Differential Diagnosis of Movement Disorders:
Multiple system atrophy
Progressive supranuclear palsy
Dementia with Lewy bodies
Drug (antipsychotic agents, antiemetics, metoclopramide, reserpine, lithium, tetrabenazine, or flunarizine)
Toxin (manganese, MPTP, mercury, methanol, ethanol, or carbon monoxide)
Head trauma (including pugilistic encephalopathy)
Selected Hereditary Disorders Associated With Parkinsonism:
Fragile X-associated tremor/ataxia syndrome
Idiopathic parkinsonism (Parkinson disease)
Idiopathic parkinsonism (Parkinson disease) is a proteinopathy characterized by the misfolding and aggregation of α-synuclein. It is thus also refered to as a synucleinopathy. Histopathologic examination at advanced stages shows loss
of pigmentation and cells in the substantia nigra and other brainstem centers, cell loss in the globus pallidus and putamen, and filamentous eosinophilic intraneural inclusion granules (Lewy bodies) containing α-synuclein in the basal ganglia, brainstem, spinal cord, and sympa thetic ganglia.
The most common variety of parkinsonism occurs without obvios cause; this idiopathic form is called Parkinson disease or paralysis agitans when there are no atypical features, it is not secondary to some known cause, and there is a sustained response to treatment with dopaminergic medication.
Px: The cardinal features of Parkinson disease (PD):
- Resting tremor (in a limb at rest) A tremor at rest is perhaps the most obvious feature of Parkinson disease and is a common presenting symptom. The tremor at rest readily disappears when sustaining a posture or during manual activities, in contrast to an essential tremor, which is an action tremor.
Bradykinesia is manifested by paucity of spontaneous movement with severely affected patients sitting unnaturally still and demonstrating a lack of facial expressiveness (“facial masking”). In addition to whole-body slowness and impairment in fine motor movements, other consequences of advanced bradykinesia include:
- Drooling of saliva due to a lack of spontaneous swallowing
- Soft monotonous speech
- Micrographia (small, cramped handwriting)
- Reduced arm swing when walking, and a short, shuffling gait
Rigidity or increased tone (ie, increased resistance to passive
movement) is characteristic of parkinsonism.
- Postural instability (loss of postural reflexes)
- Gait freezing (disturbance) flexed posture
Dx: Diagnostic criteria for PD require two of the four features. In idiopathic PD, the symptoms present asymmetrically and although the contralateral side is eventually affected, the asymmetry usually persists throughout the disease course.
Tx: Anticholinergic Drugs (trihexyphenidyl, benztropine) are more helpful in alleviating tremor and rigidity than hypokinesia but are generally less effective than dopaminergic drugs. Anticholinergic drugs are best avoided in the elderly because of their side effects, which include dry mouth, constipation, urinary retention, defective pupillary accommodation, and confusion.
Amantadine - Unclear mechanism; causes ankle edema and livedo reticularis (a mottled vascular pattern on the lower extremities)
Levodopa ameliorates all the major clinical features of parkinsonism and, unlike the anticholinergic drugs, is often particularly helpful against hypokinesia. Carbidopa is a drug that reduces the extracerebral (peripheral) metabolism of levodopa to dopamine (causes nausea, vomiting, and hypotension) by inhibiting dopa decarboxylase but it does not cross the blood–brain barrier. Carbidopa is generally combined with levodopa in a fixed proportion (1:10 or 1:4) as carbidopa/levodopa.
The most common early side effects include hallucinations, confusion, agitation, dizziness, hypotension, somnolence, and nausea. Involuntary movements (eg, dyskinesia, dystonia) typically occur after 5–10 years of therapy in nearly 50% of patients taking levodopa/carbidopa
Another late complication of levodopa therapy or consequence of advancing disease is response fluctuation such as the wearing-off effect, in which deterioration occurs shortly before the next dose is to be taken, or the on–off phenomenon, in which abrupt but transient fluctuations in the severity of parkinsonism occur at frequent intervals during the day, apparently without any relationship to the last dose of levodopa.
Dopamine Agonists: Ergot derivatives such as bromocriptine, which stimulates dopamine D2 receptors. It is perhaps slightly less effective than levodopa in relieving the symptoms of parkinsonism but is less likely to cause dyskinesias.
Catechol-O-Methyltransferase Inhibitors may be used to reduce the dose requirements of and any response fluctuations to levodopa. Their use leads to more sustained plasma levels of levodopa, with improved transport into the blood and across the blood–brain barrier. Tolcapone, entacapone.
Monoamine Oxidase Inhibitors Selegiline, an irreversible monoamine oxidase type B (MAO-B) inhibitor, inhibits the metabolic breakdown of dopamine.
The most likely diagnosis in a younger (<50 years of age) patient with a symmetric action/postural movement disorder. Approximately one-half of all cases of ET appear to occur because of an autosomal dominant genetic mutation.
Hx: The tremor typically involves one or both hands, the head, the voice, or some combination of these, but the legs tend to be spared.
