non motor manifestation of parkinson disease

NON-MOTOR SYMPTOMS OF PARKINSON'S DISEASE

Osama ragab

introduction

Introduction

First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.”

“Involuntary tremulous motion with lessened muscular power, in parts not in action and even when supported: with a propensity to bend the trunk forwards and to pass from a walking to a running pace: the senses and intellect being uninjured.”

later disease stages ‘‘sleep becomes much disturbed’’, ‘‘the bowels demand stimulating medicines of very considerable power’’ and ‘‘urine and faeces are passed involuntarily’

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease and estimated to affect about 1–2% of the population over 65 years.

Primarily defined by its cardinal motor symptoms such as bradykinesia, tremor and rigidity and postural instability.

Introduction

non-motor features of the disease have recently come more and more into the focus of clinical interest.

It is known that almost 90% of PD patients experience non-motor manifestations during the course of disease.

Non-motor complaints in PD patients may be induced by side effects of antiparkinsonian pharmacotherapy, such as hallucinations, daytime sleepiness and leg edema.

Introduction

Spectrum of non-motor features in PD Neuropsychiatric symptoms

Depression Hallucinations and psychosis Cognitive dysfunction and dementia Anxiety Apathy and anhedonia

Sleep disorders Restless legs/periodic limb movements in sleep Rapid eye movement sleep behaviour disorder Excessive daytime sleepiness Sleep fragmentation and insomnia

Introduction

Spectrum of non-motor features in PD Autonomic dysfunction Orthostatic hypotension

Bladder disturbances Constipation Faecal incontinence Sialorrhea Swallowing difficulties Sexual dysfunction

Sensory symptoms Olfactory dysfunction Pain Impaired colour discrimination Abnormal sensations

Introduction

Spectrum of non-motor features in PD

Miscellaneous symptoms Fatigue Diplopia Blurred vision Seborrhoea Weight loss/gain

Introduction

Patho-physiology

The main pathological feature of Parkinson’s disease is the degeneration of neuromelanin-containing neurons in the pars compacta of the substantia nigra, which leads to putaminal, degeneration.

dopaminergic deficiency destabilizes the interaction between the two main functional basal ganglia circuits: the direct D1-linked (stimulatory) and the indirect D2-linked (inhibitory) pathways.

In Parkinson’s disease, dopamine cell degeneration leads to bradykinesia.

Patho-physiology

it has for long been recognised that PD is not just a dopamine-deficit disorder resulting from a loss of nigro-striatal dopaminergic projections, but also affects various non-mesencephalic brain regions as well as the peripheral autonomic which account for many of its non-motor symptoms.

This was supported by several non-motor features of Parkinson’s disease, including olfactory loss, sleep disorders such as rapid eye movement (REM) behavior disorder (RBD), and constipation, which precede the development of motor Parkinson’s disease

Patho-physiology

A “bottom-up” phenomenon was suggested, whereby Lewy body formation actually occurs in the brain stem in the lower medulla and the olfactory bundle (stage 1 Parkinson’s disease),Lewy bodies are also found in the peripheral nervous system in the gut.

In stage 2 more of the dorsal medulla and pons become involved.

At stage 3 that the midbrain and the substantia nigra are involved. Therefore, according to this hypothesis, the motor deficit of Parkinson’s disease is manifest at stage 3 .

Patho-physiology

The “Braak” Lewy body-based bottom-up theory for development of Parkinson’s disease

Patho-physiology

Basal ganglia circuits

Introduction

he main components of the basal ganglia are the striatum, the globus pallidus, the substantia nigra, and the subthalamic nucleus.

The largest component, the striatum, receives input from many brain areas but sends output only to other components of the basal ganglia.

The pallidum receives input from the striatum, and sends inhibitory output to a number of motor-related areas.

The substantia nigra is the source of the striatal input of the neurotransmitter dopamine, which plays an important role in basal ganglia function.

The subthalamic nucleus receives input mainly from the striatum and cerebral cortex, and projects to the globus pallidus.

Each of these areas has a complex internal anatomical and neurochemical organization.


