Advanced Parkinson Disease & Atypical Parkinsonism

Motor Complications of Long-Term Levodopa

Why fluctuations appear. Early in Parkinson disease, surviving nigrostriatal terminals store dopamine and smooth out levodopa's short plasma half-life (about 90 minutes). As terminals are lost, striatal dopamine tracks plasma levodopa and benefit rises and falls with each dose. Motor complications typically emerge within about 5 years of therapy and sooner in young-onset disease.

Wearing-off. Symptoms return predictably before the next dose. Options are shorter dosing intervals, extended-release carbidopa-levodopa, or adding a drug that prolongs dopaminergic effect: a COMT inhibitor, an MAO-B inhibitor or a dopamine agonist. Sudden "off" episodes can be rescued with apomorphine (subcutaneous or sublingual) or inhaled levodopa. Levodopa is absorbed in the proximal small bowel, and dietary protein competes with it for the large neutral amino acid transporter, so doses work best 30–60 minutes before meals.

Peak-dose dyskinesia. Choreiform writhing 1–2 hours after a dose, when levodopa peaks. Give smaller doses more often and trim levodopa boosters; amantadine, an NMDA antagonist, directly suppresses dyskinesia.

Off-dystonia and freezing. Painful early-morning foot dystonia with toe curling occurs when levels are lowest and responds to bedtime extended-release levodopa or an agonist. Freezing of gait at doorways and turns improves with dopaminergic therapy only when it occurs in the off state; "on" freezing needs physical therapy, visual or auditory cueing and walking aids. Late axial features — freezing, postural instability, dysarthria, dysphagia — respond poorly to levodopa and surgery.

Deep brain stimulation (DBS). Subthalamic nucleus or globus pallidus interna stimulation treats disabling fluctuations, dyskinesia and medication-refractory tremor. The ideal candidate has idiopathic PD with a robust levodopa response (the best predictor of benefit, except for tremor, which responds even when levodopa does not), intact cognition and no uncontrolled depression or psychosis. DBS does not fix what levodopa cannot and is not offered for dementia or atypical parkinsonism. Patients unsuitable for surgery can receive continuous levodopa by jejunal gel pump or subcutaneous infusion.

Non-Motor Symptoms

Prodrome. REM sleep behavior disorder (dream enactment from loss of REM atonia, confirmed by polysomnography), hyposmia, constipation and depression can precede motor signs by years to decades. More than 70% of people with idiopathic RBD develop PD, dementia with Lewy bodies or MSA within about 12 years. RBD is treated with bedroom safety, melatonin or clonazepam.

Orthostatic hypotension. A fall of at least 20 mmHg systolic or 10 mmHg diastolic within 3 minutes of standing. First remove offending drugs (antihypertensives, α-blockers such as tamsulosin, diuretics), then use salt, fluids, compression stockings and head-of-bed elevation. Midodrine (α1 agonist), fludrocortisone (volume expansion; hypokalemia, edema) and droxidopa (converted to norepinephrine by DOPA decarboxylase) all risk supine hypertension.

Gut, bladder, saliva and mood. Constipation responds to fiber, fluids and polyethylene glycol. For urgency, mirabegron or trospium is preferred over CNS-penetrant oxybutynin. Drooling responds to salivary gland botulinum toxin or glycopyrrolate. Dysphagia causes aspiration pneumonia, a leading cause of death in advanced PD. Depression and anxiety are common and treated with SSRIs or SNRIs. For nausea, avoid central D2 blockers (metoclopramide, prochlorperazine); ondansetron is acceptable unless the patient uses apomorphine, with which it causes profound hypotension.

Dementia. Executive, attentional and visuospatial decline arising at least a year after established motor PD defines PD dementia; dementia first or within a year of parkinsonism means dementia with Lewy bodies. Most long-term survivors are eventually affected. Rivastigmine is FDA-approved (donepezil is used off-label), and anticholinergics, amantadine and sedatives should be withdrawn.

Psychosis. Well-formed visual hallucinations, a sense of presence and paranoid delusions (often spousal infidelity) are common late, especially with dementia.

Never give haloperidol, risperidone, olanzapine or other D2-blocking antipsychotics in PD or Lewy body disease — they can precipitate severe, even life-threatening rigidity and immobility.

Impulse-control disorders. Gambling, compulsive buying, hypersexuality, binge eating and punding affect about 1 in 6 patients on dopamine agonists, more often younger patients, men and those with prior addiction. Patients hide them, so ask patient and family at every visit. Taper the agonist and substitute levodopa, watching for dopamine agonist withdrawal syndrome (anxiety, panic, dysphoria, pain). Agonists also cause sudden sleep attacks (driving risk), leg edema and hallucinations.

Atypical Parkinsonism

Red flags. Consider a Parkinson-plus syndrome when parkinsonism is symmetric, lacks rest tremor, responds poorly or briefly to an adequate levodopa trial (at least 1,000 mg/day), or brings falls within about 3 years, early severe autonomic failure, gaze palsy, cerebellar or pyramidal signs, apraxia, stridor or rapid progression. These tau or synuclein disorders progress faster than PD and are managed supportively.

Progressive supranuclear palsy (PSP). Onset in the 60s with unexplained backward falls in the first year, axial rigidity with neck extension, a staring "surprised" face, dysarthria, dysphagia and frontal dysexecutive change. Vertical saccades slow first, then a supranuclear gaze palsy develops, worst for downgaze — patients struggle with stairs and with seeing their plate — yet the doll's-eye maneuver still moves the eyes. MRI shows midbrain atrophy with a preserved pons, the "hummingbird" sign.

Multiple system atrophy (MSA). Onset in the 50s with early autonomic failure (orthostatic syncope, urinary retention or incontinence, erectile dysfunction) plus poorly levodopa-responsive parkinsonism (MSA-P) or cerebellar ataxia (MSA-C), RBD and nocturnal inspiratory stridor. Stridor from vocal cord abductor weakness can cause sudden death and warrants laryngoscopy and CPAP or tracheostomy. MRI may show the "hot cross bun" pons (mainly MSA-C) or putaminal atrophy with a hyperintense rim (MSA-P). Pathology shows α-synuclein glial cytoplasmic inclusions in oligodendrocytes; the autonomic-predominant form was once called Shy-Drager syndrome.

Corticobasal degeneration (CBD). Markedly asymmetric limb rigidity, dystonia and stimulus-sensitive myoclonus plus cortical signs: ideomotor apraxia, alien limb phenomenon and cortical sensory loss (astereognosis, agraphesthesia). Levodopa is ineffective.

DaT-SPECT shows reduced striatal uptake in PD and in PSP, MSA and CBD alike: it separates degenerative parkinsonism from essential tremor or drug-induced parkinsonism but cannot tell PD from its atypical mimics.