or by taking levodopa or a dopamine agonist during the night or first thing in the morning before arising. "Off" period dystonia during the day is managed similarly to other forms of the wearing "off" effect.

Another form of levodopa withdrawal is akathisia (motor restlessness) or restless legs, which usually occurs at night, several hours after the last dose of levodopa. This is managed by providing levodopa or a dopamine agonist before retiring.

RECOMMENDATIONS — The following treatment suggestions represent my approach to some difficult management issues that occur in advanced Parkinson's disease (PD).

Wearing "off" phenomenon Document the pattern of motor fluctuations (MF). Obtain a careful and accurate history, and observe the patient directly in an outpatient setting. Examine the effect of diet, and avoid taking levodopa with high protein meals. A sustained-release levodopa formulation may be beneficial, but only in the early stages of wearing "off" in patients with less advanced PD. In patients with more advanced PD, reduce the levodopa dose interval by 30 to 60 minutes. This may require the addition of an extra levodopa dose at the end of the day. In most cases, individual levodopa doses should be left unchanged. Consider adding the COMT inhibitors entacapone (Comtan) or tolcapone (Tasmar). Entacapone should be given first because of the small risk that tolcapone can cause an elevation of liver enzymes. Be prepared to lower the levodopa dose by up to 30 percent because of the increased peak levodopa effect if tolcapone is used. Consider adding an oral dopamine agonist such as pramipexole or ropinirole. Watch for dopaminergic toxicity such as visual hallucinations and confusion, and be prepared to lower the levodopa dose. Consider parenteral apomorphine in patients with sudden and severe wearing "off" effects. This rescue therapy is very effective, but it has the disadvantage of requiring a prophylactic antiemetic such as trimethobenzamide. In addition, the effective dose of parenteral apomorphine must be established for each patient by administration during a prolonged outpatient evaluation prior to initiating therapy. Consider the MAO B inhibitors rasagiline and selegiline. Be aware that selegiline exerts only a mild effect on the wearing "off" phenomenon, while rasagiline has an effect comparable to entacapone. Rasagiline is now approved in the United States and in the European Union.

Unpredictable "off" periods Document that "off" periods are unpredictable and long lasting. In many cases, they are sudden wearing "off" effects or transient freezing episodes. Avoid taking levodopa with high protein meals. Evaluate and treat the possible effects of anxiety, which may precipitate sudden "off" episodes. Consider raising the levodopa dose. Plasma levodopa levels may be falling below the therapeutic threshold. Alternatively, consider lowering the levodopa dose. In rare cases, sudden "off" episodes may be due to excessive levodopa effects

Failure or delay of the "on" response Avoid taking levodopa with high protein meals. Examine gastrointestinal absorption. Avoid wearing "off" effects. Failure or delay of the "on" responses often occur after prolonged wearing "off" episodes

Dyskinesia and dystonia:
Lower the levodopa dose when possible.
Replace a portion of the levodopa dose with a dopamine agonist, if necessary.
Replace sustained-release levodopa with regular levodopa, if dyskinesia is occurring in the late afternoon and evening.
Add amantadine to counteract dyskinesia.
Manage diphasic dyskinesia with more frequent levodopa dosing.
Use middle-of-the-night levodopa or a dopamine agonist to treat early morning "off" period dystonia.
Reduce the levodopa dose intervals or add a dopamine agonist to treat "off" period dystonia during the day

MRI and MRS in Parkinson disease.

Parkinson’s disease (PD) is a progressive neurological disorder characterized by a variable degree of impairment in motor skills, speech, and other CNS functions. Rest tremor, bradykinesia, rigidity, and loss of postural reflexes are generally considered the cardinal signs of PD. Other clinical features include secondary motor symptoms (e.g. dysphagia, sialorrhoea, micrographia, shuffling gait, and festination) and non-motor symptoms (e.g. autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders, and sensory abnormalities). The symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine due to an idiopathic degeneration of the brain dopaminergic system. The mechanism by which brain cells are lost may consist of an abnormal protein accumulation (alphasynuclein to ubiquitin) in the damaged cells, which leads to the accumulation of the characteristic inclusions called Lewy bodies. Excessive accumulation of iron, which is toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Recently, genetic mutations, protein mishandling, increased oxidative stress, mitochondrial dysfunction, inflammation, and other pathogenic mechanisms have been identified as contributing factors in the death of dopaminergic and non-dopaminergic cells in the brains of PD patients. There are no definitive diagnostic tests for the diagnosis of PD. Thus the disease must be diagnosed based on clinical criteria, which are typically based on the presence of a combination of cardinal motor features, associated and exclusionary symptoms, and response to levodopa. Pathological confirmation of the hallmark Lewy bodies on autopsy is still considered the criterion for definite PD diagnosis.
The disease is not fatal, but it progresses with time, dramatically worsening the subject’s quality of life and decreasing his/her average life expectancy.
The treatment includes drug therapy (e.g. levodopa, dopamine agonists, and monoamine oxidase-B inhibitors), as well as surgery and deep brain stimulation (in advanced PD patients for whom drug therapy is no longer sufficient).
Although the diagnosis of PD is straightforward when patients have a classical presentation, differentiating PD from other forms of PD related disorders is difficult. These affections include secondary (acquired) Parkinsonism, progressive supranuclear palsy (PSP), multiple system degeneration (MSA), and corticobasal degeneration (CBD). The absence of rest tremor, early occurrence of gait difficulty, postural instability, dementia, and the presence of dysautonomia, ophthalmoparesis, ataxia, and other atypical features, coupled with poor or no response to levodopa, can help in the differential diagnosis of these disorders.
However, at early disease stages, when signs and symptoms overlap, this can be very challenging, leading to a significant number of misdiagnoses. Due to the very different natural histories of these diseases, an early differentiation between PD and related disorders is important for correct prognosis and treatment strategy.