Intrinsic circuit anatomy of the motor circuit. The cortical motor areas give rise to a specific motor subcircuit. Red arrows indicate inhibitory (-aminobutyric acid [GABA]–ergic) connections; green arrows, excitatory (glutamatergic) connections. CM indicates centromedian nucleus of thalamus; CMAr, rostral portion of cingulate motor area; CMAd, dorsal portion of cingulate motor area; CMAv, ventral portion of cingulate motor area; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; M1, primary motor cortex; Pf, parafascicular nucleus of the thalamus; PMd, dorsal premotor cortex; PMv, ventral premotor cortex; PPN, pedunculopontine nucleus; SMA, supplementary motor area; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VApc, ventral anterior nucleus of thalamus pars parvocellularis; VLm, ventrolateral nucleus of thalamus pars medialis; VLo, ventrolateral nucleus of thalamus pars oralis; VLcr, ventrolateral nucleus of thalamus rostral pars caudalis; c, caudal; cl, caudolateral; and d, dorsal.


(PPT) is is located in caudal mesencephalic tegmentum, anddivided into pars compacta (cholinergic neurons) and a pars dissipata (cholinergic and non-cholinergic neurons).

it is a part of the ‘ascending reticular activating system’, it is a critical modulator of activated behavioral state such as wakefulness, motivation, attention and (REM) sleep.

recently it is investigated as a potential target for (DBS) in (PD) to improve dopa-unresponsive axial symptoms as gait and posture disorders .

Basal ganglia circuitsThe Pedunculopontine nucleus

Five parallel and separate closed circuits through the basal ganglia have been proposed.

These are the motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and limbic loops .

It is now generally agreed that these loops form three major divisions sensorimotor, associative, and limbic that are related to motor, cognitive, and emotional functions, respectively


Parallel organization of motor & non-motor basal ganglia loops

Dopamine belongs to the family of catecholamines.

Dopamine is the major neurotransmitter in the nigrostriatal dopamine system; it has excitatory or inhibitory actions depending on the properties of the stimulated receptor.

Significant role in learning, goal-directed behavior, regulation of hormones, motor control.

Basal ganglia circuits Dopamine

Mesolimbic Pathway Mesocortical Pathway Nigrostriatal Pathway Tuberoinfundibular Pathway Incertohypothalamic Pathway Medullary Periventricular Retinal Olfactory bulb


In patients with PD, cellular loss in the nucleus basalis of Meynert, has been linked with cognitive impairment.

inhibition of or diminished cholinergic neurotransmission in clinical and pre-clinical paradigms of PD results in attention dysfunction, cognitive impairment and executive dysfunction,

whereas enhanced cholinergic neurotransmission is associated with lessening of several non-motor symptoms, including anxiety, apathy, attention dysfunction, orthostatic hypotension, cognitive impairment and sleep disorders

Basal ganglia circuitsCholinergic neurotransmission

The globus pallidus and substantia nigra receive a dense serotonin-mediated innervation that originates predominantly from the brainstem raphe nuclei.

Reductions in serotonin levels of nearly 50% have been reported in the cortex and basal ganglia of patients with PD.

Low serotonin levels have been linked to alterations in mood, such as depression, and changes in sleep architecture.

Basal ganglia circuitsSerotonergic neurotransmission

Serotonin implicated in modulating pain. Treatment of pain symptoms with the serotonin and adrenaline reuptake inhibitor resulted in varying degrees of pain relief for 65%of patients with PD, whilst various 5-HT receptor agents are under investigation for the treatment of pain

the serotonin is also believed to be involved in GI motility, as the activation of 5-HT4 receptors located along the GI tract enhances motility ,the 5-HT4 agonists mosapride provided relief to patients with PD suffering from constipation.

Basal ganglia circuitsSerotonergic neurotransmission

Loss of noradrenaline, occurs at early stages of PD increase the susceptibility of dopaminergic neurons to degeneration or by inhibiting the repair of neurons that are already damaged.

loss of noradrenergic innervation facilitates the onset of dyskinesia during dopamine replacement therapy.

Basal ganglia circuitsAdrenergic neurotransmission

Alpha 2-adrenergic receptors modulate the sensitivity of dopaminergic receptors, and activation of a-2 receptors facilitates movements produced by activation of the direct pathway of the basal ganglia motor circuit.

