Focus on Movement Disorders - Selected Abstracts, November 19, 2009
The XDP Story
Pathology of XDP
Neuroimaging Findings in XDP
Neuropsychological Profile of XDP Patients
Genetics of XDP
Oral Pharmacology in XDP
Chemodenervation with Botulinum Toxin-A and Muscle Afferent Block in XDP
Session 2: All about XDP
The XDP Story
Lillian V. Lee, MD
Attention was drawn to the high incidence of a movement disorder from the island of Panay, Philippines when 5 of 6 cases, then diagnosed as dystonia musculprum deformans were presented at the Philippine General Hospital (PGH) in 1969. This led to the presentation of Torsion Dystonia from Panay at the 2nd Dystonia Meeting in New York in 1975. The meeting's documentation was published in the Advances in Neurology on Dystonia in 1976. Thus started the saga of XDP, also known as 'lubag'.
Sex-linked dystonia Parkinson syndrome or XDP is a movement disorder affecting the adult Filipino males during their most productive years (second to fifth decade). The disease is transmitted recessively thru the X chromosome. A female carrier remains healthy but gives birth to affected sons. On the other hand, all daughters of an affected male can carry the defective gene but all his sons are phenotypically and genotypically normal. The clinical picture is dominated by sustained muscular twisting which results in abnormal postures. Sometimes parkinsonian features like fine tremors and shuffling gait may supervene. In 98% of cases, symptoms generalize within 5 years after onset. The course is progressive and severely disabling. Terminally, patients become totally dependent while remaining mentally alert. The disease is endemic in Panay.
Pathology of X-linked Dystonia Parkinsonism
Edwin Munoz, MD
The consistent neuropathologic finding in X-linked dystonia parkinsonism (XDP) is atrophy of the caudate nucleus and putamen. Histological findings of neuronal loss with gliosis ranging from mild to severe were demonstrated in 13 autopsy brains studied to date. These patients had age ranging from 38-59 years and duration of illness ranging from 3-24 years.
The involvement of the striosomal and matrix compartments of the striatum was further studied in 5 brains of patients in the dystonic phase of the disease and 2 brains in the parkinsonian phase. In the dystonic phase, the striatum showed neuronal loss with gliosis in the striosomal compartment with relative preservation of the matrix compartment. The latter showed almost normal neuronal density and appeared like pathces sharply outlined by gliotic areas, giving the striatum a mosaic appearance. Corresponding decrease in the striosomal projections in the striatopallidal and striatonigral pathways were demonstrated. In the parkinsonian phase, the striatum showed marked loss of neurons and gliosis in both striosomal and matrix compartments with loss of the mosaic pattern.
It is postulated that in the dystonic phase, the loss of striosomal inhibitory projections lead to disinhibition of nigral dopaminergic neurons resulting in a hyperkinetic state. The eventual depletion of the matrix compartment in the parkinsonian phase leads to severe and critical reduction of matrix-based projection resulting in extranigral form of parkinsonism.
Neuroimaging Findings in XDP
Claro B. Ison, MD
There is a dearth of published literature describing the imaging findings of patients with XDP. The published articles of Lee et al. initially described the MRI findings of XDP patients based on 16 male XDP patients. They described the predominant imaging features of XDP and correlated them with the clinical findings, such as the age of the patient, the length of disease, and the extent of dystonic and parkinsonian features. In their preliminary study, they observed the presence of hyperintense putaminal rim with no concomitant significant caudate head or putaminal atrophy in patients who are in the earlier stages of the disease, when dystonic features were the predominant clinical manifestation. During the later stages of the disease, when parkinsonism was the predominant clinical feature, bilateral caudate head and putaminal atrophy were seen alongside very prominent putaminal hyperintensity.
Recently, a review of the MRI findings of XDP was performed at the Cardnal MRI Center. This initially required the review of approximately 17,238 databases, whereupon 42 confirmed cases of XDP were identified. The images of these studies were then retrieved for evaluation, blinded as to how these were interpreted preliminarily. Two neuroradiologists were tasked to independently review the plates and/ or electronic images of the identified XDP patients and were asked to describe the observed imaging findings. Preliminary data seemed to reveal that a significant majority of the XDP patients manifested markedly hyperintense putaminal rim in all stages of the disease. Caudate head atrophy was the third most frequently-seen finding. Hyperintense putaminal rim was a constant feature in the dystonic, combined, and parkinsonian phases of the disease. Caudate head atrophy and putaminal atrophy were again more commonly seen in the combined and parkinsonian stages of the disease. These findings appear to corroborate the earlier described imaging findings.
Neuropsychological Profile of XDP Patients
Lourdes K. Ledesma, PhD
Currently, cognitive impairment is not commonly recognized as an accompanying feature of XDP. However, this is actually because it is not routinely investigated. To date, there is only one published article on the neuropsychological profile of a patient with the condition (Howe, et al. 2008). The evaluation, done at the McKnight Brain Institute, University of Florida (Gainesville) was undertaken to determine eligibility for deep brain stimulation surgery.
