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akinetic-rigid syndromes, i.e. slowed movement with increased tone Dyskinesias - added, uncontrollable movements.
Both akinesia/rigidity and dyskinesia may coexist; idiopathic Parkinson's disease and essential tremor are much the commonest. AKINETIC-RIGID SYNDROMES Idiopathic Parkinson's disease Is common with prevalence of 150/100 000 increasing sharply in those over 70 years. Parkinson's disease is clinically and pathologically distinct from other parkinsonian syndromes. Table 21-38. Movement disorders Akinetic-rigid syndromes Idiopathic Parkinson's disease Drug-induced parkinsonism (e.g. phenothiazines) MPTP-induced parkinsonism Postencephalitic parkinsonism Parkinsonism-plus Wilson's disease Childhood akinetic-rigid syndromes Dyskinesias Essential tremor Chorea Hemiballismus Myoclonus Tics Dystonias Paroxysmal dyskinesias The environmental agent is not responsible. Some factors possibly involved are: 1. Nicotine. PD is less prevalent in tobacco smokers. 2. MPTP. Causes severe parkinsonism. Any link with idiopathic PD is tenuous.. 3. Encephalitis lethargica. Sometimes developed severe parkinsonism. It is not thought that idiopathic PD is related to any infective agent. 4. Genetic factors. Idiopathic PD is not usually familial, but there is clustering of early-onset PD in some families. Mutations in the parkin gene on chromosome 6 have been found in families with autosomal recessive cases of PD. Parkin mutations probably account for most PD cases with onset below the age of 40. Mutations of the -synuclein gene and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). Pathology 1. Progressive neuronal degeneration in the pars compacta of the substantia
nigra and other basal ganglia nuclei. 2. Eosinophilic inclusion bodies (Lewy bodies) develop. These contain protein filaments of ubiquitin and synuclein. 3. loss of dopamine (and melanin) in the striatum. This correlates with cell loss and the degree of akinesia. Symptoms and signs The combination of tremor, rigidity and akinesia develops slowly, over months or several years, together with changes in posture. Common initial symptoms are tremor and slowness. Limbs and joints feel stiff; they ache. Fine movements become difficult. Slowness causes difficulty rising from a chair or getting into or out of bed. Writing becomes small (Micrographia) and spidery, tending to tail off. Relatives often notice other features - slowness and an impassive face. Idiopathic PD is almost always initially more prominent on one side. The diagnosis is usually evident from the overall appearance. 1. Tremor The characteristic 4-7 Hz pill-rolling tremor at rest (movements between thumb and forefinger) typically decreases with action. Tremor is often asymptomatic at first. 2. Rigidity Stiffness is equal in opposing muscle groups (in contrast to the selective increase in limb tone found in spasticity). This lead pipe-like increase in tone (plastic rigidity) is usually more marked on one side and present in the neck and axial muscles. Plastic rigidity is more easily felt when a joint is moved slowly and gently; tone increases when the opposite arm moves actively. When stiffness occurs with tremor, smooth lead pipe rigidity is broken up into a jerky resistance to passive movement - cog wheeling (cogging). 3. Akinesia Poverty/slowing of movement (bradykinesia and difficulty initiating movement. Facial immobility gives a mask-like semblance of depression. Frequency of spontaneous blinking diminishes, producing a serpentine stare. 4. Postural and gait changes Stooping is characteristic. Gait becomes hurrying and shuffling with poor arm swinging. The posture is sometimes called simian to describe the ape-like forward flexion. Balance deteriorates, but despite this the gait retains a narrow base. Falls, are common in later stages. 5. Speech is monotone and progresses to slurring dysarthria. Eventually, speech may be lost (anarthria). 6. Cognitive changes Cognitive decline may occur early in the condition. Depression is common. 7. Gastrointestinal and other symptoms These include constipation, heartburn, dribbling, dysphagia and weight loss. Urinary difficulties are common, especially in men. Skin is greasy and sweating excessive. Natural history and other features While bradykinesia and tremor worsen, power remains normal until immobility makes its assessment difficult. Patients often complain bitterly of limb and joint discomfort. There is no sensory loss. The reflexes are brisk; their asymmetry follows the increase in tone. The plantar responses remain flexor. The rate of progression is very variable; Usually the course is over 10-15 years. Death results from bronchopneumonia with immobility and cognitive impairment. Diagnosis There is no laboratory test; diagnosis is made by recognizing physical signs and