Noradrenaline is a key neurotransmitter of the endogenous pain system.

Inhibition of adrenergic neurotransmission results in worsening of depression whilst also lessening cognitive impairment.

Basal ganglia circuitsAdrenergic neurotransmission

The loss of dopamine neurons is believed to cause an increase in glutamatergic activity in the basal ganglia. Pre-clinical studies using NMDA and AMPA antagonists have demonstrated improvements in various motor symptoms of PD .

These findings suggest that the selective inhibition of glutamatergic hyperactivity may be an effective strategy for the treatment of some PD symptoms, particularly those that do not respond to L-dopa therapy

Basal ganglia circuits Glutamatergic neurotransmission

GABAergic pathways largely regulate signal processing throughout much of the basal ganglia, in particular between the striatum and the globus pallidus.

Although several of the non-motor symptoms associated with PD have been shown to involve GABAergic neurotransmission such as pain, sleep disorders and depression, there is a lack of evidence as to how these symptoms are modulated by changes in GABA concentrations in PD.

Basal ganglia circuitsGABAergic neurotransmission

non-motor symptoms

Depression

prevalence of major depressive disorder is 17%, minor depression 22%, dysthymia 13% and clinically significant depression in 35% .

subtypes of depression in PD: (1) nonspecific casual comorbid dPD. (2) nonspecific reactive comorbid dPD . (3) specific dPD, directly related to the

pathophysiology of PD.

Etiology Dopamine Dopaminergic medications in some

patients induce neuropsychiatric complications.

Dopaminergic transmission in mood, motivation and reward suggests that also depression in PD is related to loss of dopaminergic neurons.

Depression

Non dopamine Lewy body deposition in brainstem areas implicated

in depression, including the serotoninergic raphe nuclei and the noradrenergic locus coeruleus.

Trans-cranial sonography has shown hypo-echogenicity of the dorsal raphe to be associated with onset of depression preceding motor deficit in PD.

A PET study examining cortical acetylcholinesterase activity demonstrated that depressive symptoms in PD are associated with cortical cholinergic denervation.

Depression

Diagnosis DSM-IV-R diagnosis of major depression requires

one or more of the two core criteria (depressed mood, loss of interest or pleasure), and a total of five or more symptoms including significant weight change, insomnia or hypersomnia, psychomotor retardation or agitation, fatigue, expression of worthlessness or guilt, reduced concentration or decisiveness or recurrent thoughts of death, with exclusion of symptoms attributable to medication or an underlying medical condition

Depression

(NINDS/NIMH) working group recommendations : (1) The diagnosis should be made using an

inclusive approach to include all symptoms, irrespective of potential aetiological basis.

(2) The timing of assessment should be specified in patients with motor fluctuations, as a significant proportion of these patients describe prominent mood fluctuations.

(3) Anhedonia should only be diagnosed based on loss of pleasure rather than loss of interest for diagnosis of minor depression .

Depression

Treatment Pharmacotherapy Pharmacological agents used for depression

in general psychiatry practice, including (TCA), the tricyclic-related drugs (e.g. trazodone), (SSRIs), (SNRIs) venlafaxine, the (NRIs) reboxetine, the presynaptic alpha-2 adrenoreceptor antagonist mirtazapine and the (NDRI) bupropion may all have a role in treatment of mood disorders in PD

Depression

Clinical trails 1-One study comparing desipramine and citalopram for the

treatment of depression in PD reported that desipramine was superior to citalopram .

2- Two of the placebo-controlled studies using the SSRIs citalopram and sertraline showed no advantage over placebo.

3- An open-label trial comparing fluoxetine and nefazodone had similar benefit in both.

4- In a study comparing nortriptyline with placebo, an improvement was reported.

5- an open-label study comparing amitriptyline with fluoxetine, there was a significant difference in favour of amitriptyline .

Depression

6-A large meta-analysis of DBS studies in PD showed improvement in motor scales with depression was prospectively assessed as secondary outcome measure, 83.3% reported an improvement. However, of concern was the completed suicide rate (0.16–0.32%) which was significantly higher than expected.