The talk presented the neuropsychological profile of two XDP patients who are candidates for DBS surgery here in the Philippines. Unlike the patient in the USA, they do not present with significant cognitive decline, although subtle deficits in attention and executive functions are evident. Understandably, they also experience emotional concerns revolving around their life circumstance that merits psychotherapeutic intervention.
There is a need to follow these patients as the disease progresses in order to determine its impact on higher cortical functioning. The challenge is to identify, if not develop an instrument that can monitor their cognitive abilities even when they have become severely disabled.
Genetics of X-linked Dystonia Parkinsonism
Marita V. T. Reyes, MD and Paul Matthew D. Pasco, MD
X-linked dystonia parkinsonism (XDP) is an ideal disease to study genetically because it is caused by a founder gene (and therefore, has homogeneous mutation/s) and the inheritance pattern in family studies is typically x-linked that readily directs the gene location to the X chromosome. This makes for the skipping of many more linkage and mapping steps if the gene were instead located in one of the 22 autosomes.
In 2003, Nolte et al. found a multiple transcript system that had five disease specific single nucleotide changes (DSCs) and a 48-bp deletion unique to XDP. Only one of the DSCs lies within an exon which was used by all alternative transcripts. The multiple transcript system is then referred to as DYT3 (disease locus in XDP).
On the other hand, in 2007, using genomic sequencing analysis followed by expression analysis in brain tissues, Makino et al. reported a disease -specific short interspersed nuclear element, variable number of tandem repeats, and Alu composite (SVA) retrotransposon in an intron of TAF1, with significantly reduced expression of the TAF1 and the dopamine receptor D2 gene in the caudate nucleus of individuals with XDP.
The distal portions of the TAF1 gene are included in the transcripts described in DYT3.
The normal gene product of the DYT3 gene is not known. Whether abnormal protein results from the/ in DYT3/ TAF1 is also not known. Nolte et al. (2003), however hypothesized that the DYT3-specific sequence changes may affect splicing of transcripts. Whereas Makino et al. (2007) suggested that the SVA transposon insertion into TAF1 alters the expression of TAF1 isoforms (including the neuron-specific T41A-391), possibly through alteration of DNA methylation.
Oral Pharmacology in X-Linked Dystonia-Parkinsonism
Roland Dominic G. Jamora, MD
There is paucity of published literature on the different oral medications tried for XDP.
In practice, most patients are tried or have been tried on anti-cholinergics as these are the standard medications for dystonia patients.
In a personal communication with Dr. Lillian Lee, they noticed some patients who were consuming a lot of colas and were observed to be mildly or not dystonic at all. With these observations, they tried giving patients capsulized coffee, only to note increased involuntary movements among their patients.
In the first published report (1976) on XDP (then known as Torsion Dystonia in Panay), 20 patients (of the reported 28) have been tried on various medications. These medications were in the form of anti-parkinsonian drugs, anti-histaminics, and phenothiazines. A patient was reported to have responded partially to levodopa and another patient responded to haloperidol. There was however, no mention of which symptoms improved, and to what degree.
In 1993, a case report by Gordon et al. reported on the use of milacemide on 10 patients with various neurodegenerative conditions. Case # 8 was a Filipino with XDP with severe freezing of gait. This patient was on Diazepam 30 mg/ day, trihexyphenidyl 30 mg/ day, levodopa 300 mg/ day, and carbidopa 75 mg/ day. He was able to reach the top dose of milacemide (4800 mg/ day) without any benefit.
In 2002, Evidente reported on 3 XDP patients tried on zolpidem with improvement of the dystonia.
|41/ M||66 -> 0||38 -> 22.5 (40%)||Optimal effect in 1 hour; initially lasted 8 hours; with chronic use, 2 hours|
|38/ M||30 -> 20.5 (32%)||36.5 -> 24 (34%)||Optimal effect in 2 hours; effect lasts 3 hours; developed diarrhea with chronic use|
|36/ M||38.5 -> 26.5 (31%)||53.5 -> 53.5||Optimal effect in 1 hour; effect initially lasted 2.5 hours; with chronic use, 2 hours|
At present, we are conducting the first randomized, placebo-controlled trial on the use of levodopa/ carbidopa for XDP patients.
