Parkinsonism-Plus Syndromes

Parkinsonism-Plus Syndromes Fifteen–Twenty High-Yield Points Definition and approach

Parkinsonism-plus (atypical parkinsonian) syndromes are neurodegenerative diseases in which an extrapyramidal syndrome is accompanied by additional features not seen in idiopathic PD, and in which the response to levodopa is poor or absent.

The general red flags for atypical parkinsonism are: early falls and postural instability, early severe autonomic failure, early dementia, supranuclear gaze palsy, cerebellar or pyramidal signs, symmetrical onset, absence of rest tremor, and rapid progression. Most of these appear in the exclusion criteria of the Queen Square Brain Bank criteria for PD.

Response to levodopa is assessed by giving 150–250 mg of levodopa with a decarboxylase inhibitor to a fasting patient and assessing tremor, rigidity and limb akinesia every 30 minutes for two to three hours. A negative response to large doses of levodopa (malabsorption excluded) is an exclusion criterion for PD.

PSP is frequently misdiagnosed as PD. It is a 4-repeat tauopathy characterised by an extrapyramidal syndrome with complex eye movement dysfunction.

Tremor is infrequent and rigidity predominates in the spine (axial rigidity), with neck dystonia (retrocollis).

Postural and gait abnormalities occur early and cause repeated falls, aggravated by attentional and visual problems. Falls within the first year are a classic examination point.

Eye movement problems: inability to shift gaze voluntarily downward, impaired (slowed) saccades, and difficulty controlling the eyelids (apraxia of lid opening, blepharospasm). Limitation of vertical gaze is the cardinal sign.

Motor symptoms are unresponsive to levodopa. As the disease progresses, personality change, dementia and swallowing problems are common.

MRI shows midbrain atrophy, and ocular electrophysiology (impaired saccades) also helps recognise the disease.

MSA is very rarely observed as very late-onset parkinsonism. It is an α-synucleinopathy with glial cytoplasmic inclusions.

The defining feature is severe dysautonomia early in the course of parkinsonism — orthostatic hypotension, urinary disorder, sexual dysfunction and gastrointestinal symptoms.

Pyramidal or cerebellar signs accompany the parkinsonism. Subtypes are MSA-P (parkinsonian predominant) and MSA-C (cerebellar predominant, with dysmetria, scanning speech, saccadic abnormalities and truncal ataxia).

Corticobasal degeneration: dystonia, myoclonus, cortical sensory loss and alien (foreign) hand syndrome, typically markedly asymmetrical.

Dementia with Lewy bodies: dementia occurring a few months before or after the onset of parkinsonism, with visual hallucinations, fluctuating alertness and severe adverse reactions to neuroleptics. By contrast, PD dementia occurs in advanced stages after several years of PD.

Drug-induced parkinsonism: exposure to neuroleptics (present or past) must be sought carefully by interviewing patients, proxies, physicians and pharmacists. It is symmetrical, tremor-poor, and loflurane SPECT is normal. Neuroleptic treatment at onset of symptoms is a Queen Square exclusion criterion.

Vascular (cerebrovascular) parkinsonism: multiple infarcts, usually a multilacunar state, with subcortical dementia and pseudobulbar state; posture, gait and swallowing problems are prominent, tremor is infrequent and levodopa response is poor. Onset or worsening of extrapyramidal signs within one month of a stroke strongly supports the diagnosis. MRI shows multiple lacunae and/or severe leukoaraiosis.

Normal pressure hydrocephalus: gait disturbance, dementia and urinary incontinence, with short shuffling steps but no tremor or rigidity; imaging shows marked ventricular enlargement out of proportion to cortical atrophy.

Other rarer causes: Huntington's disease (chorea, familial), Wilson's disease (liver disease, Kayser-Fleischer ring, psychiatric symptoms), and toxic, post-encephalitic and repeated head trauma-related parkinsonism.

About 15% of patients with Alzheimer's disease develop extrapyramidal signs; these are usually mild, and their presence at diagnosis predicts more rapid decline. Loflurane SPECT is normal in AD and abnormal in DLB, which is the key discriminator.

Management is largely supportive: a levodopa trial is still justified (a minority of MSA and PSP patients show partial benefit), with physiotherapy, speech and swallow therapy, falls prevention, treatment of orthostatic hypotension, and early advance care planning. Prognosis is substantially worse than PD, with median survival of about 6–9 years.