Double-Blind Clinical Trial of Subthalamic Nucleus Deep Brain Stimulation in Early-Stage Parkinson's Disease

Prior treatment

• Previous brain operation or injury.
• Any prior movement disorder treatments that involved intracranial surgery or device implantation.
• Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time course consistent with drug-induced parkinsonism.

Other illness

• Evidence of an alternative diagnosis or secondary parkinsonism, as suggested by:
  • Features unusual early in the clinical course (e.g., prominent postural instability, freezing phenomena, or hallucinations unrelated to medications in the first 3 years after symptom onset)
  • Dementia preceding motor symptoms
  • Neurologic signs of upper motor neuron or cerebellar involvement
  • Significant orthostatic hypotension unrelated to medications
  • Unequivocal cortical sensory loss (i.e., graphesthesia, sterognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia
  • Vertical supranuclear gaze palsy, or selective slowing of vertical saccades
  • Unequivocal cerebellar abnormalities on examination, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (e.g., sustained gaze-evoked nystagmus, macro square wave jerks, hypermetric saccades)
  • Documentation of a condition known to produce parkinsonism and plausibly connected to the subject's symptoms (e.g., MRI scan with evidence of significant brain atrophy, lacunar infarcts, or iron deposits in the putamen; history of stroke, exposure to toxins, or encephalitis; or neuroleptic use within the past 6 months)
  • The expert evaluating physician, based on the full diagnostic assessment, believes that an alternative syndrome is more likely than PD.
• Uncontrolled medical condition or clinically significant medical disease that would increase the risk of developing pre- or postoperative complications (e.g., significant cardiac or pulmonary disease, uncontrolled hypertension).
• Dementia as evidenced by a Dementia Rating Score of less than 123.
• Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia.
• Currently active diagnosis of a major psychiatric disorder.
• Subjects with cardiac pacemakers or medical conditions that require repeat MRI scans.
• Any current substance use disorder.
• Any history of recurrent or unprovoked seizures.
• Any other active implanted intracranial device (e.g., cochlear implant) or implanted device to treat movement disorders (e.g., duodopa pump) whether turned on or off.
• A condition requiring or likely to require the use of magnetic resonance imaging (MRI) or diathermy.
• History of suicide attempt.
• Rapid progression of gait impairment requiring regular use of a wheelchair.
• Bilateral symmetric parkinsonism throughout the disease course. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination.

Other

• Active participation in another clinical trial for the treatment of PD.
• Evidence of existing dyskinesia
• A female who is breastfeeding or of child-bearing potential with a positive urine pregnancy test or not using adequate contraception.
• Inability or unwillingness of subject to give written informed consent.
• Parkinsonian features restricted to the lower limbs for more than three years.
• Normal functional neuroimaging of the presynaptic dopaminergic system, as measured by DaTSCAN.
• Early bulbar dysfunction, defined as one of severe dysphonia, dysarthria (speech unintelligible most of the time), or dysphagia (requiring soft food, nasogastric (NG) tube, or gastrostomy feeding).
• Inspiratory respiratory dysfunction defined as either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs.
• Recurrent (\>1/year) falls because of impaired balance within 3 years of onset.
• Otherwise unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry in the more affected limb and isolated extensor plantar response).

• A clinical diagnosis of idiopathic Parkinson's disease (PD). The diagnosis will be based upon the presence of at least two of the three cardinal motor signs of this disorder (akinesia/bradykinesia, rest tremor, and rigidity) with at least one of the signs being rest tremor or bradykinesia.
• Clear and dramatic beneficial response to dopaminergic therapy, defined as ≥30% in UPDRS III with administration of the patient's medication during the screening neurological examination.
• Hoehn and Yahr (H\&Y) stage II when OFF medication.
• No contraindications to surgery (i.e., subject does not have uncontrollable medical or psychiatric illness; Exclusion Criteria).
• Age between 50 and 75 years old.
• Dopaminergic therapy for greater than one year and less than four years.
• Available for follow-up for the entire duration of the study.
• Informed Consent (Appendix C): The subject is willing and able to provide written informed consent.
• MRI within normal range (Exclusion Criteria).
• Subjects receiving antidepressant medication used specifically for the treatment of depression must be on stable doses for at least eight weeks prior to enrolling in the study.
• Subjects must agree to maintain a stable regimen, if deemed medically appropriate by the treating physician, of any psychotropic medications throughout the blinded treatment phase.