Chemodenervation with Botulinum Toxin-A and Muscle Afferent Block in X-linked Dystonia-Parkinsonism
Raymond L. Rosales, MD, PhD
Botulinum toxin type A (BoNT-A), purposely to reduce co-contracting muscles in hyperactivity, is considered a safe therapeutic regimen in dystonia. Muscle afferent block (MAB) with lidocaine to block spindle afferents and ethanol to prolong its effects, has been considered an alternative therapeutic approach in dystonia. With regard X-linked dystonia-parkinsonism (XDP), our data and elsewhere indicated that BoNT-A and MAB may be useful therapies for focal dystonias. Herein for dystonia in XDP, we aimed to compare the chemodenervation effects between the two BONT-A preparations (Dysport® and Botox®) and MAB. There were 46 cases with XDP who underwent 60 different injection sessions (indicating that some cases had injections in other areas at another time). Ascertaining of cases was based on history, detailed neurologic examination and genograms. At the time of injection, the ages of these male cases, as well as their onset ages were from 28 to 49 years, and 25 to 42 years, respectively. Dysport® sessions were done in 20 cases with cervical dystonia (CD), 6 cases with oromandibular dystonias (OMD) and 2 cases with foot dystonia (FD). Botox® sessions were done in 18 cases with CD, 6 cases with OMD and 2 cases with FD. MAB was done in 6 cases with CD. On week 4, the TWSTRS (for CD), Disability rating scales (for OMD and FD) and global assessments showed significant improvement in majority of cases, whether Dysport® or Botox® were used. MAB in CD provided temporary relief within week 1 and did not last until week 4. The adverse events included dysphagia (with Dysport®: 6cases; with Botox®: 5 cases), excessive weakness (with Dysport®:1 case; with Botox®:1 case), injection pain (with MAB:3 cases) and dizziness (with MAB:1 case). Thus, BoNT-A is efficacious and have a long lasting effect in focal dystonias of XDP, compared to MAB. BoNT-A is known to have extrafusal and intrafusal muscle cholinergic blockade. This distinct advantage of BoNT-A over a pure MAB with lidocaine, despite addition of ethanol, may explain the better and more lasting effects of BoNT-A in dystonia. However, MAB may find its applicability in XDP as a cheap alternative to BoNT-A or as a therapeutic test to select muscles for ultimate injections with BoNT-A.
Session 3: Updates in Parkinson's Disease and Related Diseases
Movement Disorders in the Philippines
Roland Dominic G. Jamora, MD
Movement disorders is a relatively young subspecialty in the Philippines. The Movement Disorders Center at St. Luke's Medical Center is the only one of its kind in the Philippines. It is staffed by 3 movement disorders specialists and a specialty nurse.
We reviewed the records of patients seen two of these physicians to determine the spectrum of the different diseases seen at the MD clinics. A total of 1039 patients, with an age range of 8 mos. - 94 years, were seen over a period of 7 years (2001- 2007). There were 985 (94.8%) adult patients and 54 (5.2%) patients were aged 18 years and below. A total of 168 patients underwent botulinum toxin injections.
Among the pediatric patients, 39 (72%) were males. The most common types of movement disorders seen were tics (n=26, 48%), dystonia (n=11, 20%), and myoclonus (n=5, 9.2%), paroxysmal dyskinesias (n=5, 9.2%), and tremors (n=4, 7.5%). Chronic motor tics (n=18) was the most common disease entity seen among the pediatric age group. This was followed by Tourette syndrome (n=8), secondary dystonia from cerebral palsy (n=6), paroxysmal kinesigenic dyskinesia (n=5), and essential tremors (n=3). Other diseases seen were dopa-responsive dystonia, Wilson's disease, hemifacial spasm, Sydenham's chorea.
Among the adult population, there were 517 males (52.5%). The most common types of movement disorders seen were parkinsonism (n=471, 47.8%), dystonia (n=186, 18.9%), and myoclonus (n=143, 14.5%). Others were tremors (n=78, 7.9%), tics (n=23, 2.3%), tardive syndromes (n=12, 1.2%), chorea/ ballism (n=14, 1.4%), restless legs and periodic leg movements (n=12, 1.2%), and ataxias (n=7, 0.7%). Seven cases of psychogenic movement disorders (0.7%) were likewise seen. Twenty cases (2%) of post-stroke spasticity were also seen, usually referred to the clinic for botulinum toxin injections.
Parkinson's disease (n=370, 37.5%) remains the most common disease seen at the specialty clinic. This was followed by primary dystonia (n=138, 14.1%), hemifacial spasms (n=126, 12.8%), essential tremors (n=70, 7.1%), X-linked dystonia-parkinsonism (XDP) (n=33, 3.3%), and progressive supranuclear palsy (n=29, 2.9%), chronic motor tics (n=17, 1.7%). Among the primary dystonia cases (n=139), focal dystonia accounted for 75% (n=104), segmental dystonia (n=26, 18.8%) and generalized dystonia (n=9, 6.5%). Cervical dystonia (n=60) remains the most common focal dystonia seen, followed by blepharospasm (n=18), writer's cramps and limb dystonia (n=11 each). Other patients seen in the clinics were spinocerebellar ataxias (n=4), primary handwriting tremor (n=3), Wilson's disease (n=3), and episodic ataxia (n=1).
