2/16/2019
Pearls and Pitfalls in the treatment Initial and subsequent medication of Movement Disorders therapy of Parkinson’s disease A Case-based approach
case 1 52nd Annual Recent Advances Alberto J. Espay, MD, MSc in Neurology February 4-16, 2019 Professor of Neurology IUCSF, San Francisco Director and Endowed Chair James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders University of Cincinnati Academic Health Center
Case summary
56-year-old woman with right arm pain and left shoulder pain for 11 years. 5 years ago: Left foot “sticking up” 2 years ago: greater difficulty with walking, having to walk "on the ball of her feet". No falls but stumbling due to "weight shifting" to the right. 1 year ago: anxious and depressed, Fluoxetine given with no benefits. 6 months ago: left-hand tremor when holding her arms outstretched.
1 2/16/2019
After Levodopa Excellent response to L-dopa BUT… wearing off and dyskinesia appeared within 3 months
Pitfall: “Levodopa induces dyskinesia”. Pitfall: “Motor fluctuations worsen with levodopa” Dyskinesia is linearly correlated with L-dopa dose. Levodopa is necessary but not sufficient to CALM-PD, PSG, Arch Neurol, 2004 induce dyskinesia. It requires: the disease (PD) and a pulsatile drug delivery (short half-life). Levodopa administered continuously via intestinal More levodopa, more OFF… infusion reduces pre-existing dyskinesia, even at higher doses. ELLDOPA, NEJM, 2004 Dyskinesia is, thus, an artifact of the method of administration of levodopa rather than an intrinsic molecular effect of levodopa itself.
Fahn et. N Engl J Med. 2004;351(24):2498-2508. …The perception of “OFF” depends on the perception of “ON” Antonini et al Mov Disord. 2016;31(4):530-537.
2 2/16/2019
Pitfall: “Motor fluctuations and 3 models of levodopa use and cumulative disability dyskinesia worsen with levodopa”
“Off” periods can only become apparent after marked improvement of motor features has created the awareness of an “on” state
Dopamine agonists are largely incapable of generating dyskinesia without co-administered levodopa –They don’t just “delay” dyskinesia
Espay and Lang, JAMA Neurology 2017 Espay and Lang, JAMA Neurology 2017
Motor fluctuations in PD As the clock for dyskinesia development (and other reasons for rapid decline) begins to tick with disease onset rather than with levodopa initiation, deliberately delaying levodopa serves no practical purpose. cases 2-4
Espay and Lang, JAMA Neurology 2017 Cilia et al. Brain. 2014;137(Pt 10):2731-2742. Fox SH, Lang AE. Brain. 2014;137(Pt 10):2628-2630.
3 2/16/2019
“Rapidly progressing” Parkinson’s disease After discontinuing amantadine
74-year-old man with PD for 16 years, able to walk 3 miles per day until about 6 weeks ago, when he rapidly declined, and over days he was Clues: Diffuse myoclonic movements, marked postural and gait impairments, livedo unable to walk at all, being virtually confined to a wheelchair. reticularis. He had mild dementia.
He was treated with pramipexole 1.5 mg qid (6 mg/day), carbidopa/L-dopa Sequential steps: Amantadine was discontinued, pramipexole reduced to 4.5 mg/day, and CLE dose was 150/entacapone (CLE [Stalevo] 150), 1 tablet qid, controlled release carbidopa/L-dopa increased from 150 to 200 per dose. His motor function improved 200% (UPDRS decreased from 64 to 22/108) and his subjective cognitive benefits were matched by gains in the MMSE (from 21 to 25/30). His livedo reticularis (sinemet CR 25/100), 0.5 tablets qid, amantadine 100 mg tid, and clonazepam 1 mg qhs was no longer apparent. Postural myoclonus was markedly reduced.
Case summary: Timeline --and pitfalls A twist in the tale: diphasic dyskinesia
Dyskinesia was targeted successfully with amantadine Amantadine use was associated with shortcomings: importantly, cognitive impairment and gait freezing Amantadine removal led to reemergence of dyskinesia (tolerable) but with restoration of cognitive and gait function Beware of the pitfalls of aggressively treating (or preventing) dyskinesia!
Verhagen Metman and Espay, Neurology 2017
4 2/16/2019
Diphasic dyskinesia: differential approach
Supratherapeutic window to treatment A Therapeutic window B Often mistaken as a peak-dose phenomenon,
Transitional C the diphasic variant (beginning-of-dose or window
plasma LD concentration LD plasma end-of-dose) may be ignored Undertherapeutic window Recognition of dyskinesia subtype based on LD doseSingle LD dose cycle LD dose the relationship with levodopa dose cycles OFF DiDysk ON ON with peak-dose dyskinesia ON DiDys OFF Dose A (Figure) facilitates their differing management OFF DiDysk ON without dyskinesia DiDys OFF in PD: while dopaminergic stimulation needs Dose B reduction in peak-dose dyskinesia, it should OFF DiDysk OFF Dose C be increased in diphasic.
Espay et al, Ann Neurol 2018 Verhagen Metman and Espay, Neurology 2017
Final word on PD management Amantadine-induced myoclonus in PD
Amantadine at 300 mg/day Amantadine discontinued
Myoclonus in the setting of suspected PD suggests: (1) an alternative diagnosis, (2) developing dementia, or (3) an iatrogenic complication. Amantadine is typically associated with multifocal myoclonus of the limbs and and orofacial region, and disappears when treatment is stopped. Involvement of speech may be more common
Gupta and Lang Mov Disord 2010;25(13):2264-2265
5 2/16/2019
Second Layer of Nomenclature: Testing cutoff Pitfalls of omission: Missing key elements
Cases 5 and 6
Paroxysmal disorder: EMU evaluation
Seen at the clinic “Remote stroke in the right hemisphere”
6 2/16/2019
Diagnosis: Glioblastoma multiforme (presenting as paroxysmal dystonia? Or as focal motor seizures?)
