Parkinsonism In Young Adults

The Parkinson's-Reversing Breakthrough

Parkinson Disease Treaments

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The onset of parkinsonism under the age of 40 is usually called young onset parkinsonism. When symptoms begin under the age of 20, the term "juvenile parkinsonism" is sometimes used (111). Under the age of 20, parkinsonism typically occurs as a component of a more widespread degenerative disorder. However, parkin mutations have been described in some young patients (2).

Dopa Responsive Dystonia

There is a significant overlap in young patients with dystonia and parkinsonism. Patients with young onset parkinsonism manifest dystonia that may be responsive to dopaminergic drugs (112). However, the response may deteriorate upon long-term fol-lowup. Patients with hereditary dopa responsive dystonia have an excellent and sustained response to low doses of levodopa (113). In addition, PET scans show markedly reduced 6-fluorodopa uptake in patients with young onset PD, whereas the fluo-rodopa uptake is normal in patients with dopa responsive dystonia (114). Patients with dopa responsive dystonia have a guanosine triphosphate-cyclohydrolase deficiency that is not a feature of PD in young adults.

Wilson's Disease

Wilson's disease usually presents primarily with neuropsychiatric impairment. It should be considered in every case of young onset parkinsonism, because it is eminently treatable and the consequences of nonrecognition can be grievous. The most common neurological manifestations are tremor, dystonia, rigidity, dysarthria, drooling, and ataxia. A combination of parkinsonism and ataxia is particularly indicative of neurological Wilson's disease (115). Parkinsonism is the most prevalent motor dysfunction, whereas about 25% of patients present with disabling cerebellar ataxia, tremor, or dysarthria (116). Typically, the tremor involves the upper limbs and the head and rarely the lower limbs. It can be present at rest with postural maintenance and may persist with voluntary movements. The classic tremor is coarse and irregular and present during action. Holding the arms forward and flexed horizontally can emphasize that the proximal muscles are active (wing-beating tremor). Less commonly, tremor may affect just the tongue and the orofacial area (117). Dystonia is also quite common in Wilson's disease. The characteristic feature is an empty smile due to facial dystonia. Dysarthria is very common and may take the form of a dystonic or scanning dysarthria. Approximately 30% of patients present with behavioral and mental status changes (118). The psychiatric disorder may take the form of paranoid symptoms, sometimes accompanied by delusional thinking and hallucinations.

Early presentation may be a decline in memory and school performance. Patients may develop anxiety, moodiness, disinhibited behavior, and loss of insight. A characteristic feature is inappropriate laughter. Although eye movements are typically normal, some cases of Wilson's disease may show a saccadic pursuit, gaze distractibility, or difficulty in fixation (119).

Kayser-Fleischer rings (KF rings) due to copper deposition in the cornea may be easy to recognize in patients with a light colored iris; however, in patients with brown irides, these rings may be very difficult to see. Usually, the ring is golden-brown in color and involves the whole circumference of the cornea. However, in the early stages, the ring may be more apparent in the upper than the lower pole. Rarely, these rings can be unilateral. KF rings are best appreciated by a slit-lamp examination done by a neurophthalmologist. Typically, the absence of KF rings on the slit-lamp examination rules out neurological Wilson's disease. However, there are reports of patients with typical neurological Wilson's disease without any KF rings (120,121).

Radiologically, advanced cases of Wilson's disease may have cavitation of the putamen (122). However, putaminal lesions are not specific to Wilson's disease. Other causes of putaminal cavitation or lesions include hypoxic ischemic damage, methanol poisoning, mitochondrial encephalomyopathy, and wasp-sting encephalopathy. Nearly half the patients of established neurological Wilson's disease have hypoden-sities of the putamina on CT scans in contrast to patients with hepatic disease who frequently have normal CT scans (123). MRI is more sensitive, and almost all patients with neurological features have some disturbance on T2-weighted images in the basal ganglia with a pattern of symmetric, bilateral, concentric-laminar T2 hyperin-tensity and the involvement of the pars compacta of the substantia nigra, periaque-ductal gray matter, pontine tegmentum, and thalamus (124). The hepatic component of Wilson's disease may cause increased T1 signal intensity in the globus pallidus (125). In the adult age group, the basal ganglia lesions may be different from those in the pediatric group. Putaminal lesions may not be present, and the globus pal-lidus and substantia nigra may show increased hypointensity on T2-weighted images. Cortical and subcortical lesions may also be present with a predilection to the frontal lobe. However, rare cases of neurological Wilson's disease may have a normal MRI (126). PET scans of Wilson's disease may show a reduction of 6-fluorodopa uptake (127).