Non-Motor Aspects of Parkinson's Disease: Emphasis on Neuropsychiatric Manifestations
Hubert H. Fernandez, MD
Neuropsychiatric features are experienced by almost all patients with Parkinson's disease (PD). It can be the single greatest contributor to a patient's worsening of quality of life. Neurospyschiatric complications include: depression, apathy, anxiety, psychosis, sleep disorders, and impulsive and compulsive disorder. The pathogenesis of these neuropsychiatric disturbances are complex and implicate dysfunction in neuroanatomical structures/circuitry between the pre-frontal cortex and basal ganglia, and neurochemical imbalance (dopamine, norepinephrine, serotonin). These are either intrinsic to the disorder or triggered by the PD. Early recognition and screening for neuropsychiatric features in PD is important for successful treatment. General management of neuropsychiatric symptoms is by adjusting dopaminergic medications and finding the balance between optimizing motor function and minimizing iatrogenic complications. In most cases, a multi-disciplinary approach utilizing pharmacotherapy (using psychotropic medications), cognitive and behavioral therapy/psychotherapy, family counseling and education are necessary ingredients in successfully treating these complications. While much research and clinical attention has been given to the neuropsychiatric features in PD in the last decade, more systematic studies that focus on determining its underlying pathology and promote the development of preventive and symptomatic treatments are necessary.
Depression in PD is characterized by long periods of sadness or loss of interest/pleasure in almost all activities. The depressed PD patient feels gloomy, has decreased energy, is constantly fatigued, has poor concentration, difficulty sleeping, and appetite changes. They can also be preoccupied with guilt, feelings of worthlessness, and hopelessness. Some may have physical or somatic complaints. The clinical appearance of depression in PD often include slowing of motor functions and result in poorer performance of activities of daily living. Incidence of depression in PD varies between 40% to 50%, and is increased significantly in younger (before age 55) and older (after age 66) PD patients. Fortunately, only a small percentage ( < 20%) of depressed PD patients are labeled to have major depression. The majority suffer from dysthymia and minor depression.
The precise etiology of depression in PD remains unclear, but some biological models hypothesize that the loss of dopaminergic neurons in the mesocortical limbic pathway in PD may cause orbitofrontal cortex dysfunction. This can also indirectly lessen the serotonergic neurons in the dorsal raphe nucleus. This serotonergic (5-HT) deficit is postulated to cause depression in PD patients. The psychosocial model from Brown et al hypothesizes that depression in the early stages of PD may be due to the inability of the patient to accept the diagnosis of PD. Depression in the later stages may be part of disease progression. Patients with previous depression, a family history of PD, cognitive impairment, and women, have increased frequency and worse depressive symptoms. The association between depression and motor function is intricate. Improvement of motor function will not always be accompanied by improvement of depressive symptoms, while alleviating depressive symptoms often result in improved motor function.
Diagnosing depression in PD can sometimes be challenging as some somatic features of depression such as insomnia, weight loss, anorexia, psychomotor retardation are also intrinsic features of PD. Occasionally, depression can be a non-motor manifestation of "wearing-off".
Clinical depression is under recognized. The initial approach to the management of depression in PD involves optimizing dopaminergic medication to improve motor symptoms and minimize motor fluctuations. Dopaminergic medications such as levodopa, dopamine agonist and selegiline also have a mild antidepressant effect. Cognitive behavioral therapy and psychotherapy are often helpful in enhancing the coping mechanism in the PD patient. Selective serotonin reuptake inhibitors (SSRIs) are the most well-tolerated and most commonly used medications to treat depression in the elderly, followed by tricyclic antidepressants (TCA), serotonin norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOIs), and selective D3 antagonists (ropinorole and pramipexole). However, recent studies show that TCA may be equally effective in PD depression and also well-tolerated. The choice of antidepressant medications should be based on medication's pharmacologic profile, patient's co-morbidities, and symptoms. For instance, the depressed PD patient with a sleeping disorder may gain more advantage from mirtazapine, fluvoxamine, and TCA; while the patient with depression and anxiety may benefit more from paroxetine, sertaline or venaflaxine. Patients unresponsive or refractory to medications may respond to electroconvulsive therapy. Repetitive transcranial magnetic stimulation also seems promising and has been recently approved by the United States Food and Drug Administration (US FDA) for the treatment of depression in the general population.
Apathy is characterized by "diminished motivation, a lack/absence of feeling, emotion, interest or concern". It has three components: cognitive (loss of interest in new experience, lack of concern for out's problems), behavioral (lack of effort and productivity, dependence on others for structuring daily activities) and affective (flattened affect and lack of response to positive and negative events). The incidence of apathy in PD is approximately 45%It is thought to be caused by disruption of the emotional-affective processing circuitry in pre frontal cortex (PFC) and basal ganglia. This dysfunction can be found during emotion processing (orbito-medial PFC, ventral striatum and pallidum of basal ganglia), cognitive processing (lateral PFC, dorsal caudate, nucleus, dorsal pallidum of basal ganglia), 'autoactivation' of both limbic territories of the basal ganglia and dorsal-medial PFC. Apathy can be a feature of depression or stand alone as a symptom. Unfortunately, there have be no consistently reported effective treatment for apathy in PD. Antidepressants may be tried, and improvement can be seen usually if apathy is a component of depression.