7- (rTMS) on mood in PD has been proposed, but the evidence has been inconclusive

8- Small open-label studies of (CBT) in PD have given encouraging results, in reducing depressive symptoms and negative cognitions, and in improving perception of social support .

9- the role of ECT is investigational.

Depression

Adverse effects of these medications can however limit their use,

particularly in the elderly. 1- autonomic phenomena exacerbation by the anticholinergic effects

of TCA, and to a lesser extent SSRIs. 2-The anti-cholinergic action of these drugs may worsen cognitive

impairment, visual hallucinations and delusional thought disorder. 3- The SSRIs have important pharmacological interactions with the

MAO-B inhibitors selegiline and, to a lesser degree, rasagiline and thus theoretical predilection to a serotonin syndrome. However, this effect is rare because at therapeutic doses selective MAO-B inhibitors produce no significant MAO-A inhibition.

4- Hyponatremia may be associated with SSRI use, especially in elderly people with concomitant use of diuretics, thought to be secondary to the development of the (SIADH), with the incidence varying from 0.5% to 32%.

Depression

Depression

Psychosis in Parkinson’s Disease

These psychotic symptoms occur in 20–40% of PD patients.

Psychosis in PD is characterized by hallucinations (primarily visual), delusions and illusions

visual hallucinations usually consists of people or animals but may also feature inanimate objects.

Auditory hallucinations occur less commonly . Tactile, olfactory and gustatory hallucinations have

also been reported . Paranoid thoughts have also been documented.

Etiology 1-All PD medications (not just levodopa) have been

implicated in the appearance of psychotic features. 2-hypersensitization of dopamine receptors in the

nigrostriatal pathway following chronic stimulation, which may lead to dysfunction of limbic structures.This dysfunction may result in misattributions of internal stimuli to be originated from the external sensory world

3-. Dopamine deficiency at the level of the retina is also found in PD and has been linked to the occurrence of visual hallucinations.


4- Visual hallucinations in PD have been purported by some to represent a narcolepsy-like phenomena involving the intrusion of REM dream imagery into the waking state.

5- cholinergic deficit in the nucleus basalis of Meynert is risk factors for the development of psychosis in PD.

6- clinic-pathological examination of PD patients with a history of visual hallucinations revealed a significantly greater Lewy body burden in the amygdala and cortical areas.


Management Medication Reduction Most authorities would recommend the

gradual removal of anti-PD drugs in the following order: anticholinergics, selegiline, amantadine, dopamine agonists, then catechol-O-methyltransferase (COMT) inhibitors, and lastly, levodopa.. If no improve, the addition of an antipsychotic agent considered.


Antipsychotic Agents “atypical” antipsychotics, are the

choice for combating psychosis associated with PD.

clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. The differences between these agents lie in their relative tendencies to worsen motor symptoms, and the clinician’s choice of an antipsychotic agent is based largely on its unique side effect profile


Clozapine is the only SGA fully recommended for the

treatment of psychosis in PD. At higher dosages, subjects reported severe

sedation, which may partially explain the exaggeration of PD motor symptoms.

It is now known that PD patients can experience therapeutic benefit at doses as low as 6.25mg/d.

the use of clozapine must be accompanied by weekly WBC count monitoring during the first six months of use and bi-weekly monitoring


Risperidone it has been shown to behave more like

“typical” neuroleptics in that it exhibits a dose-dependent incidence of extrapyramidal side effects and prolactin elevation.

Due to numerous reports of motor worsening in PD patients treated with risperidone and the agent’s “typical” antipsychotic behavior, many movement disorders specialists are reluctant to use this agent to treat PD psychosis.


Olanzapine olanzapine appears ineffective in the treatment of

psychosis in PD and can lead to intolerable motor deterioration even at low doses.

Quetiapine One report found that 35 out of 43 PD patients

experienced a significant improvement in psychotic symptoms when treated with quetiapine.

There have been some reports suggesting that quetiapine may have a positive effect on sleep architecture.


Ziprasidone Available data on the use of ziprasidone to treat PD

psychosis is limited Its use has been limited because of its effects on the

heart’s electrical cycle, causing prolonging the QT interval.

