Amantadine in Parkinson’s Disease: An Expert Opinion Vinay Goyal
INDEX
Page numbers followed by f refer to figure, fc refer to flowchart, and t refer to table.
A
Akinesia 3
Alanine aminotransferase 46
Amantadine 16, 17, 19, 20, 21f, 22, 23, 25, 2730, 32t, 3439, 42, 44, 47, 48
adverse effects of 42, 45t
clearance of 23, 25t
concentrations 25
dosage 42, 43t
dose of 42
duration of 33
effectiveness 34
efficacy of 28
exhibits 38
general pharmacodynamics of 20
mechanism of action of 20
overdosage of 43
pharmacokinetic properties of 24t
safety of 28, 29
structure of 20f
therapy 35t, 36t
treatment 34
use of 37
Anticholinergics 16
Antidyskinetic effects 28
Antiparkinsonian drugs 42
Antiviral agent 37
Ataxia, management of 38
B
Blood 45
pressure 46, 48
Blurred vision 44
Bradykinesia 3, 35, 36
Brain bank criteria 11
C
Cardiac disorders 45
Cardiovascular system 44
Central nervous system 44
Concomitant therapy, dosage for 42
Constipation 44
Corticostriatal tract 22f
D
Degenerative cerebellar ataxias 38
Dementia 6
Dizziness 48
Dopamine agonist 28
Dopaminergic
medications 16
pathway 38
system 20
Drug–drug interactions 42, 47
Dyskinesia 33
developed 29
risk of 28
levodopa-induced 17, 28
E
End-stage renal disease 47
Erectile dysfunction 7
Extrapyramidal reactions, dosage for drug-induced 43
F
Freezing of gait 31
efficacy of amantadine in 31
questionnaire 33fc
response 32t
G
Gait questionnaire score 33f
Gastric aspiration 44
Gastrointestinal disorders 45
Glutamatergic system 21
H
Hypokinesia 3
Hypophonia 4
I
Immunomodulation 21
Inspiratory respiratory dysfunction 14
L
Levodopa 13, 28
treatment 20
Levodopa-induced dyskinesia, treatment of 29
Lewy body
break staging of 11t
deposition, staging of 11
Liver function test 46
Lymphatic system disorder 45
M
Mental status 46, 48
Metabolism 25, 46
Motor symptoms 4fc
Movement Disorder Society 13, 30
Multiple system atrophy 33fc, 34, 36
N
Nervous system disorders 45
Neurodegenerative movement disorder 1
Nigrostriatal nerve terminal 22f
N-methyl-d-aspartate 21f
Nonmotor symptoms 5, 5fc, 6, 7t
Noradrenergic pathway 38
Noradrenergic system 21
Nutrition disorder 46
O
Overdosage, management of 44
Oxidative stress 10
P
Parkinson's disease 1, 4fc, 5fc, 8, 10, 17, 21, 28, 33fc, 43, 46, 47
advanced 7
clinical signs and symptoms of 1
diagnosis 10, 11, 14fc
dosage for 42
drug therapy 6
early 28
epidemiology of 1
estimated prevalence of 2f
idiopathic 23
management of 15, 16t
pathophysiology 10
postural reflex impairment in 31
premotor 7t
risk factors of 3
role of amantadine in 19
severe 19, 33
supportive criteria for 12
symptoms 4f
Parkinson's hyperpyrexia syndrome 6
Parkinsonian syndrome bradykinesia, diagnosis of 12
Parkinsonism 35, 36
signs of 3
treatment of 22
Periodic skin examinations 46
Placebo arm 39
Plasma
acetylamantadine 25
amantadine concentration 30
concentrations 26
proteins 23
Postural instability 5
Potent neurotoxins 10
Presynaptic dopaminergic system 13
Primary progressive freezing gait 33fc
Progressive supranuclear palsy 33fc, 34, 35
Psychiatric
disorders 45
symptoms 8
Q
Quinidine 47
Quinine 47
R
Renal function 46
Respiratory system 44
Resting tremor 36
Rigidity 5
T
Thioridazine 47
Traumatic brain injury 38
management of 38
Tremor 5
U
Unified dyskinesia rating scale 30
V
Visual hallucinations 44
Vomiting 44
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Chapter Notes