According to DSM IV-TR, anxiety is classified into panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without panic disorder, specific phobia, social phobia, obsessive-compulsive disorder (OCD), post traumatic stress disorder, generalized anxiety disorder (GAD), anxiety disorder due to general medical condition, substance induced anxiety disorder, and anxiety disorder not otherwise specified.
Anxiety, phobia, and panic disorder are frequently found in PD (seen in up to 40% in some series) . It is common among female PD patients who have "on-off" fluctuations with a tendency to worsen during the "off" state, and right-sided parkinsonism with the dominant side primarily affected. It can present as separate entity or be a component of depression. Anxiety may be the result of a psychological reaction to the motor symptoms. Patients feel uncomfortable about their physical impairment. Severe anxiety reactions can worsen motor symptoms in PD. However, some studies show that anxiety in PD is not closely correlated with the severity of motor symptoms and dopaminergic medications. There is growing evidence that anxiety intrinsic to the neurobiology of PD rather than supply a reaction to disability and is caused by neurotransmitter changes in PD patient. Anxiety occurs more in PD patients compared to other diseases of equal disability (e.g., rheumatoid arthritis, multiple sclerosis).
The management of anxiety in PD patients may entail adjusting dopaminergic medications by reducing the "off "state and sustained psychological support (i.e., family support, counseling). A short acting benzodiazepine and buspirone may improve anxiety symptoms without the side effects of long term benzodiazepines (i.e., over-sedation, fall, cognitive impairment/drowsiness). Low dose buspirone may also improve anxiety. High dose buspirone can worsen parkinsonism symptoms. Other options such as SSRI (venaflaxine, sertaline) can also improve anxiety symptoms, especially when it is accompanied by depression. TCAs are also an option; however their use in PD may be limited by anticholinergic side effects.
Psychosis occurs in almost 40% of PD patients. In the early stage of PD psychosis, the patient often still has a clear sensorium and retains insight, but this tends to worsen over time and insight may eventually be lost. At later stages, patients have impaired reality testing; that is, they are unable to distinguish personal, subjective experiences from the reality of the external world. Psychosis in PD patients frequently occurs initially in the evening. Visual hallucinations occur more frequently than auditory hallucinations. Other forms of hallucinations such as tactile, olfactory, and gustatory have also been reported, however they are less common and tend to co-occur with visual hallucinations. Paranoid thoughts, such as spousal infidelity, are often the theme of delusions in PD.
Psychosis in PD is believed due to long term use of parkinsonian medications especially dopaminergic and anticholinergic drugs. However, significant medication exposure is no longer a pre-requisite in PD psychosis . The continuum hypothesis states that medication-induced psychiatric symptoms in PD starts with sleep disturbances accompanied by vivid dreams, and develops into hallucinations and delusions, and ends in delirium. However this theory is now being challenged . Visual hallucination are also contributed by visual processing deficits, ocular pathology (i.e., cataracts, retinal disease, glaucoma), and dopamine deficiency at the retina. Frontal lobe dysfunction (BA 44, 6) and subcortical regions (caudate nucleus) in PD also may frail retinal-striatal-cortical signals caused visual hallucination[19, 20]. Other neurotransmitters such as serotonin and acetylcholine and their interaction with dopamine may play a part in inducing psychotic symptoms. Concomitant Lewy body depositions in the temporal lobe (in particular the amygdala and parahippocampus) in PD have also been reported among visual hallucinators at autopsy .
Some scales are used to screen psychosis in PD; however, none of these scales capture the entire phenomenology of PD psychosis . The management of psychosis include: (1) ruling out the possible reversible causes (e.g., infection, metabolic and electrolyte imbalance, sleep disorders); (2) decreasing or discontinuing adjunctive antiparkinsonian drugs (with cautious supervision of motor function) in the following order: anticholinergics, amantidine, selegiline/rasagiline, dopamine agonist, catechol O-methyltransferase (COMT) inhibitor, and finally levodopa; (3) simplifying the PD medication regimen; (4) adding an atypical (second generation) antipsychotic: quetiapine or clozapine (with regular blood count monitoring). Other atypical antipsychotics such as risperidone and olanzapine are not recommended because they can worsen PD symptoms; (5) If pyschosis occurs in a PD patient with cognitive impairment or dementia, a cholinesterase inhibitor (donepezil, rivastigmine) may be considered; (6) Cholinomimetic therapy such as ordansentron(5-HT3 antagonist) has been reported to be of benefit. Cognitive behavioral therapy, supportive therapy and psycho-education may also be useful. Electroconvulsive (ECT) can be considered especially when the psychosis proves to be medication resistant and associated with depression.