distinguishing idiopathic PD from other parkinsonian syndromes. Conventional imaging (MR) is normal initially; atrophy develops. Dopamine transporter (DAT) imaging is abnormal but discriminates poorly between PD and other akinetic-rigid syndromes. similar features of parkinsonism seen in idiopathic PD Can be seen in y Alzheimer's disease y Multi-infarct dementia y Sequelae of repeated head injury y Late effects of severe hypoxia or CO poisoning. Slowing also occurs in hypothyroidism, and in depression. Treatment All antiparkinsonian drugs can provoke visual hallucinations, especially at night, and exacerbate cognitive impairment. Levodopa and/or dopaminergic agonists produce striking initial improvement. Drugs are avoided until clinically necessary because of delayed unwanted effects. Older treatments such as antimuscarinics, e.g. trihexyphenidyl (benzhexol), helped little and frequently caused confusion; they remain of some value in severe tremor. Levodopa crosses the blood-brain barrier, enters the nigrostriatal neurone and is converted to dopamine. A. Carbidopa and benserazide reduce peripheral conversion of levodopa to dopamine, thus reducing side-effects of circulating dopamine. B. Dietary amino acids from high-protein meals can inhibit active transport across bloodbrain barrier by competing with levodopa. C. Levodopa is converted (AAAD) to dopamine. D. Amantadine enhances dopamine release. E. Dopamine agonists react with dopamine receptors. F. Monoamine oxidase B inhibitors block dopamine breakdown. G. COMT inhibitors prolong dopamine activity by blocking breakdown. AAAD, aromatic amino acid decarboxylase; COMT, catechol-O-methyl transferase. y Levodopa Levodopa is combined with an AAAD inhibitor - benserazide (co-beneldopa, as Madopar) or carbidopa (co-careldopa, as Sinemet). The AAAD inhibitor reduces peripheral side-effects, principally nausea, of levodopa and its metabolites. Levodopa treatment is commenced (co-beneldopa 62.5 mg or co-careldopa 110 mg, one tablet three times daily) and gradually increased. The majority of idiopathic PD cases (but not other parkinsonian syndromes) improves initially with levodopa. Response in a severe, previously untreated case is sometimes dramatic. Unwanted effects of levodopa therapy Nausea and vomiting are the most common immediate symptoms of excess levodopa. Confusion, formed visual pseudo-hallucinations and chorea also occur. After several years levodopa gradually becomes ineffective, even with increasing doses. As treatment continues, episodes of immobility develop (freezing). Falls are common. Fluctuation in response to levodopa also emerges, its effect turning on and off, to cause freezing alternating with Dopa-induced dyskinesias (chorea and dystonic movements). Levodopa duration of action shrinks, with dyskinesias becoming prominent several hours after a dose (end-of-dose dyskinesia). The patient begins to suffer from a chronic levodopa-induced movement disorder. Levodopa does not alter the natural progression of PD. After 5 years' treatment, around half of PD cases suffer from minor or major unwanted effects of levodopa. Approaches to treatment of these complications include:
Shortening the interval between levodopa doses and increasing each dose.
Monoamine oxidase B inhibitors inhibit catabolism of dopamine in the brain. They are used to smooth out the end-of-dose fluctuations with levodopa. 3. Dopaminergic agonists are added, or replace levodopa. directly acting dopamine receptor agonists, acting principally on D1 and D2 receptors, and also on receptors D3-5
Bromocriptine, pergolide, cabergoline (all ergot derivatives), Ropinirole is the usual drug of choice. The ergot derivatives are associated with pulmonary, retroperitoneal and pericardial fibrotic reactions. They less effective than levodopa in treating symptoms, but cause fewer late unwanted dyskinesias. There is variation in clinical practice between the use of levodopa and dopamine receptor agonists. The trend is towards the use of receptor agonists as primary treatment (before levodopa) in cases below 65, and levodopa initially for older cases. COMT inhibitors (entacapone and tolcapone) prevent the peripheral breakdown of levodopa, allowing lower doses to be used. 5. Apomorphine a potent D1 and D2 agonist given by subcutaneous pump to smooth out fluctuations in response to levodopa. Vomiting is common. Hemolytic anaemia is an unusual side-effect.