Dx: Positron emission tomography (PET) scanning shows that certain parts of the brain—including the thalamus—have increased activity.
Tx: Lifestyle changes, such as getting enough sleep and reduction of caffeine, can be helpful. Essential tremor characteristically improves with alcohol intake, and patients with essential tremor are at increased risk of alcohol misuse because of this.
Rx: If lifestyle modifications do not adequately control essential tremor symptoms, medications, including β-blockers (such as propranolol) 40 to 160 mg orally twice daily and anticonvulsants (such as primidone), are usually effective.
This group of disorders is characterized by parkinsonism plus clinical evidence of more widespread disease from degeneration in other neuronal systems. Depending on the disorder, they are either synucleinopathies or tauopathies.
They typically respond poorly to dopaminergic medication and have a poorer prognosis than Parkinson disease. These disorders include diffuse Lewy body disease, multisystem atrophy, progressive supranuclear palsy, and corticobasal
Multiple system atrophy (Shy-Drager syndrome) is a progressive neurodegenerative disorder (a synucleinopathy) with multisystem motor abnormalities and often a dysautonomia. It is more common in men and occurs usually in the sixth decade. It consists of:
- Autonomic dysfunction (postural hypotension, abnormal sweating, disturbance of bowel or bladder control, abnormal salivation or lacrimation, impotence, gastroparesis, etc.)
- Widespread neurological signs (cerebellar, pyramidal or lower motor neuron)
Hx: When autonomic insufficiency is a conspicuous accompaniment, the ponymous designation of Shy-Drager syndrome is sometimes used. This latter syndrome is characterized by parkinsonian features, autonomic insufficiency (leading to postural hypotension, anhidrosis, disturbance of sphincter control, impotence, and signs of more widespread neurologic involvement (pyramidal or lower motor neuron signs and often a cerebellar deficit). The autonomic and multisystem—often symmetric— motor findings with marked anterocollis distinguish the disorder from classic Parkinson disease.
Dx: MRI reveals a hypointense putamen with a hyperintense rim.
The disease follows a progressive course leading to death over about 8 to 10 years.
Lewy body Disease
Characterized by parkinsonism that is responsive to dopaminergic therapy, visual hallucinations, and/or fluctuating cognition. The characteristic cognitive profile of dementia in patients with dementia with Lewy bodies includes impaired learning and attention, psychomotor slowing, constructional apraxia, and more profound visuospatial impairment but less memory impairment than in similarly staged patients with Alzheimer disease.
Dx: Intraneuronal Lewy body inclusions in the cerebral cortex.
Tx: Management of Lewy body disease is difficult because levodopa induces hallucinations and exacerbates the cognitive and behavioral disturbances while providing only limited benefit to the motor disturbance. Anticholinergic drugs are best avoided because they also may exacerbate cognitive dysfunction. The dementia and behavioral abnormalities often respond favorably to cholinesterase inhibitors.
Progressive supranuclear palsy
Progressive supranuclear palsy is an idiopathic, usually sporadic, degenerative disorder, a tauopathy that primarily affects subcortical gray matter regions of the brain. There is much overlap clinically and pathologically with corticobasal degeneration. The principal neuropathologic finding is neuronal degeneration with the presence of neurofibrillary tangles in the midbrain, pons, basal ganglia, and dentate nuclei of the cerebellum.
Hx: The classic clinical features are gait disturbance with early falls, supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia
with or without extrapyramidal rigidity of the limbs, and dementia.
Supranuclear ophthalmoplegia is characterized by prominent failure of voluntary vertical gaze, with later paralysis of horizontal gaze; oculocephalic and oculovestibular reflexes are preserved. Vertical saccades may initially be slowed.
Parkinson disease differs from the classic form of progressive supranuclear palsy in that voluntary downward and horizontal gaze are not usually lost, axial posture tends to be characterized by flexion rather than extension, tremor is common, the course is less fulminant, and antiparkinsonian medications are more often effective.
It sometimes simulates Parkinson disease when bradykinesia and rigidity are conspicuous features. Postural-action tremor may also occur, but the usual cause of profound disability is limb apraxia (often leads to a useless limb) and clumsiness rather than extrapyramidal deficits. Other clinical features include speech disturbances (aphasic, apraxic, or dysarthric), acalculia, cortical sensory deficits (eg, neglect syndromes), stimulus-sensitive myoclonus, alien limb phenomenon (the tendency for a limb to move semipurposefully, involuntarily, and without the knowledge of its owner), dysphagia, postural disturbances, dystonic features, and ultimately cognitive decline and behavioral changes.
The disorder follows a progressive course, leading to increasing disability and dependence. Death typically follows within 10 years, often sooner, from aspiration pneumonia.
Huntington disease is a hereditary, progressive neurodegenerative disorder of the nervous system characterized by the gradual onset and subsequent progression of chorea and dementia.