Sleep disorders are perhaps the most common non-motor feature in PD affecting up to 98% of patients. It includes insomnia, hypersomnia, and parasomnia. Insomnia in PD patients is characterized by inadequate or poor quality sleep that leads to fatigue. Patients report difficulty in initiating sleep, sleep fragmentation, and early awakening. Many factors interfere with sleep in PD patients, including mood swings, depression, anxiety, cognitive impairment, pain, motor manifestations (tremor, cramps, dystonic movement, inability to move in bed and adjusting bed clothes), other disorder related to sleep (obstructive sleep apnea, restless leg syndrome), dopaminergic medications and certain medications (benzodiazepines, psychiatric medications).
Some also suffer from excessive daytime sleepiness (EDS) and sleep attacks (hypersomnia) without warning. During the sleep, vivid dreaming, nocturnal hallucinations, night terrors, sleep walking, sleep talking, and panic attacks can occur (parasomnia). Rapid eye movement (REM) behavior disorder (RBD) may also occur, with patients acting out their dreams grabbing, yelling, kicking, shouting, jumping out of bed, or falling from bed. Sleep disturbances in PD are often multifactorial. The underlying nature of PD, effect of dopaminergic medication, and psychiatric co-morbidities all contribute to the sleep disorder).
Treatment includes: (1) improving sleep hygiene (maximize daytime activities and minimize daytime napping, avoid stimulants food or drinks before bedtime [e.g., coffee, alcohol, cigarettes], avoiding eating large amount of food before bed, practicing relaxation techniques before bed, following regular sleep schedule and maintain bedtime routine, limit sleeping time to 7-8 hour; (2) Adjusting dopaminergic medications by taking an extra dose of controlled release levodopa before sleep (for sleep fragmentation); (3) anxiolytic agents for anxiety, cholinesterase inhibitor (cognitive) and low dose antipsychotic (quetiapine, clozapine) for psychosis and; (4) continuous positive airway pressure (CPAP) for obstructive sleep apnea; (5) discontinuation of dopamine agonists to alleviate sleep attacks.
IMPULSIVE and COMPULSIVE DISORDERS
An impulsive and compulsive disorder (ICD) is defined as a failure to resist impulse, drive, or temptation to perform an act that is harmful to the person doing it or to others. Manifestations of ICD in PD include pathological gambling, hypersexuality, excessive shopping and binge eating. Manifestations of compulsive behavior include punding and compulsive medications use. Dopamine agonist use has been the most frequently associated risk factor for the development of ICD. The mechanism appears to be the impairment in cortico-striato-thalamic circuits.
Many factors play a role in developing impulsive and compulsive behavior in PD. Individual susceptibility factors such as male gender, right-sided onset, early PD onset, and large dose of dopamine agonist may play role determining impulsivity in PD. Although not an exact and absolute rule, the higher the dosage of dopaminergic drugs, the greater is the risk of ICD. In PD patients who are vulnerable and had chronic exposure of dopaminergic drugs, their dopaminergic neurons in mesolimbic area are postulated to be hypersensitive to intermittent dopaminergic medication intake, causing behavioral sensitization resulting in addiction and maladaptive processing in the "reward-pathway" (dopamine dysregulation syndrome). Excessive dopaminergic medication use may also affect the reward and learning pathways that respond to stimuli to get reward. Once these behaviors are learned, they eventually habituate
Management of ICD in PD is achieved through (1) reduction of the dose of dopamine agonist with concomitant increase in levodopa as necessary; (2) switching dopamine agonists; (3) treating comorbid disorders including depression, anxiety, psychosis, mania, dementia; (4) giving trials of low-dose quetiapine or clozapine; (5) family support; (6) psychological counseling; (7) Antidepressant (SSRI) to decrease obsessional ideation. If the ICD is refractory to treatment, a referral to a psychiatrist and/or psychologist may be needed for cognitive behavioral therapy.
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Atypical Parkinsonian Syndromes
Dirk Dressler, MD
The classical parkinsonian syndrome describes the triad of resting tremor, rigidity, and bradykinesia with rest tremor being the most typical sign of idiopathic Parkinson disease (IPD). Over time, associated IPD features including reduced arm swing, unilateral onset, camptocormia, loss of postural reflexes and dementia have been described. Some degree of action tremor, myoclonus, and dystonia can occur. In reality however, the clinical presentation of the parkinsonian syndrome may not be complete generating considerable uncertainty about the patient's diagnosis. When IPD is diagnosed, tremulous, akinetic-rigid and mixed subtypes can be identified. Excellent response to levodopa confirms the diagnosis.
Apart from IPD, patients wit atypical parkinsonism have been described. Since they feature some elements of the parkinsonian triad (mainly bradykinesia and rigidity, and rarely rest tremor), they have also been called Parkinson-plus syndromes. Since their pathology shows degeneration in the post-synaptic rather than the pre-synaptic nigrostriatal pathway, their common feature is lack of dopa-sensitivity.
Progressive supranuclear palsy (PSP) is characterized by progressive parkinsonism, gaze palsy most typical when downward gaze is impaired, postural instability, gait apraxia, frontal lobe dysfunction, apraxia or eyelid opening and dysphagia.