Antioxidant compounds such as vitamins C and E as possible neuroprotective agents and evidence of benefit is poor. 7. Amantadine has a modest effect in PD. 8. Rasagiline and Rivastigmine may help cognitive changes and possibly the movement disorder. 9. Stereotactic neurosurgery Thalamic stimulation is used increasingly, sometimes with dramatic improvement. 10. Tissue transplantation 11. Physiotherapy and physical aids 12. Neuropsychiatric aspects Cognitive impairment and depression are common as PD progresses. SSRIs are the drugs of choice for depression. Tricyclic antidepressants (e.g. Amitriptyline) have Extrapyramidal side-effects. Type A MAO inhibitors (e.g. phenelzine) are contraindicated with levodopa. OTHER AKINETIC-RIGID SYNDROMES 1. Drug-induced parkinsonism Phenothiazines and Butyrophenones -Neuroleptics / (also reserpine and methyldopa) induce parkinsonism, usually with little tremor. Tricyclic antidepressants also cause some slowing. These unwanted effects tend not to progress and settle when drugs are stopped. 2. Neuroleptics and movement disorders Neuroleptics also produce other movement disorders.
6. y y
Akathisia. This is a restless, repetitive and irresistible need to move. Acute dystonic reactions. Spasmodic torticollis, trismus and oculogyric crises (episodes of sustained upward gaze) develop, dramatically and unpredictably, after single doses of neuroleptics and related drugs used widely as antiemetics and vestibular sedatives (e.g. metoclopramide and prochlorperazine).
These acute dystonias respond promptly to i.v. antimuscarinics, e.g. Benzatropine 1-2 mg or Procyclidine 5-10 mg. The offending drug (and all similar drugs) should be avoided, forever.
Chronic tardive dyskinesias. These mouthing and lip-smacking grimaces occur several years after commencing neuroleptics. They often become temporarily worse when the drug is stopped or the dose reduced. Even if treatment ceases, resolution seldom follows.
3. Parkinsonism-plus There is parkinsonism with additional features of specific pathology. Progressive supranuclear palsy (Steele-Richardson-Olzewski syndrome) is the commonest. It consists of parkinsonism, axial rigidity, falls, dementia and inability to move the eyes vertically or laterally. These disorders are progressive, although they sometimes respond to levodopa, and usually cause death within a decade. 4. Post-encephalitic parkinsonism and MPTP 5. Wilson's disease This rare and treatable disorder of copper metabolism is inherited as an autosomal recessive. Copper deposition occurs in the basal ganglia, the cornea and liver ,where it can cause cirrhosis. All young patients with an akinetic-rigid syndrome with or without dyskinesia, or with liver cirrhosis should be screened for Wilson's disease. Intellectual impairment develops. Neurological damage is reversible with early treatment.
Benign essential tremor This common, inherited as an autosomal dominant trait, causes 5-8 Hz tremor, usually worse in the upper limbs. The head is often tremulous and sometimes the trunk. Pathologically there is patchy neuronal loss in the cerebellum and its connections. Tremor develops when the hands adopt a posture, such as holding a glass or a spoon. Essential tremor occurs at any age but occurs most frequently in later life. Tremor is slowly progressive but rarely produces severe disability. Writing is shaky and untidy: Micrographia is absent. Anxiety exacerbates the tremor, sometimes dramatically. In essential tremor, shaking occasionally occurs at rest, as in PD, or on action, as in cerebellar disease. Treatment is often unnecessary. Many patients are reassured. Small amounts of alcohol, beta-blockers (propranolol), primidone or the antidepressant Mirtazapine may help. Sympathomimetics (e.g. Salbutamol) make all tremors worse. Stereotactic thalamotomy and thalamic stimulation are used in severe cases. 2. Chorea Chorea means jerky, quasi-purposive, explosive, fidgety movements, flitting around the body. y Huntington's disease relentlessly progressive chorea and dementia, usually in middle life but sometimes in childhood, are hallmarks of this inherited disease. Prevalence is 5 in 100 000. Inheritance is as an AD trait with full penetrance. A mutation occurs in chromosome 4 with a variable expansion of a CAGrepeat sequence. This results in extended glutamine sequence in huntingtin. Huntingtin is expressed throughout the body. Pathology: Cerebral atrophy progresses, with marked loss of neurones in the caudate nucleus and putamen.