The most useful diagnostic test is serum ceruloplasmin, and a 24-hour urinary copper excretion supplemented by a slit-lamp examination for KF rings. Unfortunately, not all patients with Wilson's disease have a low ceruloplasmin level (128). Measurement of liver copper concentration makes a definitive diagnosis. In heterozygotes, it is between 50 and 100 |g/g of tissue, and in patients with Wilson's disease, it may be over 200 |g/g (129).

Pantothenate Kinase-Associated Neurodegeneration (Hallervorden-Spatz Disease)

Previously known as Hallervorden-Spatz Disease (HSD), pantothenate kinase-associated neurodegeneration is usually a disease of children but young adults may be affected. Typically, the disease occurs before the age of 20. Facial dystonia tends to be prominent, coupled with gait difficulty and postural instability. Patients may have night blindness progressing to visual loss secondary to retinitis pigmentosa. Other extrapyramidal signs include choreoathetosis and a tremor that has been poorly characterized. Cognitive problems include impairment of frontal tasks and memory disturbances, and psychiatric manifestations have been reported. CT scans are often normal; however, low-density lesions have been described in the globus pallidus. MRI, especially using a high field strength magnet, shows decreased signal intensity in the globus pallidus with a central hyperintensity. This has been called the "eye of the tiger sign" (130). Genetic testing for PANK 2 mutation is now commercially available and may be performed in doubtful cases (131).

Juvenile Huntington's Disease

This autosomal dominant neurodegenerative disorder typically presents with chorea, difficulty with gait, and cognitive problems. However, the "Westphal variant" of the disease affecting the young may manifest bradykinesia, tremulousness, myoclonic jerks and, occasionally, seizures and cognitive disturbances (132). Eye movement abnormalities including apraxia can be remarkable. When coupled with a lack of family history, these young patients may be confused with young onset PD; however, neuroimaging and genetic testing should easily distinguish the two.

Hemiparkinsonism Hemiatrophy Syndrome

These patients have a long-standing hemiatrophy of the body and develop a progressive bradykinesia and dystonic movements around the age of 40 (133). Ipsilateral corticospinal tract signs may be found, which are not a feature of PD. Neuroimaging reveals brain asymmetry with atrophy of the contralateral hemisphere with compensatory ventricular dilatation. Regional cerebral metabolic rates are diminished in the hemisphere contralateral to the clinical hemiatrophy in the putamen and the medial frontal cortex, whereas in PD the regional cerebral metabolic rates are normal or increased contralateral to the clinically affected side (134).

X-linked Dystonia Parkinsonism (Lubag)

This inherited disorder usually occurs in the Philippines. However, rare cases are seen in other parts of the world (135). Typical age of presentation is around the age of 30 to 40 years. Focal dystonia or tremor is the initial finding followed by other parkinsonian features. Rarely, parkinsonian features may precede dystonia. Clinically, this disorder is differentiated from idiopathic PD by the presence of marked dystonia and the pattern of inheritance.

Neuroacanthocytosis

This is a rare cause of parkinsonism and typically presents with a hyperkinetic movement disorder, including chorea, tic-like features, and polyneuropathy. MRI shows a characteristic atrophy of the caudate and a hyperintensity in the putamen on T2-weighted images and acanthocytes are revealed on a fresh blood smear (136).

DIAGNOSTIC CRITERIA FOR PARKINSON'S DISEASE

From the preceding discussion, it is obvious that there are a large number of disorders that can be confused with PD. In an effort to improve diagnostic accuracy, several sets of clinical diagnostic criteria for PD have been proposed (137-141). Table 7 lists the United Kingdom Parkinson's Disease Society Brain Bank clinical diagnostic criteria.

TABLE 7 United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria

Inclusion criteria

Exclusion criteria

Supportive criteria

Bradykinesia (slowness of

—History of repeated

(Three or more required for

initiation of voluntary

strokes with stepwise

diagnosis of definite PD)

movement with progressive

progression of

—Unilateral onset

reduction in speed and

parkinsonian features

—Rest tremor present

amplitude of repetitive

—History of repeated head

—Progressive disorder

actions) and at least

injury

—Persistent asymmetry

one of the following:

—History of definite

affecting side of onset

■ muscular rigidity

encephalitis

most

■ 4-6 Hz rest tremor

—Oculogyric crises

—Excellent response

■ postural instability

—Neuroleptic treatment at

(70-100%) to levodopa

not caused by primary

onset of symptoms

—Severe levodopa-

visual, vestibular,

—More than one affected

induced chorea

cerebellar, or

relative

—Levodopa response

proprioceptive

—Sustained remission

for 5 yr or more

dysfunction

—Strictly unilateral features

—Clinical course of 10 yr

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