Multiple system atrophy (MSA) is a condition featuring autonomic dysfunction including impotence, urinary incontinence, orthstatic hypotension with progressive parkinsonism (MSA-P, striatonigral degeneration) with rare and atypical tremor, or progressive parkinsonism with cerebellar ataxia (MSA-C, olivopontocerebellar atrophy). Associated features include myoclonus, dysarthria, anterocollis and pyramidal signs.
Corticobasal ganglionic degeneration (CBD or CBGD) refers to parkinsonism with unilateral arm dystonia (often fixed), apraxia (alien limb phenomenon) and myoclonus. The ipsilateral leg may also be involved. Pyramidal tract and oculomotor impairment may also be present.
Lewy body dementia (LBD) is dementia with accompanying parkinsonism, and the parkinsonism-dementia-ALS complex of Guam may also be considered atypical parkinsonian syndromes.
Session 4: Therapeutics in PD & other Movement Disorders
Non-pharmacological treatment of Parkinson's disease and other movement disorders
Petr Kanovsky, MD and Katerina Farnikova, MD
The term "non-pharmacological treatment" covers usually surgical procedures and rehabilitation medicine techniques as physiotherapy, artetherapy, occupational therapy and others. In movement disorders, the main therapeutic domain of all these is the surgical treatment. Nevertheless, in Parkinson's disease and also in dystonia are rehabilitation techniques of certain (albeit limited) importance.
A. Surgical therapy
1. Parkinson's disease
In Parkinson's disease, the surgical procedures were used already in the mid 1950. Parkinsonism (including many postencephalitic cases) was treated using the lesions of thalamus, ansa lenticularis and pallidum. In 1952, Cooper inadvertently interrupted the anterior choriodal artery in a patient with Parkinson's disease, and the patient awake with resolution of tremor and no deficit. However, the lesions of thalamus more reliably abolished tremor, so that by the late 1950 this had become the preferred target, and particularly the ventromediate nucleus (ViM). Following the introduction of levodopa in the late 1960, stereotactic surgery for Parkinson's disease was hardly performed and interest in this field (except lesions targetted to treat isolated tremor) waned. The next 15 years saw increasing number of patients with dyskinesias and motor fluctuations due to levodopa treatment and the surgical solution has been revisited. In the late 1980 pallidotomy was resurrected and following several years, many groups confirmed its effectiveness in alleviating levodopa induced dyskinesias. However, in the first half 1990, the method of deep brain stimulation has been introduced, which made lesional surgery a procedure performed only rare. The first stimulation target was medial pallidum. In 1993 Benabid reported the beneficial effect of subthalamic nucleus stimulation on almost all features of parkinsonism. Subthalamic nucleus remained the universal stimulation target since. The next technical improvements and the next development of the whole procedure made the deep brain stimulation the method of first choice in the treatment of late motor complications of Parkinson's disease. The stimulation of medial pallidum underwent some improvements and remains currently on the position of alternative treatment when subthalamic nucleus is not considered. There were several attempts to introduce the striatal fetal adrenal grafts into the therapeutic options of Parkinson's disease, mainly from Lindvall's group. However, after the report of Greene and Fahn in 2001 this procedure remained experimental.
The lesions of several different brain regions in the attempt to treat dystonia were performed by Cooper in the mid 1950. However, the effects (if any) lasted only very short time, and the whole procedure fails to show any substantial benefit. In the 1970, some groups in Central Europe (Nadvornik, Vladyka, Stejskal) performed more than 200 lesions within different regions of brainstem and basal ganglia in torticollis patients, and achieved in almost 30% of cases a considerable improvement. The introduction of botulinum toxin into the treatment of dystonia put the lesional surgery into the rare and relative dangerous procedures. However, when deep brain stimulation in Parkinson's disease gained its full reputation, the surgery in dystonia has been revisited. Since the end of 1990, numerous reports of beneficial effect of stimulation of pallidum appeared, particularly in generalised dystonia. The targets other than pallidum were thalamus (VPL), subthalamic nucleus and dentate nucleus. Nevertheless, only the stimulation of medial pallidum brought considerable effect, and remained actually the sole target for the treatment of generalised (mainly DYT1) dystonia and those cases of focal and segmental dystonia, which do not respond to the botulinum toxin treatment.
It was again Cooper, who introduced the selective lesion of ViM nucleus of thalamus in the treatment of essential tremor in the first half of 1960. The procedure has been relatively simple, with none or very few side effects. After the standardisation and improvements of MRI-navigated stereotactic surgery, it has been performed bilaterally with sufficient level of safety. However, when deep brain stimulation in Parkinson's disease rocketed to its current position, the shift fom lesions to stimulation occurred also in the treatment of essential tremor. Nowadays, the bilateral stimulation of ViM nucleus of thalamus is the treatment of choice in essential tremor, which does not respond to betalytic or primidone treatment.