Aripiprazole aripiprazole is a partial agonist at both D2 and 5-HT1

receptors. It is believed to carry a relatively low risk of

extrapyramidal ,However, available data on aripiprazole suggest that its efficacy and tolerability in PD patients is variable.


Electroconvulsive Therapy (ECT) it appears that ECT may be useful in reducing

psychotic symptoms in PD, especially when pharmacologic therapies have been unsuccessful.

Reports also indicate that ECT may temporarily improve motor symptoms.

Psychological Approaches Structured psychological interventions, including

cognitive-behavioral therapy, supportive therapy, and psychoeducation, have also been useful in the treatment of PD


Dementia in PD

the prevalence is 40%. These numbers indicate that PD patients have a 4- to 6-fold increased risk compared to age-matched general population.

the mean duration from diagnosis of PD to development of dementia is approximately 10 years

Pathophysiology

1-the striatum of the basal ganglia is a primary substrate for the learning and performance of skills .

2-Dopamine in the putamen – connecting to the lateral prefrontal cortex – are critical in the development of working memory .

3-degeneration of cholinergic efferent nuclei in the basal forebrain is early affected in PD .

4-loss of gray matter in the limbic/paralimbic system, including the amygdala, hippocampal and parahippocampal cortices, and the anterior cingulate cortex .

Dementia in PD

clinical feature

1-word-finding difficulties that may slow speech fluency .

2-Complaints of recollection for recent episodic events.

3-Difficulties in performing dual-tasks, planning activities and organizing daily life (correspondence, finances, work projects) with executive dysfunction .

4- problems understanding and producing language, and a tendency to lose the thread of speech.

Dementia in PD

Management

There is insufficient evidence for donepezil to be rated for the treatment of dementia in PD.

Rivastigmine can be rated as efficacious for the treatment of dementia in PD. Nausea and vomiting were the most common side effects observed with rivastigmine.

There is insufficient evidence for galantamine to be rated for the treatment of dementia in PD. Worsening of tremor occurred in some patients treated with galantamine.

Dementia in PD

Cholinesterase inhibitors should not be discontinued without gradual taper as sudden decline in cognition has been reported in these patients .

There is insufficient evidence for memantine to be rated for the treatment of dementia in PD. no safety concerns identified for the treatment of dementia in PD

Dementia in PD Management

Dementia in PD

Fatigue in PD

fatigue occurred in about 58 % of a patients. pathophysiology

fatigue has been reported to be associated with reduced glucose metabolism in the frontal cortex and the basal ganglia.

Bilateral posteroventral pallidotomy for treatment of Parkinson’s disease can also lead to profound fatigue, sleepiness, changes in behaviour and poor initiative in executive functions despite improvement in motor control.

reduced serotonin transmission could have a role in the occurrence of fatigue in patients with Parkinson’s disease.

patients with PD have a lower pain threshold than healthy people.

Management. Methylphenidate long-term therapy might cause drug

dependence, psychotic symptoms and behavioral sensitization, similar to other stimulants.

Modafinil has is insufficient evidence to be rated for the treatment of fatigue in PD.

Rare cases of serious or life-threatening rash, including Stevens- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in adults and children in worldwide postmarketing

AEs associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression.

Fatigue in PD

Fatigue in PD

Medication-Related Impulse Dyscontrol and Abnormal Repetitive Behaviors in PD

These behaviors include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, hobbyism, and compulsive medication use.

The prevalence of pathological gambling in PD in systematic clinical studies in North America has been reported as 3% to 8%.This compares with 1.7% among the North American general population

Dopaminergic medications may be associated with aberrant behavior by several mechanisms:

(1) Interference with the pattern of dopamine release and its normal physiological role as an error prediction or teaching signal

(2) Dopaminergic stimulation enhancing the shift from goal-directed behaviors to stimulus response or habit formation.


there is insufficient evidence for amantadine to be rated for the treatment of pathological gambling in PD.

As One study has demonstrated that amantadine use in PD is associated with impulse control disorders in general, and with compulsive gambling, buying, and sexual behavior in particular, also there is association with corneal edeama.