Changes in neurotransmitters occur:
y y y
Reduced acetylcholine synthesis (due to reduced choline acetyl transferase) and GABA with high somatostatin levels in the corpus striatum. Increased transglutaminase (catalyses aggregates of huntingtin) in cortex, cerebellum and corpus striatum. depleted GABA, angiotensin-converting enzyme and met-enkephalin in substantia nigra
In contrast to PD, dopamine and tyrosine hydroxylase remain normal. Management and course Imaging in Huntington's shows caudate nucleus atrophy. There is steady progression of both dementia and chorea. While nothing arrests this, phenothiazines (e.g. sulpiride) and tetrabenazine reduce chorea. Death usually occurs 10-20 years from the onset. Table 21-39. Causes of chorea Huntington's disease Dentato-rubro-pallido-luysian atrophy Sydenham's chorea Benign hereditary chorea Abetalipoproteinaemia with chorea Chorea associated with: Drugs - phenytoin, levodopa, alcohol Thyrotoxicosis, pregnancy and the oral contraceptive pill Hypoparathyroidism Systemic lupus erythematosus Polycythaemia vera Encephalitis lethargica Stroke (basal ganglia) Other, e.g. tumour, trauma, subdural haematoma, following carbon monoxide poisoning, paroxysmal choreoathetosis, Wilson's disease y Sydenham's chorea (St Vitus's dance) This transient postinfective chorea occurs largely in children and young adults. Streptococcal infection is one cause: about 1/2 the cases follow rheumatic fever, typically within 3 months. Sydenham's may recur, or present in adult life, during pregnancy as chorea gravidarum, and with hormonal contraceptives. There is diffuse mild encephalitis. The onset is gradual over a few weeks. There is irritability, emotional lability and inattentiveness with fidgetiness, sometimes mainly unilateral. Rheumatic heart disease is sometimes found. Fever is unusual. Antistreptolysin-O (ASO) titre and ESR are typically normal. Sedation may be needed. Recovery occurs spontaneously within weeks or months. Phenoxymethylpenicillin should continue to the age of 20 to prevent recurrence. 3. Hemiballismus Violent swinging movements of one side caused usually by infarction or haemorrhage in the contralateral subthalamic nucleus.
4. Myoclonus Myoclonus is sudden, involuntary jerking of a single muscle or a group of muscles. This occurs in a wide range of disorders and is sometimes provoked by sudden stimuli such as loud noise. y Benign essential myoclonus is not pathological. y Myoclonus in epilepsy y Progressive myoclonic epilepsies: These rare conditions include familial and metabolic disorders where myoclonus accompanies progressive encephalopathy y Static myoclonic encephalopathy 5. Tics Gilles de la Tourette syndrome This describes multiple tics (motor and speech) with behavioral problems including attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). It develops in childhood or adolescence, more commonly in males, and is lifelong. There is sometimes explosive barking and grunting of obscenities and gestures. The cause is believed to be an inherited disorder of synaptic transmission. Haloperidol is sometimes helpful. 6. Dystonias Movement caused by prolonged muscular contraction - part of the body is thrown into spasm. Their causes are largely unknown. y Primary torsion dystonia (PTD): Dystonia affecting gait and posture in childhood progresses, spreading to all parts of the body over one to four decades. Cognitive function remains normal. Spontaneous remissions occur occasionally. This rare disease is usually inherited as an autosomal dominant. y Spasmodic torticollis Dystonic spasms gradually develop around the neck, usually in the third to fifth decade. These cause the head to turn (torticollis) or to be drawn backwards (retrocollis) or forwards (antecollis). Minor dystonic movements often also affect the trunk and limbs. A curious feature in some patients is a single trigger area, often on the jaw. A gentle touch with a finger tip at a specific site relieves the spasm temporarily. Torticollis may remit but often persists indefinitely. Similar features can be seen when no organic disease is present, for example people malingering following minor neck trauma.
Table 21-40. A classification of dystonias Generalized dystonia Primary torsion dystonia (PTD) Dopamine-responsive dystonia (DRD) Drug-induced dystonia (e.g. metoclopramide) Symptomatic dystonia (e.g. after encephalitis lethargica or in Wilson's disease) Paroxysmal dystonia (very rare, familial, with marked fluctuation) Focal dystonia Spasmodic torticollis Writer's cramp Oromandibular dystonia Blepharospasm
Hemiplegic dystonia, e.g. following stroke Multiple sclerosis - rare Treatment All dystonic movement disorders are particularly difficult to alleviate. Butyrophenones (e.g. haloperidol and sulpiride) and antimuscarinics (e.g. trihexyphenidyl (benzhexol)) are sometimes helpful. Carefully sited botulinum toxin injections can help, temporarily, blepharospasm, torticollis and writer's cramp. Neurosurgical treatment, principally stereotactic thalamotomy for torticollis, or neurostimulation offers some respite in selected cases.