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Clinical Signs and Symptoms of Parkinson's DiseaseCHAPTER 1

 
INTRODUCTION
Parkinson's disease (PD) is the common neurodegenerative movement disorder.1 The disease is characterized by the degeneration of dopaminergic (DA) neurons of the brain.2 The disease is associated with motor symptoms and nonmotor symptoms.3
 
EPIDEMIOLOGY OF PARKINSON'S DISEASE
Globally, the prevalence of PD is estimated to be 10 million people and 1% of those above 60 years are affected with PD (see Fig. 1).4 It is expected to double worldwide by 2040.5
With increase in age, the incidence and prevalence of PD increase. In some patients, the onset of PD is seen as early as 40 years and it accounts for 15–25% of all PD cases. In India, there is no homogeneous and large epidemiological data on PD. However, the prevalence rate over the age of 60 years was 247/100,000. Crude prevalence rate of 14.1 per 100,000 from rural Kashmir, 27/100,000 from Bengaluru, 16.1/100,000 from rural Bengal, and 328.3/100,000 in Mumbai (see Fig. 2).62
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FIG. 1: Estimated prevalence of PD.
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FIG. 2: Incidence and prevalence of PD-Indian context.
3
 
RISK FACTORS OF PARKINSON'S DISEASE
Various risk factors contribute toward PD, some of which include:4,6
  • Age—most important risk factor
  • Male—confers a moderate risk
  • Family history
  • Environmental factors: Pesticides and rural living
  • Exposure to toxic levels of manganese, trichloroethylene, and carbon monoxide
  • β2-adrenoreceptor antagonists
  • Elevated cholesterol
  • Head trauma, e.g., boxing
  • High caloric intake
  • Increased body mass index
  • Inflammation associated with activation of microglia
  • Oxidative stress
  • Postinfection states
 
SYMPTOMS
The symptoms are given in Figure 3.
 
Motor Symptoms (Flowchart 1)
The important symptoms of PD include bradykinesia, tremor, rigidity, and postural instability.3
 
Bradykinesia
Bradykinesia is cardinal and earliest signs of Parkinsonism, which is the result of reduced dopamine levels in the brain. The term bradykinesia in Greek means slow movement, which is experienced by nearly 98% of people with PD. Bradykinesia can affect one limb, one side of your body, or your whole body, which can make you unnaturally still.4
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FIG. 3: PD symptoms.
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FLOWCHART 1: Motor symptoms observed in PD patients.
Akinesia and hypokinesia are terms, which are often used in relation to bradykinesia. Associated features are small handwriting (micrographia) or soft voice (hypophonia).75
 
Tremor
Another common symptom associated with PD is tremor. Tremor is defined as an involuntary, rhythmic movement that affects a part of the body, for example, hand, which is because of rapid and alternating contraction of agonistic and antagonistic muscles. Nearly, 70% of people with PD have a tremor at the time of diagnosis. Rest tremor is classic for PD. Rest tremor usually affects upper limbs, but legs, lips, and tongue may also be involved.7
 
Rigidity
One of another main motor symptoms of PD is rigidity, which is present in 90–99% of people. This leads to muscle aches, stiffness, or muscle fatigue.7
 
Postural Instability
Postural instability is one of late features of PD.8,9 Within 2 years of PD diagnosis, nearly 34% of patients develop postural instability, which increases to 71% in 10 years and 92% at 15 years.8
 