7 2/16/2019
Testing cutoff for nosology The duration cutoff When does the movement become too long for paroxysmal dystonia?
Tonic spasm Focal seizure
Electrographic correlate No electrographic correlate Tonic spasm Focal seizure Disorder of Movement Movement Disorder Tonic spasm Focal seizure
5 sec 15 sec 30 sec >45 sec
Additional observation Self-generated-movement effect
Self-induced jerking Abnormal Spontaneous jerking Movement Movement
(Clonus is not catalogued as Disorder a disorder of movement)
8 2/16/2019
Abnormal gait: foot dystonia Rest of the examination
50-year-old woman who noted some “pressure” in the bottom of her right foot four months prior to evaluation Hyperreflexia with jaw jerk, right leg spasticity, right ankle In short sequence: limping and clumsiness in right leg clonus, and right weakness of proximal and distal muscles of leg > arm Lately: episodes of right arm flexion, hand clenching Mild to moderate cortical sensory loss
Brain MRI
9 2/16/2019
Diagnosis: Glioblastoma multiforme (presenting as foot dystonia) (with superimposed focal seizures?)
10 2/16/2019
History
65 y/o woman presented with cramping and jerky movements Restless legs syndrome of legs, after taking promethazine for vomiting Started after a day of promethazine 25mg PRN Started with R calf pain and progresses to involve bilateral legs and thighs Next day, she started having cramps and then jerky cases 7-9 movements of both legs No family h/o similar movements Her meds: gabapentin, promethazine 25mg PRN, omeprazole and naproxen PRN
Case courtesy: Dr. Kapil Sethi
Initial diagnosis
• Initially diagnosed with adverse effects related to promethazine and she was given diphenhydramine
• Symptoms worsened with diphenhydramine
Courtesy: Dr. Kapil Sethi
11 2/16/2019
Case summary After 2 mg of morphine
What happened?
Courtesy: Dr. Kapil Sethi
The two-insult full story Iatrogenic akathisia: one extra pearl (Malignant Restless leg syndrome)
Admitted as biballism --urgent MRI was negative.
She had a history of very mild RLS in the past. After a cholecystectomy, she experienced nausea: Was given Promethazine (first insult) The movements she later had were misdiagnosed as a case of acute dystonic reaction. Was given diphenhydramine (second insult). “That drove her crazy” (Kapil Sethi’s own explanation) - the last part of the video is after 2
dosages of 2mg morphine. 21-year-old woman with renal failure given promethazine for nausea In RLS or at-risk RLS patients: Growing reports of “allergy” to diphenhydramine (likely also akathisia)
12 2/16/2019
Management of RLS Movements in a double amputee
First line: Gabapentin, benzodiazepines (clonazepam, temazepam), anticonvulsants 54-year-old man with history of insulin- Second line: Dopamine agonists, ropinirole (0.5–6 mg/d), pramipexole (0.25–1.5 mg/d), and rotigotine (2-4 mg/d) dependent diabetes, hypertension, Ropinirole does not undergo renal metabolism and may diabetic/hypertensive nephropathy, and be more effective in uremic RLS patients. bilateral amputation due to complicated Levodopa is effective but may cause symptom augmentation ischemic limbs (November 2013). presumably from overstimulation of D1 versus D2 spinal dopamine receptors. January 2014: post-prandial abdominal Third line: opioids (oxycodone, oxycodone/naloxone, pain and vomiting (diagnosis: mesenteric propoxyphene) Iron replacement when ferritin level is <45 g/L. Iron ischemia). supplementation and opiates can counter augmentation. February 2014: Movements appeared Winkelman et al, Neurology. 2016 Dec 13;87(24):2585-2593. Case Courtesy: Andres de la Cerda
Review of prior records Metoclopramide 10 mg q 8 hours given for one month before onset of movements The patient complained of an epigastric sensation that he admitted to helping relieve by moving.
There was a sense of urge and partial volitional control.
Metoclopramide-induce tardive dyskinesia (copulatory dyskinesia) – Risk factor: nephropathy Case Courtesy: Andres de la Cerda
13 2/16/2019
Video received from spouse of PD patient: Clinical pearls “Back from ER but my wife is worse” Patients given prochlorperazine or metoclopramide must be monitored for akathisia that can develop at any time over 48 hours post administration
Ondansetron is as effective as promethazine and is not associated with sedation or akathisia.
PD patient administered promethazine for L-dopa induced nausea
Difficulty walking
Pitfalls in recognition
Case 10
Courtesy: Dr. Don Gilbert, Cincinnati Children’s Hospitals, University of Cincinnati
14 2/16/2019
Snapping hip syndrome Rhythmic movement: oculomasticatory (coxa saltans, iliopsoas tendinitis, or dancer's hip) myorhythmia
Convergent-divergent nystagmus
Inflammation of the iliopsoas Concurrent bursae causes the iliotibial band, contractions of the tensor fascia lata, or gluteus medius masticatory muscles tendon to slide back and forth across Supranuclear vertical the greater trochanter. gaze palsy Correcting biomechanical Definite CNS Whipple’s Disease must abnormalities and stretching have any 1 of the following criteria: tightened muscles, such as the Don’t forget common non-neurological sources 1.Oculomasticatory myorhythmia iliopsoas muscle or iliotibial band, is of abnormal movement! 2.Positive tissue biopsy Revilla et al. Neurology 2008;70(6):e25 3.Positive PCR analysis Louis ED et al Ann Neurol 1996;40:561 the goal of treatment. Gilbert DL, Espay AJ, Wu SW.. Neurology. 2018 Aug 7;91(6):276-277
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