Autonomic Dysfunction in PD

Orthostatic Hypotension in PD

OH is defined as a persistent, consistent, orthostatic fall in systolic blood pressure of 20mmHg or diastolic pressure of 10 mmHg by 3 min of standing up.

Using 18F-DA PET scanning we found that PD+OH patients consistently have very low sympathetic nerve endings in the left ventricular myocardium.

Early, prominent OH in patients with Parkinsonism has been considered to exclude PD and to support another diagnosis, such as the Parkinsonian form of multiple system atrophy (MSA)

There is insufficient evidence for both fludrocortisone to be rated for the treatment of OH in PD.

Gastrointestinal Motility Problems in PD

Survey studies indicate that 70-78% of PD patients are aware of excessive amounts of saliva.

difficulty swallowing in individuals with PD, with reports ranging from 30% to over 80%.

nausea present in 16% of PD patients and a sense of bloating in 43%.

Decreased bowel movement frequency the reported number of PD patients experiencing decreased bowel movement frequency ranges from 20-89% in various studies.

All stages of swallowing oral, pharyngeal, and esophageal may be affected in PD.

Rigidity, bradykinesia, and even tremor of the tongue and oral musculature may impede bolus formation and slow oral transit time.

impaired gastric emptying also s may be one cause of motor response fluctuations in patients receiving levodopa.

Gastrointestinal Motility Problems in PD

Pathophysiology of GI dysfunction in PD

The dorsal motor nucleus of the vagus (DMV), which provides parasympathetic innervation to much of the GI tract, is profoundly involved in PD .

Lewy bodies were first identified within the ENS. Recently, it has been proposed that alpha

synuclein deposition within the ENS in the stomach may be the earliest site of pathology in PD .

Saliva accumulation is, indead, the consequence of diminished frequency and reduced efficiency of swallowing

Anticholinergic agents may be useful. Sublingual administration of atropine ophthalmic drops or ipratropium spray may reduce saliva production without producing systemic effects. Botulinum toxin injections into the salivary glands have also been shown to reduce saliva production, with benefit typically persisting from seven weeks to seven months .

Glycopyrrolate is efficacious for the very short-term treatment of sialorrhea in PD.

management of GI dysfunction in PD

No universally effective treatment approach for dysphagia in PD has been identified. Responsiveness of oropharyngeal dysphagia to dopaminergic medication has been noted by some investigators, but only in a minority of patients.

Domperidone, a D2 receptor antagonist that does not cross the blood brain barrier, has been shown to improve both gastric emptying and levodopa absorption in PD patients .


Cisapride and mosapride have both been specifically shown to improve gastric emptying in patients with PD , but use of these drugs has been limited by their proclivity to produce cardiotoxicity.

Erythromycin, which in addition to being an antibiotic is also a motilin agonist, is effective in accelerating gastric emptying but has not been evaluated in the setting of PD .

Mirtazapine has been reported to be effective in improving gastric emptying in a single patient with refractory gastroparesis, but no formal study of this agent has been reported .


Botulinum toxin injection into the pyloric sphincter has recently been reported to be effective in ameliorating gastroparesis .

Several such laxatives are available, but polyethylene glycol (macrogol) has been specifically studied in PD patients and found to be effective [93,94]. Prokinetic agents, intended to accelerate colon transit, have also been investigated in persons with PD

Botulinum toxin injections into the puborectalis muscle under ultrasonic guidance have been reported to produce symptomatic improvement in over 50% of PD patients, with improvement typically persisting for several months.


Genitourinary dysfunction

The reported prevalence of LUT symptoms (LUTS) in patients with PD ranges from 38 to 71%.

Storage symptoms are the most common of the LUTS symptom types. Storage symptoms include nocturia (nighttime urinary frequency), which is the most prevalent

symptom reported by patients with PD (>60%). Patients also complain of urinary urgency (33–

54%) and daytime frequency (16–36%). Urinary incontinence was present in 26% of male and 28% of female patients with PD.

The net effect of the basal ganglia on micturition is thought to be inhibitory.

