The Parkinson's-Reversing Breakthrough

Parkinson Disease Guide

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Acute onset

Vascular parkinsonism, toxin-induced, psychogenic

Stepwise deterioration

Vascular parkinsonism

Abbreviations: CBD, cortiobasal degeneration; CJD, Creutzfeld-Jakob disease; DLB, dementia with Lewy bodies; MSA, multiple system atrophy; OPCA, olivopontocerebellar atrophy; PSG, progressive subcortical gliosis; PSP, progressive supranuclear palsy; SND, striatonigral degeneration.

Abbreviations: CBD, cortiobasal degeneration; CJD, Creutzfeld-Jakob disease; DLB, dementia with Lewy bodies; MSA, multiple system atrophy; OPCA, olivopontocerebellar atrophy; PSG, progressive subcortical gliosis; PSP, progressive supranuclear palsy; SND, striatonigral degeneration.

TABLE 3 Differentiating Essential Tremor from Parkinson's Disease

Essential tremor

Parkinson's disease

Body parts

Arms > Head > Voice > Legs Arms > Jaw > Legs

Rest tremor

Postural tremor

Kinetic tremor




Family history

Response to beta blockers

Response to levodopa

Postural instability

7-12 Hz

are at an increased risk to develop PD (9). Psychomotor slowing in a severely depressed individual may resemble PD but there is no tremor and patients improve with antidepressant therapy.


Drug-induced parkinsonism is a common complication of antipsychotic drug use with a reported prevalence of 15% to 60% (10). In one study, 51% of 95 patients referred for evaluation to a geriatric medicine service had neuroleptic-induced parkinsonism (11). Frequently, these patients are misdiagnosed as PD and treated with dopaminergic drugs without any benefit. In a community study, 18% of all cases initially thought to be PD were subsequently diagnosed as drug-induced parkinsonism (12).

The symptoms of drug-induced parkinsonism may be indistinguishable from PD. Drug-induced parkinsonism is often described as symmetrical whereas PD is often asymmetrical. However, one series found asymmetry of signs and symptoms in 30% of drug-induced patients (13). Patients with drug-induced parkinsonism are as varied in their clinical manifestations as patients with PD. Some patients have predominant bradykinesia, whereas others are tremor predominant. Postural reflexes may be impaired, festination is uncommon, and freezing is rare (13,14).

When the patient is on a dopamine-blocking agent, it is difficult to distinguish underlying PD from drug-induced parkinsonism. If possible, the typical dopamine-blocking agents should be stopped or substituted with atypical antipsychotics and the symptoms and signs of parkinsonism should resolve within a few weeks to a few months, but it could take up to six months or more for signs and symptoms to resolve completely (15). Cerebrospinal fluid (CSF) dopamine metabolites have been studied in drug-induced parkinsonism. These may be low in untreated PD but are relatively normal or increased in drug-induced parkinsonism. However, the Deprenyl and Tocopherol Antioxidative Therapy of Parkinson's Disease (DATATOP) cohort CSF study showed that there is a significant overlap between PD and normals, making this test of doubtful clinical value (16). One study utilizing 6-flurodopa positron emission tomography (PET) scanning showed that a normal PET scan predicted good recovery from drug-induced parkinsonism upon cessation of the dopamine-blocking

TABLE 4 Drugs Known to Cause Parkinsonism

Generic Name










Triflupromazine hydrochloride


Carphenazine maleate


Acetophenazine maleate






Butaperazine maleate

Repoise maleate



Molindone hydrochloride




Trifluoperazine hydrochloride




Fluphenazine hydrochloride

Prolixin, 5mg




Loxitane, Daxolin

















Combination drugs

Etrafon, Triavil

aIn high dosages.

agent and an abnormal PET scan was associated with persistence of signs in some but not in all patients (17).

Drug-induced parkinsonism should be considered and inquiry should be made about intake of antipsychotic drugs and other dopamine-blocking agents like metoclopramide (Table 4). Once drug-induced parkinsonism has been considered and ruled out, the most common conditions confused with PD include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and frontotemporal dementia (FTD) with parkinsonism. Together these entities are referred to as atypical forms of parkinsonism.

Progressive Supranuclear Palsy

PSP also known as Steele Richardson Olszewski syndrome is easy to diagnose in advanced stages (18). However, diagnostic confusion may occur early in the disease and in cases that have atypical features. Typically, the disorder presents with a gait disturbance with resultant falls in over half the cases (19). Measurable bradykinesia in the upper extremity may not be present at the initial presentation. The clinical features of PSP consist of supranuclear gaze palsy, especially involving the downgaze with nuchal extension and predominant truncal extensor rigidity. Varying degrees of bradykinesia, dysphagia, personality changes, and other behavioral disturbances coexist. Patients often exhibit a motor recklessness and get up abruptly out of a chair (Rocket sign) even if this results in a fall. Another sign is the "applause sign" where the patient is unable to stop clapping after given directions to clap the hands three times (20).

Extraocular movement (EOM) abnormalities are very characteristic but may not be present at the onset of the illness or for several years (21). These abnormalities consist of square wave jerks, instability of fixation, slow or hypometric saccades, and predominantly a downgaze abnormality (22,23). Asking the patient to generate a saccade in the direction opposite to a stimulus (antisaccade test) is frequently abnormal in PSP (23). The oculocephalic responses are present in early disease, but may be lost with advancing disease suggesting a nuclear element to the gaze palsy. Bell's phenomenon may be lost in advanced cases. Some patients with PSP have a limb dystonia that can be asymmetric, which can cause confusion with CBD (24). Rest tremor is rare but has been reported in pathologically confirmed PSP (25).

