Neurodegenerative disorders: Making their presence felt
Neurodegenerative diseases are defined as hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral structures of the nervous system. Some of the well known neurodegenerative disorder are as follows 1.Parkinson's Disease, 2.Brain Cancer, 3.Degenerative Nerve Diseases, 4.Encephalitis, 5.Epilepsy, 6.Genetic Brain Disorders, 7.Head and Brain Malformations, 8.Hydrocephalus, Stroke, 9.Alzheimer's Disease and other dementias, 10.Multiple Sclerosis, 11.Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), 12.Huntington's Disease and others. In my this blog I will throw some light on the most common neurodegenerative disorder that is "PARKINSON'S DISEASE". PARKINSON'S DISEASE CLINICAL FEATURES Parkinsonism consists of tremor, rigidity, bradykinesia, and characteristic abnormalities of gait and posture; may occur with many disorders. Parkinson's disease (PD) is idiopathic parkinsonism without evidence of more widespread neurologic involvement. PD afflicts 1 million individuals in the United States (1% of those _55 years). Peak age of onset in the 60s (range is 35 to 85); course progressive over 10 to 25 years. Tremor ("pill rolling" of hands) at rest (4-6 Hz); worsens with stress. A faster (7-8 Hz) "action tremor" may also occur when the hands are held against gravity. Presentation with tremor confined to one limbor side of body is common. Other findings: rigidity ("cogwheeling"-- increased ratchet-like resistance to passive limbmovements), bradykinesia (slowness of voluntary movements), fixed expressionless face (facial masking) with reduced frequency of blinking, hypophonic voice, drooling, impaired rapid alternating movements, micrographia (small handwriting), reduced arm swing while walking, flexed "stooped" posture with walking, shuffling gait, difficulty initiating or stopping walking, en-bloc turning (multiple small steps required to turn), retropulsion (tendency to fall backwards). Non-motor aspects of PD include depression and anxiety, cognitive impairment, sleep disturbances, sensation of inner restlessness, loss of smell (anosmia), and disturbances of autonomic function. In advanced PD, intellectual and behavioral deterioration, aspiration pneumonia, and bedsores (due to immobility) common. Normal muscular strength, deep tendon reflexes, and sensory exam. Diagnosis based upon history and examination; neuroimaging, EEG, and CSF studies usually normal for age. ETIOLOGY Degeneration of pigmented pars compacta neurons of the substantia nigra in the midbrain resulting in lack of dopaminergic input to striatum; accumulation of beosinophilic intraneural inclusion granules (Lewy bodies). Cause of cell death is unknown, but it may result from generation of free radicals and oxidative stress. Rare genetic forms of parkinsonism exist; most common are mutations in synuclein or parkin genes. Early age of onset suggests a possible genetic cause of PD. PATHOPHYSIOLOGY The symptoms of Parkinson's disease result from the greatly reduced activity of pigmented dopamine-secreting (dopaminergic) cells in the pars compacta region of the substantia nigra (literally "black substance"). These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway. The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack ofdopamine results in increased inhibition of the ventral anterior nucleus of thethalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia. There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in earlyParkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinsons disease. DIFFERENTIAL DIAGNOSIS Features of parkinsonism may occur with: depression (paucity of vocal inflection and facial movement); essential tremor (high-frequency tremor with limbs held against gravity, head tremor, improves with alcohol); normal-pressure hydrocephalus (apraxic gait, urinary incontinence, dementia); Wilson's disease (early age of onset, Kayser-Fleischer rings, low serum copper, low ceruloplasmin); Huntington's disease (family history, chorea, dementia); multiple system atrophy (early urinary incontinence, orthostatic hypotension, dysarthria); dementia with Lewy bodies (early hallucinations, behavioral disturbances); progressive supranuclear palsy (early imbalance and falls, downgaze paresis). UNIFIED PARKINSON'S DISEASE RATING SCALE (UPDRS) I. MENTATION, BEHAVIOR AND MOOD 1. Intellectual Impairment 2. Thought Disorder (Due to dementia or drug intoxication) 3. Depression 4. Motivation/Initiative II. ACTIVITIES OF DAILY LIVING (for both "on" and "off") 5. Speech 6. Salivation 7. Swallowing 8. Handwriting 9. Cutting food and handling utensils 10. Dressing 11. Hygiene 12. Turning in bed and adjusting bed clothes 13. Falling (unrelated to freezing) 14. Freezing when walking 15. Walking 16. Tremor (Symptomatic complaint of tremor in any part of body.) 17. Sensory complaints related to parkinsonism III. MOTOR EXAMINATION 18. Speech 19. Facial Expression 20. Tremor at rest (head, upper and lower extremities) 21. Action or Postural Tremor of hands 22. Rigidity (Judged on passive movement of major joints with patient relaxed in sitting position. Cogwheeling to be ignored.) 23. Finger Taps (Patient taps thumb with index finger in rapid succession.) 24. Hand Movements (Patient opens and closes hands in rapid succesion.) 25. Rapid Alternating Movements of Hands (Pronation-supination movements of hands, vertically and horizontally, with as large an amplitude as possible, both hands simultaneously.) 