It has been Huntington's disease, which has been surgically treated among all movement disorders as a first. The breakthrough in the development of human stereotactic surgery came in fact in 1947, when Speigel and Wycis decided to use the landmarks within the brain, rather than the skull. Their first patient had a pallidal lesion for Huntington's chorea. The surgery has been abandoned for more than 50 years, when the first reports of beneficial effects of pallidal stimulation occurred at the end of 1990. The pallidal stimulation is still widely used for the treatment of debilitating chorea in Huntington's disease.
Deep brain stimulation of internal pallidum or VoC nucleus of thalamus has been reported to be beneficial in the refractory Tourette syndrome. However, the ethical issues of deep brain stimulation in the childhood remain to be resolved.
In rare cases of the spinal or paraspinal myoclonus, the selective dorsal rhizotomy helped to relieve the debilitating muscle jerks.
In spasticity, the surgery is currently used only in the cases which do not respond to the baclofen or botulinum toxin treatment. The selective dorsal rhizotomy is used mainly in the spinal spasticity.
B. Rehabilitation treatment
1. Parkinsons's disease
Classical techniques of physiotherapy and occupational therapy are used in the treatment of Parkinson's disease. Usually, the musical therapy is the most effective, probably due to the known "paradoxic kinesias" in Parkinson's disease.
J.P. Bleton, working with Pierre Rondot in the 1970 and 1980, developed a sophisticated, physiology-based physiotherapy protocol to treat the cervical dystonia. In the 1990, it has been adjusted to the botulinum toxin era. Nowadays, the combination of botulinum toxin injections together with Bleton's techniques remains probably the most effective treatment of torticollis. Physiotherapy in combination with cogntive-behavioral treatment is sometimes used to treat the musicians' cramps.
Chemodeneravation in Parkinson's disease and other Movement Disorders
Dirk Dressler, MD and Fereshte Saberi, MD
Muscles can be denervated by the use of chemicals. When phenol or alcohol are injected directly into peripheral nerves, they induce destruction with subsequent denervation, i. e., paresis and atrophy lasting for several weeks to months. Affection of sensory nerve fibers and inflammation may produce dysesthesias and pain. Direct intramuscular injections of phenol may also produce paresis. To reduce inflammation and necrosis, phenol has to be diluted thus reducing the duration of action to a few weeks. Despite its cost-effectiveness and lack of antigenicity, phenol and alcohol are only occasionally used in current medical practice.
Intramuscular injections of botulinum toxin (BT) may also produce muscle paresis and atrophy. When injected into a target muscle, it selectively binds with the binding domain of its heavy chain to glycopreotein structures on cholinergic nerve terminals. It is then internalized with its translocation domain using the SV2 receptor on the peripheral nerve ending. Once intracellular, BT's light chain cleaves different SNARE proteins transporting the acetylcholine vesicles into the synaptic cleft.
BTs paralyzing effect occurs after a few days, remains stable for 4 to 6 weeks and then gradually resolves. Re-injections usually become necessary after 12 weeks. BT does not produce inflammation, pain or any permanent alterations of the target muscle. The extent of its paralyzing effect can effectively be controlled by the amount of BT applied. Adverse effects include obligatory ones, i. e., target muscle paresis, local ones caused by BT infusion into adjacent muscles and systemic ones cased by BT transported within the blood circulation. With usual therapeutic doses, systemic adverse effects can only be seen when BT type B is applied. Long term experience does not reveal additional adverse effects.
BT therapy can be planned based upon clinical evaluation. Occasionally, electromyography may be used for this purpose. Application of BT into target muscles can be helped by EMG with additional stimulation techniques. In limb muscles, ultrasound sonography may also be used.
Since BT therapy is a symptomatic therapy, muscle hyperactivity due to various etiologies can be treated. Muscle relaxation induced by BT therapy may produce improved control of body parts, pain reduction, functional benefit, improved hygiene and cosmesis. BT therapy can easily be combined with oral drug treatment, with intrathecal baclofen pumps, and with deep brain stimulation.
Dystonia is a classical indication for BT therapy. Apart from focal dystonias, more wide-spread forms such as multi-focal, segmental or axial dystonias may be targeted. In generalized dystonia, only a selected number of target muscles can be treated and careful muscle selection becomes necessary. Other movement disorders include hemifacial spasms, re-innervation synkinesias, tardive dyskinesias, motor tics and tremor. Stiff person syndrome and tetanus are rare indications. In parkinsonian syndromes, stereotype on-dystonias can be successfully with BT. Dystonia associated with idiopathic Parkinson disease or with MSA, eyelid opening apraxia in PSP are other indications. Tonic limb dystonia in CBGD can be treated with BT therapy before they become contracted. BT injections into the parotid and submandibular glands can reduce relative hypersalivation in parkinsonian syndromes. Camptocormia, an apraxia of posture, is resistant to BT regardless whether it is still mobile or whether it progressed into contractures. Spastic conditions, i. e. muscle hyperactivity syndromes associated with paresis due to stroke, multiple sclerosis and tumor, is a rapidly emerging area for BT therapy.