Pφ

The central component of PD is the loss of the dopamine-secreting cells originating in the substantia nigra pars compacta. This causes a chain reaction throughout the basal ganglia that results in higher levels of inhibitory signals sent to the thalamus and motor cortex, thus slowing voluntary movement. There are also many nonmotor symptoms of PD, which are probably due to widespread neurodegeneration, suggesting involvement of neurotransmitters other than dopamine. They may include mood disorders, cognitive decline, orthostatic hypotension, speech difficulty, and dysphagia. Pathologically, the cells of the substantia nigra demonstrate Lewy bodies, which are intracellular collections of abnormal proteins, including α-synuclein (a membrane protein) and ubiquitin.

TP

PD usually presents unilaterally, with abnormal movements in one arm or hand or occasionally one leg. Frequently, tremor is the initial symptom, but not always. In non–tremor-predominant variants (i.e., akinetic-rigid syndromes), patients may notice rigidity and loss of dexterity in their hands before any tremor. Patients may recall a permanent loss of sense of smell, often beginning several years before the onset of motor symptoms. There may also be a history that sounds similar to REM behavior disorder (which involves acting out of dreams or even just talking in one’s sleep) and constipation.

Dx

Rule out secondary (drug-induced) parkinsonism by determining neuroleptic use. There are genetic tests available if the patient is uncommonly young or has an extensive PD family history. If there are atypical symptoms or an atypical pattern of symptom development (e.g., stepwise progression, gait and balance being affected first, cognitive decline appearing unusually early), an MRI can be performed to rule out vascular parkinsonism or perhaps some of the “parkinson plus” conditions (e.g., multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies). PET scans can be used to delineate decreased activity in the basal ganglia, but they are expensive and not completely reliable. Clinical assessment via thorough history and examination, possibly including a standardized rating scale, is the usual method of diagnosis and subsequent monitoring.

Pφ

MSA is characterized by the development of α-synuclein inclusions in glial cells of various regions of the brain, including substantia nigra pars compacta, locus ceruleus, putamen, inferior olive, pontine nuclei, cerebellar Purkinje cells, and intermediolateral columns. The degeneration may occur in different proportions, resulting in a spectrum of syndromes that vary based on the affected area. MSA-parkinsonism (MSA-P) involves mostly the degeneration of the striatonigral pathways. While it was originally thought that MSA affects presynaptic and postsynaptic dopaminergic neurons, patients with MSA-P may be responsive, at least in part, to levodopa therapy. MSA-cerebellar (MSA-C) mostly affects the olivocerebellar connections, with disproportionate involvement of the middle cerebellar peduncles. MSA-autonomic (MSA-A, also known as Shy-Drager syndrome) is characterized by the degeneration of the locus ceruleus, the dorsal motor nucleus of cranial nerve X, and the catecholamine-producing neurons of the ventrolateral medulla.

TP

Although there are three variants of MSA, a typical patient may have components of all of them. MSA-C shows disproportionate ataxia, MSA-P includes parkinsonism, and MSA-A is primarily characterized by autonomic dysfunction, which may include orthostatic hypotension and bladder dysfunction. The presence of symptoms from two of these categories suggests a diagnosis of MSA.

Dx

There is no definitive test for MSA, much as seen for PD. The diagnosis is clinical, and the probability of having MSA rises with an increased number of symptoms from an increased number of categories (autonomic dysfunction, parkinsonism, and cerebellar dysfunction).

Pφ

PSP is characterized by inclusion bodies similar to the neurofibrillary tangles of Alzheimer disease and composed of tau protein. Both neurons and glial cells are affected. Tufted astrocytes and globose tangles can be seen in the brainstem, particularly in the midbrain; the basal ganglia, particularly the subthalamic nucleus, substantia nigra, and globus pallidus; and in the cerebral cortex of the frontal lobes.

TP

PSP usually manifests with early gait impairment or balance problems associated with falls. Eye movement abnormalities (slow saccades, vertical gaze palsy) are typical but may present late in the course. In addition, dysarthria and dysphagia commonly occur in PSP, as well as some degree of cognitive impairment. The dementia of PSP (as with all parkinsonian disorders) tends to be a subcortical dementia with loss of frontal functions, which include judgment and executive decision making. Thus, there tends to be a “dysexecutive syndrome” with mild behavioral abnormality. This is unlike Alzheimer disease, which tends to affect primarily memory or visuospatial recognition. Some PSP patients may exhibit typical parkinsonism, though with a poor response to levodopa.