26. Leg Agility (Patient taps heel on the ground in rapid succession picking up entire leg. Amplitude should be at least 3 inches.) 27. Arising from Chair (Patient attempts to rise from a straightbacked chair, with arms folded across chest.) 28. Posture 29. Gait 30. Postural Stability (Response to sudden, strong posterior displacement produced by pull on shoulders while patient erect with eyes open and feet slightly apart. Patient is prepared.) 31. Body Bradykinesia and Hypokinesia (Combining slowness, hesitancy, decreased armswing, small amplitude, and poverty of movement in general.) TREATMENT Goals are to maintain function and avoid drug-induced complications. It is not always possible to exclude other causes of parkinsonism prior to initiating treatment for PD. Bradykinesia, tremor, rigidity, and abnormal posture respond early in illness; cognitive symptoms, hypophonia, autonomic dysfunction, and balance difficulties respond poorly. THERAPY Dopaminomimetic therapy initiated when symptoms interfere with quality of life. In early PD, dopamine agonist monotherapy well tolerated and reduces risk of later treatment-related complications such as motor fluctuations and dyskinesias (50% of pts treated over 5 years with levodopa). Motor fluctuations are the exaggerated ebb and flow of parkinsonian signs between doses of medications. Dyskinesias refer to choreiform and dystonic movements that can occur as a peak dose effect or at the beginning or end of the dose. Dopamine agonist monotherapy requires higher doses than needed when agonist is used to supplement levodopa slow titration necessary to avoid side effects. Most pts require addition of levodopa or another agent within 1 to 3 years of initiating dopamine agonist monotherapy. Levodopa, the metabolic precurser of dopamine, remains most effective treatment for PD. Dopamine Agonists Compared to levodopa, they are longer acting and thus provide a more uniform stimulation of dopamine receptors. They are effective as monotherapeutic agents and as adjuncts to carbidopa/levodopa therapy. They can also be used in combination with anticholinergics and amantadine. Agonists are effective against bradykinesia and gait disturbances but less effective against tremor. Side effects include nausea, postural hypotension, psychiatric symptoms, daytime sedation, and occasional sleep attacks. Carbidopa/Levodopa Formulations Available in regular, immediate release (IR) formulations (Sinemet, Atamet and others; 10/100 mg, 25/100 mg, and 25/250 mg), controlled release (CR) formulations (Sinemet CR 25/ 100 mg, 50/200 mg), and more recently as Stalevo (Table 191-1). The latter combines IR carbidopa/levodopa with 200 mg of entacapone . Carbidopa blocks peripheral levodopa decarboxylation into dopamine and thus symptoms of nausea and orthostasis often associated with the initiationof levodopa. Initial target doses of these medications are summarized in the table. Gradual dose escalation recommended; initiation of dosing at mealtimes will reduce nausea. Levodopa Augmentation Selegiline is a selective and irreversible monoamine oxidase (MAO) B inhibitor with a weak symptomatic effect when used as monotherapy or as an adjunct to carbidopa/levodopa. Typically, selegiline is used as initial therapy or is added to alleviate tremor or levodopaassociated wearing off; dose is 5 mg with breakfast and lunch. A side effect is insomnia. Older individuals, and those with cardiac disease, may benefit from doses as low as 2.5 mg/d. The potential role of selegiline as neuroprotective therapy remains controversial. The catechol O-methyltransferase (COMT) inhibitors entacapone and tolcapone offer yet another strategy to augment the effects of levodopa by blocking the enzymatic degradation of levodopa and dopamine. Entacapone is preferred to tolcapone (hepatic and hematologic side effects). When used with carbidopa/levodopa, these agents alleviate wearing-off symptoms and increase time a pt remains "on" (i.e., well medicated) during the day. Common side effects are gastrointestinal and hyperdopaminergic, including increased dyskinesias. The dose of entacapone is 200 mg coadministered with each dose of carbidopa/levodopa. The dose of tolcapone is 50 to 200 mg tid. Anticholinergics and amantadine are useful adjuncts. Anticholinergics (trihexyphenidyl, 2-5 mg tid; benztropine, 0.5-2 mg tid) are particularly useful for controlling rest tremor and dystonia, and amantadine can reduce druginduced dyskinesias by up to 70%. The mechanism of action of amantadine (100 mg bid) is unknown; it has anticholinergic, dopaminomimetic, and glutamate antagonist properties. In older patients, it may aggravate confusion and psychosis. Surgical Treatments In refractory cases, surgical treatment of PD should be considered. The use of ablation (e.g., pallidotomy or thalamotomy) has decreased greatly since the introduction of deep-brain stimulation. The selection of suitable patients for surgery is most important, since in general patients with atypical Parkinson's do not have a favorable response. The indications for surgery are (1) a diagnosis of idiopathic PD, (2) a clear response to levodopa, (3) significant intractable symptoms of PD, and/or (4) druginduced dyskinesias and wearing off. Contraindications to surgery include atypical PD, cognitive impairment, major psychiatric illness, substantial medical comorbidities, and advanced age (a relative factor). 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