Initial and subsequent medication of Movement Disorders therapy of - PowerPoint PPT Presentation

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 52 nd Annual Recent Advances Alberto J. Espay, MD, MSc in Neurology Professor of Neurology February 4-16, 2019 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: “Motor fluctuations worsen Pitfall: “Levodopa induces dyskinesia”. 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). More levodopa, more OFF…  Levodopa administered continuously via intestinal 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. …The perception of “OFF” depends on the perception of “ON” Fahn et. N Engl J Med. 2004;351(24):2498-2508. 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  reticularis. He had mild dementia. unable to walk at all, being virtually confined to a wheelchair. 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 to treatment Supratherapeutic window A Therapeutic plasma LD concentration  Often mistaken as a peak-dose phenomenon, window B the diphasic variant (beginning-of-dose or C Transitional window end-of-dose) may be ignored Undertherapeutic  Recognition of dyskinesia subtype based on window the relationship with levodopa dose cycles LD dose LD dose Single LD dose cycle (Figure) facilitates their differing management OFF DiDysk ON ON with peak-dose dyskinesia ON DiDys OFF Dose A in PD: while dopaminergic stimulation needs OFF DiDysk ON without dyskinesia DiDys OFF Dose B reduction in peak-dose dyskinesia, it should OFF DiDysk OFF be increased in diphasic. Dose C 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 “Remote stroke in the right Seen at the clinic 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 Tonic spasm Focal seizure Electrographic correlate No electrographic correlate Disorder of Movement Tonic spasm Focal seizure Movement Disorder 5 sec 15 sec 30 sec >45 sec Additional observation Self-generated-movement effect Self-induced jerking Abnormal Spontaneous jerking Movement Movement Disorder (Clonus is not catalogued as 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 Hyperreflexia with jaw jerk, right leg spasticity, right ankle bottom of her right foot four months prior to evaluation clonus, and right weakness of proximal and distal In short sequence: limping and clumsiness in right leg 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 movements of both legs cases 7-9  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