Dx

Similar to PD and MSA, there are no specific diagnostic tests for PSP, and the diagnosis is based on an accurate history and neurologic examination. Two primary variants of PSP have been distinguished. Richardson syndrome is the name given to “classic” PSP, which presents with postural instability, eye movement abnormalities, and dysphagia or cognitive dysfunction. PSP-parkinsonism presents with more typical PD symptoms (including tremor and limb rigidity), may be more responsive to levodopa therapy, and has a better prognosis overall. A specific rating scale has recently been created to support the diagnosis and clinical monitoring of PSP.

Brain MRI may show atrophy of midbrain, superior colliculi, superior cerebellar peduncle, and the region around the third ventricle. This results in enlargement of the third ventricle and the interpeduncular cistern. One may see the “penguin” or “hummingbird” sign on a midline sagittal cut, due to the abnormal thinning of the midbrain tegmentum. Detailed neuropsychological testing can help in establishing the severity of the cognitive dysfunction.

Pφ

The pathophysiology of ET is poorly understood, but it seems to be related to the involvement of cerebello-thalamo-cortical circuitry. Since ET runs in families, there seems to be a genetic predisposition, although no gene has as yet been identified. A number of environmental factors, including toxins, are also under investigation. Recent studies have suggested that ET might have a neurodegenerative component. ET might be a family of degenerative diseases rather than a single disease.

TP

Symptoms may be unilateral or bilateral, and usually manifest as a postural or an action tremor. That is, the shaking becomes more apparent when trying to perform an action, such as pouring a drink, bringing a cup to the mouth, or writing. There is little stiffness or postural instability, although severe tremor can affect walking and balance. There may be tremor in the head or in the voice.

Dx

The diagnosis is made on clinical grounds. About 50% of ET cases are familial, so having an affected family member aids in the diagnosis. Various tasks are performed to assess tremor severity. There are blood tests that can help to rule out other conditions that may present with tremor, such as hyperthyroidism. In addition, tremor improvement with alcohol intake strongly suggests a diagnosis of ET.

Pφ

Ischemic lesions of the basal ganglia may cause parkinsonian symptoms without pathologic degeneration of the dopaminergic cells. Significant atherosclerotic disease can lead to microvascular changes in the basal ganglia and in the corticospinal tracts. The attribution of the parkinsonism disorder to vascular lesions identified at imaging is often quite tricky, but a few anatomic and clinical observations have confirmed that vascular parkinsonism does exist.

TP

Most frequently, vascular parkinsonism presents as an “atypical” parkinsonian syndrome, with predominant gait disorder, little or no resting tremor, presence of associated neurologic signs, and lower sensitivity to levodopa. There may also be a more postural tremor.

Dx

Clinically, these patients are older, have more vascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, and smoking), and present with early gait abnormality. Brain MRI shows subcortical white-matter disease that can be extensive.

Pφ

There are numerous therapeutic agents that can block dopamine synapses. For example, antipsychotics such as haloperidol are powerful blockers of dopamine D2 receptors. An understandable side effect of these medicines is the development of parkinsonian symptoms, including tremor, rigidity, and slowness of movement.

TP

Neuroleptic-induced syndromes can develop acutely within hours or a few days, subacutely over several weeks, or after prolonged exposure to the dopamine blocker. When parkinsonism develops ≥6 months after exposure, the term “tardive” is used, implying a delayed onset. Drug-induced parkinsonism resembles idiopathic PD, with tremor, rigidity, and akinesia. Symptoms are usually (though not necessarily) bilateral and possibly reversible.

Dx

Diagnosis is suspected through the history. Patients with tardive parkinsonism normally have a psychiatric history and a known history of neuroleptics intake. It is important to consider that patients, particularly when hospitalized, are administered drugs, the purpose of which they may be unaware. For example, an elderly person developing parkinsonian symptoms after being discharged from the hospital may have received haloperidol for agitation. Some antiemetic medications also have antidopaminergic activity (e.g., metoclopramide). Symmetrical symptom progression is often an element of drug-induced parkinsonism.