Both the SNc neuronal firing and the released striatal dopamine seem to activate the dopamine D1-GABAergic direct pathway . which not only inhibits the basal ganglia output nuclei, but also may inhibit the micturition reflex via GABAergic collateral to the micturition circuit.In patients with PD, disruption of this pathway may lead to DO and resultant urinary urgency/frequenc


some reports showed that a change in medication from bromocriptine (D2 selective agonist) to pergolide (D1<2 agonist) brought lessening of nocturia.

Anticholinergics are generally used as a first-line treatment for overactive bladder. However, it is important to balance the therapeutic benefits of these drugs with their potential adverse effects.


SEXUAL DYSFUNCTION IN PD

the frequency of dysfunction in PD patients was significantl yhigher for decrease of libido (84% men, 83% women), decrease of sexual intercourse (55% men, 88%

women), decrease of orgasm (87% men), and decrease of erection (79%) and ejaculation (79%) in men.

In experimental animals, dopamine is known to facilitate erection and mating behaviors. It is reported that dopamine D1/D2 receptors in the hypothalamus participate in erection whereas only D2 receptors participate in ejaculation. Pathology studies have shown that the hypothalamus is affected in PD.

l. Sildenafil was well tolerated in the aforementioned study, transient AEs included headache, flushing, and dyspepsia. cardiovascular disease

Sleep disturbance in PD

Disturbances of sleep are highly prevalent in PD, affecting up to 88% of community dwelling patients.

neurotransmitters that mediate sleep functions (norepinephrine, serotonin, dopamine and GABA) are variably damaged in PD.

neurotransmitters involved in REM sleep (acetylcholine, serotonin and norepinephrine) are also variably disrupted in PD.

Motor difficulties, such as inability to move in bed, dystonic movements, and pain from leg cramps may all interfere with sleep maintenance.

Sleep disturbance in PD

Insomnia

Insomnia is generally divided into difficulty falling asleep (sleep initiation), staying asleep (sleep maintenance), and awakening too early in the morning.

The benzodiazepines, such as temazepam, flurazepam, and lorazepam are efficacious in short term use for sleep latency and for total sleep time

The nonbenzodiazepine hypnotics, such as zolpidem, eszopiclone, and zaleplon, also work via the benzodiazepine receptor but have an improved side effect profile and are thus widely used today

Sedating antidepressants, especially trazodone, are also widely used for insomnia, over the counter medications, such as the antihistamine diphenhydramine are also commonly used and may be helpful for some patients.

In patients with significant cognitive impairment, psychosis or very vivid dreaming (often heralding daytime psychosis) the atypical antipsychotics quetiapine or clozapine may be of use.

There is insufficient evidence to conclude on the efficacy of melatonin .

Melatonin appears to cause very few side effects may include headache, nausea or next day grogginess or irritability

Insomnia

Vivid dreams

the first approach may be to reduce the night time dopaminergic dose. If this is neither tolerated nor helpful, the addition of the atypical antipsychotic quetiapine can be considered

Restless leg syndrome and periodic limb movment.

RLS and PLMS are common in patients with PD, occurring in up to 15% of patients, and can lead to disrupted sleep and EDS.

Ropinirole and pramipexole have recently been approved for use in the United States for RLS. Other treatments that have received some support include benzodiazepines and the opiates.

Sleep attacks

Sleep attacks are abrupt and unavoidable transitions from wakefulness to sleep

there is insufficient evidence to conclude on the efficacy of modafinil for the treatment of EDS in PD.

The next slides aren't about science but

about our life

سقما بعده ليس شفاء اشفه اللهماحرسه.. اللهم بيده خذ اللهم ابدا

تنام . ال التى بعينيك احفظه و يرام ال الذى بركنك اكفه و

الليل . فى اكأله و ~ضام ي ال الذى بعزكالنهار . فى و

. و ثقته أنت عليهّ بقدرتك ارحمه وُم~فرج . يا الهم كاشف يا رجائه

الم~ضطرين . دعوة ُم~جيب يا الكرب والعافية الصحة ثوب البسه اللهم

.. الراحمين ياأرحم اجال غير عاجال اللهم اشفه اللهم اشفه اللهم

. اُمين.. اللهم اشفه

non motor manifestation of parkinson disease

Health & Medicine

Transcript of non motor manifestation of parkinson disease