Invasive Treatment Strategies in a Patient with PARK 15–Associated Parkinsonism

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Video. Segment 1: The 20-year-old PARK 15 patient in the OFF period, exhibiting severe generalized akinesia and anarthria. Segment 2: The 21-year-old PARK 15 patient under combined therapy with SC apomorphine infusions and GPi DBS, showing marked improvement of motor fluctuations.

Authors:  Sabine Spielberger, Klaus Seppi, Elisabeth Wolf, Wilhelm Eisner and Werner Poewe

Article first published online:   25 JUL 2015 | DOI: 10.1002/mdc3.12151


Mutations in the F-BOX only protein 7 (FBXO7) gene have been associated with the development of autosomal-recessive parkinson pyramidal disease (PPD).[1] Patients with PPD present with juvenile-onset parkinsonism and variable presence of pyramidal tract signs, ataxia, and dystonia (PARK 15). Parkinsonian symptoms usually show a good and sustained response to levodopa, but early development of drug-induced dyskinesias is common.[2] Though invasive therapies such as continuous dopaminergic drug infusions or DBS are standard treatments to control refractory l-dopa-related motor complications in patients with idiopathic Parkinson's disease (PD), there have been no reports on the efficacy and safety of such treatment strategies in symptomatic PARK 15 mutation carriers. We here report on a 21-year-old female PARK 15 patient who required a combination of continuous subcutaneous (SC) infusion of apomorphine and bilateral DBS of the globus pallidus internus (GPi) to control disabling motor fluctuations and dyskinesias.

 

At the age of 16, the patient first noticed clumsiness of her right hand and, within a few months, also developed an impairment of gait with severe postural instability. At age 17, the patient was diagnosed with juvenile PD and therapy with dopamine agonists was initiated, leading to a marked improvement of motor symptoms. After 1 year, adjunct levodopa was needed to maintain satisfactory motor control (l-dopa/carbidopa/entacapone 25/6.25/50 mg 7 times daily, ropinirole 10 mg/day). When the patient first presented to our movement disorders department at the age of 20, she exhibited predictable and unpredictable disabling motor fluctuations. During OFF periods, she showed marked generalized akinesia, was unable to walk without assistance, postural instability led to repetitive falls, and there was severe dystonic dysarthria with marked hypophonic and unintelligible speech. When ON mobility greatly improved and she could walk without assistance, her speech was dysarthric, but easily intelligible, but there were disabling dystonic dyskinesias involving her trunk, neck, and limbs. Dopamine transporter imaging with single-photon emission computed tomography revealed a near complete loss of striatal tracer binding bilaterally. Genetic testing confirmed a homozygeous mutation in the FBXO7 gene. Attempts to increase individual l-dopa doses beyond 50 mg were associated with disabling bouts of dyskinesias whereas frequent dosing of 50 mg every 2 hours was associated with insufficient control of parkinsonism and persistent response fluctuations. (see Video, Segment 1). Treatment with continuous SC infusion of apomorphine (3.1 mg/hour over 16 hours from 6 am to 10 pm) was initiated and led to marked reduction of daily OFF time from approximately 75% of the waking day (score of 4 in the International Parkinson and Movement Disorder Society [MDS]-UPDRS part IV, item 3) to <25% per day (score of 1 in the MDS-UPDRS part IV, item 3). Initially, apomorphine monotherapy was associated with only mild degrees of dyskinesia, but over 6 months there was progressive worsening of predominantly dystonic trunk and neck hyperextension and mixed dystonic and choreic limb movements (score of 4 in the MDS-UPDRS part IV, item 2). Because of the disabling nature of these dystonic ON-period dyskinesias, a DBS procedure targeting the GPi bilaterally was performed after 5 years of disease onset (age 21; electrode model 3387, pulse generator Activa RC; Medtronic, Minneapolis, MN). Electrode location in the posteroventrolateral GPi was confirmed by intraoperative CT. Because the DBS procedure was conducted under general anesthesia, no microelectrode recordings were performed.[3] Two days after surgery, stimulation settings were tested and activated (case +, 1-/2-, 9-/10-, 2.9 V, 60 μs, 130 Hz) and there was marked reduction in ON-period dystonic movements within a few days (score of 2 in the MDS-UPDRS part IV, item 2; see Video, Segment 2). Gait improved, such that the patient was able to walk independently for a few steps, but she still suffered from severe postural instability with recurrent falls. Attempts to taper apomorphine led to an immediate reoccurrence of severe motor fluctuations, such that SC apomorphine infusions were eventually continued at slightly reduced doses (3 mg/hour over 16 hours). Combined SC apomorphine infusions and GPi stimulation provided satisfactory motor control over a follow-up time of 6 months. However, severe dysarthria, which was previously mainly associated with OFF periods, progressed to permanent anarthria, which likely reflects disease progression,[2] although adverse effects of GPi stimulation cannot be ruled out.[4]

In conclusion, this case is unusual and instructive in several ways: First, continuous dopaminergic drug delivery by SC apomorphine infusions was initially successful in avoiding disabling dyskinesias previously observed with l-dopa in this case, which appears consistent with current concepts of the pathogenesis of l-dopa-induced dyskinesias in PD. Second, however, this effect was only transient and severe, and disabling, predominantly dystonic dyskinesias recurred despite ongoing apomorphine infusion therapy, showing that continuous drug delivery is not always able to prevent dyskinesias. Finally, this case illustrates that combinations of SC apomorphine infusions and GPi DBS can be useful to control both motor fluctuations and drug-induced dyskinesias in cases of juvenile PD with predominantly dystonic involuntary movements.

 

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