Characterized by increasingly severe motor impairment, cognitive decline, and psychiatric symptoms. In addition to chorea, other motor symptoms include ataxia, dystonia, slurred speech, impaired swallowing, and myoclonus. Various psychiatric symptoms, such as dysphoria, agitation, irritability, anxiety, apathy, disinhibition, delusions, and hallucinations, commonly occur.
Deficits in sustained attention, memory retrieval, procedural memory (ability to acquire new skills), and visuospatial skills are predominant and early manifestations of the disorder. Language skills are usually preserved until the late stages of the disease. Personality changes and mood disturbances, including depression and mania, are frequent and can predate the onset of the dementia and the movement disorder.
Dx: CT scanning or MRI often demonstrates atrophy of the cerebral cortex and caudate nucleus in established cases. Reduction in striatal metabolic rate may be demonstrated
Tx: Dopamine blocking and depleting agents are effective in decreasing the involuntary movements of HD. Haloperidol is a dopamine receptor blocker and is commonly used for control of chorea in HD. Other neuroleptics, such as olanzapine, risperidone, and aripiprazole, are also effective in treating the chorea symptoms of HD.
Syndenham Chorea and PANDAS
Sydenham chorea occurs principally in children and adolescents as a complication of a previous group A hemolytic streptococcal infection.
Sydenham chorea is characterized by abnormal choreiform movements that are sometimes unilateral and, when mild, may be mistaken for restlessness or fidgetiness.
Tx: The traditional treatment is bed rest, sedation, and prophylactic antibiotic therapy even if there are no other signs of acute rheumatism. A course of intramuscular penicillin is generally recommended, and continuous prophylactic oral penicillin daily or intramuscular benzathine penicillin G monthly until approximately age 20 years is also frequently advised to prevent streptococcal infections.
PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) is the acronym used to refer to the association of obsessive compulsive
or tic disorders of variable severity with streptococcal infections in children.
This prion disease may be accompanied by parkinsonian features, but dementia is usually present, myoclonic jerks are common, and ataxia is sometimes prominent; there may be pyramidal or cerebellar signs and visual disturbances, and the EEG findings of periodic discharges are usually characteristic.
Normal Pressure Hydrocephalus
This condition leads to a gait disturbance, urinary incontinence, and dementia. CT scanning reveals dilation of the ventricular system of the brain without cortical atrophy. The disorder may follow head injury, intracranial hemorrhage, or meningoencephalitis, but the cause is often obscure. Surgical shunting procedures to bypass any obstruction to the flow of cerebrospinal fluid (CSF) are often beneficial.
Drug-Induced Movement Disorders
Parkinsonism frequently complicates treatment with dopamine- agents such as reserpine or dopaminereceptor antagonists such as phenothiazines or butyrophenones.
Acute dystonia or dyskinesia (such as blepharospasm, torticollis, or facial grimacing) is an occasional complication of dopamine receptor antagonist treatment, generally occurring within 1 week after introduction of such medication and often within 48 hours.
Akathisia is a state of motor restlessness characterized by an inability to sit or stand still, which is relieved by moving about.
Tardive dyskinesia may develop after long-term treatment with antipsychotic dopamine receptor antagonist drugs or with metoclopramide.
Toxin (manganese, MPTP, mercury, methanol, ethanol, or carbon monoxide)
Acquired hepatocerebral degeneration produces a neurologic disorder associated with extrapyramidal, cerebellar, and pyramidal signs as well as dementia. Extrapyramidal signs include rigidity, rest tremor, chorea, athetosis, and dystonia.
History; MRI showing stroke
Boxers and those in certain other contact sports, such as football, may develop a syndrome of dementia (dementia pugilistica), behavioral and psychiatric disturbances, parkinsonism, and pyramidal and cerebellar deficits from recurrent head trauma leading to a chronic traumatic encephalopathy. There is no satisfactory treatment.
Rapidly progressive; signs/symptoms of ataxia, encephalopathy, myoclonus
Rare; resolves with treatment
Ddx: Hereditary Disorders associated with PD:
Wilson's disease is a rare, autosomal recessive disease of younger individuals that is characterized by abnormal copper deposition in tissues such as the liver, basal ganglia, and cornea. Children and adolescents tend to present with liver disease (ranging from asymptomatic aminotransferase elevations to fulminant hepatic failure), while young adults tend to demonstrate neuropsychiatric disease (ranging widely from tremor and rigidity to depression, paranoia, and catatonia).
Dx: Classically, the diagnosis of Wilson's disease is confirmed by the presence of low serum ceruloplasmin (particularly <20 mg/dL) in conjunction with increased urinary copper excretion or Kayser-Fleischer rings. Therefore, evaluation should include measurement of serum ceruloplasmin levels and slit lamp examination of the eyes.
Cognitive/behavioral change; extremity weakness, atrophy; rigidity, bradykinesia
Autosomal dominant; begins in early life; ataxia predominates
Fragile X-associated tremor/ataxia syndrome
Ataxia, tremor, dementia