Movement disorders: Parkinson's disease dominates

Abstract

We did a 5 year follow-up study of 49 patients who had a mean age of 55 at the time of surgery, no dementia or major ongoing psychiatric illness, and severe levodopa-related motor complications. The benefit on levodopa-responsive motor features during off periods was sustained and dyskinesias were substantially decreased—partly because the dose of dopaminergic drugs was reduced by 59% throughout the study. Tolerance to stimulation did not develop. However, symptoms that do not normally respond to levodopa (eg, dysarthria, postural instability, and freezing of gait) gradually worsened. Cognitive function was stable during the first 3 years; between the third and the fifth year, three patients became demented. Therefore, subthalamic nucleus stimulation provides a sustained benefit on the motor complications of chronic levodopa therapy but does not stop disease progression. With time, many symptoms of PD become non-responsive to therapy with both levodopa and stimulation, probably in relation to the development of mainly non-dopaminergic cerebral lesions. Therapy for nigrostriatal dopamine deficiency does not treat many features that may be just as disabling as the dopamine-responsive symptoms. Braak and colleagues 2 studied the cerebral distribution of α -synucleinimmunopositve Lewy bodies or neurites, the pathological hallmark of PD. They compared the brains of patients with clinically diagnosed of PD with those of healthy people. The authors confirmed that PD is caused by progressive, multisystem neurodegeneration with a predictable sequence. Lesions first occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus; the lesions then ascend from the medulla oblongata to the midbrain (in particular the pars compacta of the substantia nigra). Cortical involvement follows, beginning with anteromedial temporal mesocortex then a few areas of the neocortex. These findings explain non-motor and levodopa-resistant symptoms and why cognitive impairment occurs late in PD whereas defects in smell and dysautonomia can be detected even at a presymptomatic phase. Glial-cell-derived neurotrophic factor (GDNF), has protective and restorative effects on midbrain dopaminergic neurons in non-human-primate models of Parkinson’s disease. Intraventricular bolus injections of GDNF in 50 patients with PD were not effective because insufficient quantities of GDNF diffused through the ventricular wall and reached the dopaminergic nigrostriatal targets. Gill and coworkers reported on the direct delivery of GDNF into the putamen—the brain area with the most severe dopamine depletion—in five patients with PD. The effects on parkinsonism, openly assessed, were highly beneficial. After 1 year, there was a 39% improvement in the off-treatment motor score and a 61% improvemnt in the activity of daily living score of the unified PD rating scale. Drug-induced dyskinesias were reduced by 64%. Fluorine-18-labelled dopamine uptake was increased in the putamen, which suggests a direct effect of GDNF on dopamine function. This study needs to be confirmed in controlled trials. New ways to release GDNF in the brain are needed to avoid complications related to the implants and the periodic refilling of the pump. The discovery of five genes since 1997 has provided important insight into the pathogenesis of PD. The ubiquitine proteasome system is integral to protein handling and detoxification. Mutations of parkin (PARK2), the most common cause of early onset PD, UCHL1 (PARK5), and the recently discovered DJ-1 (PARK7) 4 lead to a dysfunction of this system, which may contribute to the accumulation and aggregation of the α -synuclein protein (PARK1). However, the pathogenetic network seems complex because DJ-1 is thought to be an antioxidant, and mutations in NR4A2 affect another signalling pathway. In non-familial PD, genes and environment probably interact to give rise to the disease. In clinical practice, these discoveries provide great hope for the discovery of neuroprotective treatments. Hayflick and colleagues 5 looked for pantothenate kinase 2 mutations in patients with classic or atypical autosomal recessive Hallervorden–Spatz syndrome. The classic form presents with dystonia, dysarthria, and rigidity, begins in childhood, and has a rapid progression that culminates in early death. Pigmentary retinopathy is common and iron deposition in the medial globus pallidus is evident on T2weighted MRI (the so called “eye-of-the-tiger” sign). The atypical form of the syndrome has a late onset and slow progression. Mutations in the pantothenate kinase gene were found in all 49 families with the classic form, and 17 of 49 families with atypical disease. All patients with the mutation and none without had the “eye-of-the-tiger” sign. Hayflick and colleagues suggested that the name of the syndrome should be changed—given these findings and the unethical activities of the two German neuropathologists during World War II—and propose “pantothenate kinaseassociated neurodegeneration” (PKAN) for disease caused by the mutation and “neurodegeneration with brain iron accumulation” for the remainder. They also speculated that pantothenate (vitamin B5) could ameliorate symptoms.