Nonmotor Symptoms (Flowchart 2)
The nonmotor symptoms of PD include olfactory dysfunction, cognitive impairment, sleep disorder, pain, depression, anxiety, autonomic nervous dysfunction, etc., which can occur during PD or earlier than motor symptoms, adversely affecting the quality of life.3
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FLOWCHART 2: Nonmotor symptoms observed in PD patients.
6Nonmotor symptoms are critical to diagnose as well as treat PD, as it has a significant impact on individual's quality of life, especially in case of advanced PD.10 The nonmotor symptoms include cognitive impairment, neuropsychiatric symptoms, sleep disorders, and olfactory dysfunction. Some of these symptoms may precede motor symptoms in PD as early as 10 years. Compared with motor symptoms, the nonmotor symptoms have greater impact on quality of life and are significantly associated with reduced individual well-being. In patients with advanced PD, nonmotor symptoms play an important role in loss of independence. A survey evaluating the nonmotor symptoms of PD reported including sleep problems (84%), cognitive symptoms (76%), anxiety (65%), depression (56%), hallucinations (40%), and delusions (23%).11
It is difficult to put all nonmotor symptoms into one category and, therefore, following classification is recommended:12
  • Related to the disease process or pathophysiology:
    • Dopaminergic origin
    • Nondopaminergic origin
  • Related to a partial nonmotor origin (usually brainstem autonomic impairment with motor end result such as constipation or diplopia)
  • Related to nonmotor fluctuations (cognitive, autonomic, and sensory subtypes)
    • Fluctuating
    • Constant
  • Related to PD drug therapy:
    • Specific symptoms (e.g., hallucinations, delirium)
    • Syndromes—impulse control disorders, dopamine agonist withdrawal syndrome, Parkinson's hyperpyrexia syndrome (thermoregulatory failure and delirium)
  • Possibly genetically determined:
    • Dementia in cases with glucocerebrosidase mutation
    • Depression and sleep disorders in cases with leucine-rich repeat kinase-2 mutation7
  • Some symptoms may overlap: For instance, hallucination as part of the advancing disease or nonmotor fluctuations in PD
In premotor stage of PD, some of the reported nonmotor symptoms have been shown in Table 1.12
 
ADVANCED PARKINSON'S DISEASE
Advanced PD is defined as onset of disabling motor symptoms.13 The time span for a patient to reach advanced stage may reach usually in 5–10 years from the time of diagnosis. Dyskinesia and motor fluctuations are the most frequent motor symptoms in advanced PD.
TABLE 1   Nonmotor symptoms in the premotor Parkinson's disease (PD).
Commonly associated—with reasonable evidence base
Hyposmia (usually of late onset and idiopathic)
10 times increase in risk of developing PD + abnormal DAT scan—43% develop motor PD in 4 years
Rapid eye movement sleep behavior disorder
25–40% risk of developing a synucleinopathy at 5 years and 40–65% risk of developing a synucleinopathy at 10 years
Constipation
2.7–4.5 times increased risk of PD
Depression
2.4 times increased risk of developing PD
Described associations
Excessive daytime sleepiness
3.3 times increased risk of PD
Fatigue (a sense of exhaustion as opposed to sleepiness)
In 45%—a premotor symptom
Pain (often unilateral and in affected limb)
34% increased risk of PD
Erectile dysfunction
3.8 times increased risk of PD
8Meta-analyses have estimated 40% probability of developing dyskinesia and motor functions after 4 years of levodopa treatment. Motor fluctuations could get complex with progression of the disease.13
Parkinson's disease is considered advanced, if the patient experiences a fluctuating clinical state with alternating periods of good and poor symptom control. These fluctuations may affect both motor and NMS and they cannot be controlled using conventional therapy. Advanced PD gives rise to motor symptoms that respond poorly or not at all to oral levodopa. Symptoms include gait disorders, postural disorders, lack of stability, dysphagia, and dysarthria and they cause severe disability. Appearance of nonmotor complications and the development of disabling NMS (such as dementia, autonomic symptoms, pain, or psychiatric symptoms) are typical in patients with advanced PD.13
The timeline for progression to advanced PD varies from patient to patient. Various risk factors for advance PD include age, gender, disease duration, motor phenotype, olfactory changes, sleep behavior disorder, hallucinations, psychosis, and cognitive decline.13
 
SUMMARY
  • Parkinson's disease is a common neurodegenerative movement disorder.
  • Disease is characterized by the degeneration of DA neurons of the brain.
  • The important motor symptoms of PD include tremor, rigidity, bradykinesia, and postural instability.
  • Nonmotor symptoms include olfactory dysfunction, cognitive impairment, sleep disorder, pain, depression, anxiety, and autonomic nervous dysfunction.
9
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