Radiologically, PSP differs from PD in that in advanced cases there is atrophy of the midbrain tectum and tegmentum with resultant diminution of the anteropos-terior (AP) diameter of the midbrain (26,27). There may be dilatation of the third ventricle and sometimes a signal alteration may be seen in the tegmentum of the midbrain (28). PET scanning utilizing 6-flurodopa may distinguish PSP from PD in that the uptake is diminished equally in both the caudate and putamen in PSP, whereas in PD the abnormalities are largely confined to the putamen (29). PET scans using raclo-pride binding show that the T2 receptor sites are diminished in PSP, whereas in PD, these are normal (30).

Clinically, CBD, DLB, MSA, progressive subcortical gliosis (PSG), and even prion diseases have been misdiagnosed as PSP because of the presence of supranu-clear gaze palsies (31-34). PSP also needs to be distinguished from other causes of supranuclear gaze palsy, including cerebral Whipple's disease, adult onset Niemann-Pick type C, and multiple cerebral infarcts (35-37). The presence of prominent early cerebellar symptoms or early, unexplained dysautonomia would favor MSA over PSP (38), and the presence of alien limb syndrome, cortical sensory deficits, and focal cortical atrophy on magnetic resonance imaging (MRI) would favor CBD (39). The clinical diagnostic criteria proposed by Litvan et al. (40,41) may be helpful.

Multiple System Atrophy

MSA, originally coined by Graham and Oppenheimer (42), refers to a variable combination of parkinsonism, autonomic, pyramidal, or cerebellar symptoms and signs. MSA can be subdivided into three types: striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome (SDS) (43). All subtypes of MSA may have parkinsonian features. It is especially difficult to differentiate SND and PD. SND was originally described by Van Eecken et al. (44). The parkinsonian features of MSA consist of progressive bradykinesia, rigidity, and postural instability (43). However, in a clinicopathological report, one of four patients had a rest tremor characteristic of PD (45). Although symptoms are usually bilateral, unilateral presentations have been described (46). The autonomic failure is more severe than that seen in idiopathic PD and occurs early in MSA. Other useful clinical clues for the diagnosis of MSA include disproportionate anterocollis and the presence of cold blue hands.

The response to levodopa is usually incomplete in MSA (47). However, patients with MSA may initially respond to levodopa, but the benefit usually declines within one or two years of treatment (48). Levodopa induced dyskinesia may occur in MSA.

Dyskinesia typically involves the face and neck but may also involve the extremities (49). Therefore, the presence of levodopa-induced dyskinesia cannot be used to make a definite diagnosis of PD. The situation is further complicated by the fact that PD patients may develop autonomic dysfunction, including postural hypotension, urinary problems, constipation, impotence, and sweating disturbances. The autonomic dysfunction in PD may be worsened by dopaminergic therapy. Autonomic dysfunction tends to be severe in MSA and occurs early (50). Stridor can also occur early in MSA but not in PD (51). Urinary symptoms are very common in MSA. On uro-dynamic testing, there is a combination of detrusor hyperreflexia and urethral sphincter weakness (52). In addition, neurogenic anal and urethral sphincter abnormalities are very common in MSA (53). However, this finding is not diagnostic and may occur in other conditions like PSP (54). Neuroimaging may show nonspecific abnormalities like diffuse hypointensity involving the putamen, but more specific findings include a strip of lateral putaminal hyperintensity or pontine atrophy with an abnormal cross sign in the pons (55). Cardiac autonomic innervation may be tested using 123I metaiodobenzylguanidine (MIBG) scintigraphy. There is growing evidence that the MIBG scintigraphy is abnormal in PD and DLB due to postsynaptic sympathetic denervation (56). In contrast, in MSA, the uptake in the heart is normal due to the presynaptic nature of the pathology. There is some overlap between normal individuals and patients with parkinsonism, which decreases the sensitivity and specificity of this technique.

Dementia with Lewy Bodies

In DLB, Lewy bodies are found in the neocortex as well as brainstem and dien-cephalic neurons (57). Some of these patients may have associated neurofibrillary tangles. The parkinsonian syndrome of DLB may be indistinguishable from PD. However, these patients have early onset dementia and may have hallucinations, delusions, and even psychosis in the absence of dopaminergic therapy (58,59). Another characteristic feature is wide fluctuations in cognitive status. It may be difficult to distinguish PD dementia (PDD) from DLB. As a rule, if the dementia precedes or appears within one year of motor symptoms, the diagnosis of DLB is made (57). Rarely, patients with DLB may develop supranuclear gaze palsy, resulting in confusion with PSP (31,32). Some patients respond partially and temporarily to dopaminergic therapy; however, occasionally the response to levodopa is robust.

Corticobasal Degeneration

Rebeiz et al. (60) initially described this disorder as corticodentatonigral degeneration with neuronal achromasia. CBD typically presents in the sixth or seventh decade with slowly progressive unilateral, tremulous, apraxic, and rigid upper limb (61). The disorder tends to be gradually progressive with progressive gait disturbances, cortical sensory loss, and stimulus sensitive myoclonus, resulting in a "jerky useless hand" (62-64). Jerky useless lower extremity is uncommon but may occur. Rarely, these patients may develop Babinski signs and supranuclear gaze palsy.

When typical, the clinical picture is distinct and easily recognizable. However, atypical cases may be confused with PSP and the myoclonic jerking may be confused with the rest tremor of PD. The gait disturbance typically consists of slightly wide based apraxic gait rather than the typical festinating gait of PD. Fixed limb dystonia

TABLE 5 Differential Diagnosis of Parkinson's Disease

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