Conventional MRI is normal in PD patients and this investigation is usually performed to exclude a structural cause for the development of Parkinsonism. At late disease stages, the atrophy of the substantia nigra may become evident. Conventional MRI, however, may be useful in the differentiation of the various Parkinsonian syndromes, as it frequently shows abnormalities in these patients. Qualitative and quantitative studies have shown that atrophy and signal changes in putamen and infratentorial structures can differentiate patients with MSA from PD patients with high specificity at late stages, although sensitivity is suboptimal especially at early stages. An MR index based on the midbrain area and the width of superior cerebellar peduncles was able to distinguish patients with PSP from those with PD and MSA with high sensitivity and specificity. On CBD, the midbrain is generally not atrophic, which may help to distinguish this condition from other atypical Parkinsonisms. In some cases, an asymmetrical atrophy (more marked on the side opposite to the clinically involved side of the body and prevalently involving the frontoparietal cortex) can be found.

1H-MRS
Studies of MRS in PD have produced conflicting results, showing either no difference in the basal ganglia metabolite levels between PD patients and normal controls, or decreases of NAA/Cr levels in PD. The variability of the results is probably related to the difficulty of reliably assessing metabolic abnormalities in the substantia nigra, due to its small size and high iron content. Interestingly, by using high field MR strength (4 T), recent work has shown the ability to measure multiple metabolites (including GABA) very accurately in a small volume (2.2 ml) including the substantia nigra, but did not find any differences between patients and controls in a relatively small study (10 PD, 11 controls) (Figure-1).[1]

Figure-1: Short TE MRS  TE 5 ms, TR 4.5 sec, 400 averages for each subject acquired with 4 T magnet from 2.2 ml
volumes, that encompass the substantia nigra of (a) 11 healthy volunteers and (b) 10 patients with PD.
The VOI is shown in the T2-weighted images (From Oz et al. with permission).

In contrast to patients with PD, the reduction of NAA in basal ganglia and other brain regions seems to be consistent in patients with related Parkinsonian disorders. Decreases in basal ganglia levels of NAA have been reported in patients with MSA. In an MRS study at high field strength (3 T), NAA/Cr decreases were confirmed to be significantly reduced in the putamen and in the pontine base of MSA patients, suggesting that these measurements may be of diagnostic value early in the disease course.
Another study was performed in groups of patients with PD, PSP, and CBD using a multi-slice MRSI approach, which allowed the assessment of the metabolic profile of several brain regions with good spatial resolution. Decreases of NAA/Cr were observed in PSP patients in brainstem, centrum semiovale, frontal lobe, and precentral cortex, as well as a reduction of NAA/Cho in the lentiform nucleus. However, the largest decrease in NAA/Cho was in the lentiform nucleus of CBD patients, exactly where one would expect the most prominent neuropathological abnormality in this disease. Again, this study confirmed that the PD patient group showed no metabolic abnormalities in any of the brain regions studied.
Collectively, these studies suggest that there is a potential role for the use of 1H-MRS in the differential diagnosis of Parkinsonian related syndromes, and perhaps also for monitoring the effects of treatment in these disorders.

Case Presentation:

Figure-2: Left red nucleus short TE spectroscopy in parkinsonian with tremor of the left side of the body more the upper limb.

Figure-3: Short TE spectroscopy of the red nucleus of the same patient in fig-2.

Figure-4: Short TE spectroscopy of the left substancia nigra of the same patient as in figure2,3.

Fifure-5: Short TE spectroscopy of the right substancia nigra of the same patient as in fig2.3.4.

References:

1. Oz G, Terpstra M, Tkac I, Aia P, Lowary J, Tuite PJ, et al. Proton MRS of the unilateral substantia nigra in the human brain at 4 tesla: Detection of high GABA concentrations. Magn Reson Med 2006; 55: 296–301.