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

2/16/2019 1

Pearls and Pitfalls in the treatment

• f Movement Disorders

A Case-based approach

Alberto J. Espay, MD, MSc Professor of Neurology 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

52nd Annual Recent Advances in Neurology February 4-16, 2019 IUCSF, San Francisco

Initial and subsequent medication therapy of Parkinson’s disease

case 1

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.

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After Levodopa

Excellent response to L-dopa BUT… wearing

• ff and dyskinesia appeared within 3 months

Pitfall: “Levodopa induces dyskinesia”.

 Dyskinesia is linearly correlated with L-dopa dose.  Levodopa is necessary but not sufficient to

induce dyskinesia. It requires: the disease (PD) and a pulsatile drug delivery (short half-life).

 Levodopa administered continuously via intestinal

infusion reduces pre-existing dyskinesia, even at higher doses.

 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. Antonini et al Mov Disord. 2016;31(4):530-537.

Pitfall: “Motor fluctuations worsen with levodopa”

…The perception of “OFF” depends on the perception of “ON”

CALM-PD, PSG, Arch Neurol, 2004

More levodopa, more OFF…

ELLDOPA, NEJM, 2004

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Pitfall: “Motor fluctuations and 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

3 models of levodopa use and cumulative disability

Espay and Lang, JAMA Neurology 2017

 As the clock for dyskinesia development

begins to tick with disease onset rather than with levodopa initiation, deliberately delaying levodopa serves no practical purpose.

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.

Motor fluctuations in PD

(and other reasons for rapid decline)

cases 2-4

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“Rapidly progressing” Parkinson’s disease



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 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 150/entacapone (CLE [Stalevo] 150), 1 tablet qid, controlled release carbidopa/L-dopa (sinemet CR 25/100), 0.5 tablets qid, amantadine 100 mg tid, and clonazepam 1 mg qhs

After discontinuing amantadine



Clues: Diffuse myoclonic movements, marked postural and gait impairments, livedo

• reticularis. He had mild dementia.



Sequential steps: Amantadine was discontinued, pramipexole reduced to 4.5 mg/day, and CLE dose was 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 was no longer apparent. Postural myoclonus was markedly reduced.

Case summary: Timeline --and pitfalls

 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!

A twist in the tale: diphasic dyskinesia

Verhagen Metman and Espay, Neurology 2017

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Espay et al, Ann Neurol 2018 Single LD dose cycle LD dose LD dose

A B C

Supratherapeutic window Therapeutic window Transitional window Undertherapeutic window

OFF DiDysk ON ON with peak-dose dyskinesia ON DiDys OFF

Dose A

OFF DiDysk ON without dyskinesia DiDys OFF

Dose B

OFF DiDysk OFF

Dose C

plasma LD concentration

Diphasic dyskinesia: differential approach to treatment

 Often mistaken as a peak-dose phenomenon,

the diphasic variant (beginning-of-dose or end-of-dose) may be ignored

 Recognition of dyskinesia subtype based on

the relationship with levodopa dose cycles (Figure) facilitates their differing management in PD: while dopaminergic stimulation needs reduction in peak-dose dyskinesia, it should be increased in diphasic.

Verhagen Metman and Espay, Neurology 2017

Final word on PD management Amantadine-induced myoclonus in PD



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

Amantadine at 300 mg/day Amantadine discontinued

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Pitfalls of omission: Missing key elements

Cases 5 and 6

Paroxysmal disorder: EMU evaluation

Second Layer of Nomenclature: Testing cutoff Seen at the clinic “Remote stroke in the right hemisphere”

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Diagnosis: Glioblastoma multiforme

(presenting as paroxysmal dystonia? Or as focal motor seizures?)

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Disorder of Movement Testing cutoff for nosology Movement Disorder

Electrographic correlate No electrographic correlate

When does the movement become too long for paroxysmal dystonia? The duration cutoff

Tonic spasm Focal seizure Tonic spasm Focal seizure Tonic spasm Focal seizure

5 sec 15 sec 30 sec >45 sec

Additional observation Abnormal Movement Self-generated-movement effect Movement Disorder

Self-induced jerking Spontaneous jerking

(Clonus is not catalogued as a disorder of movement)

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Abnormal gait: foot dystonia

50-year-old woman who noted some “pressure” in the bottom of her right foot four months prior to evaluation In short sequence: limping and clumsiness in right leg Lately: episodes of right arm flexion, hand clenching

Rest of the examination

Hyperreflexia with jaw jerk, right leg spasticity, right ankle clonus, and right weakness of proximal and distal muscles of leg > arm Mild to moderate cortical sensory loss

Brain MRI

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Diagnosis: Glioblastoma multiforme

(presenting as foot dystonia) (with superimposed focal seizures?)

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Restless legs syndrome

cases 7-9

History

 65 y/o woman presented with cramping and jerky movements

• f 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

 No family h/o similar movements  Her meds: gabapentin, promethazine 25mg PRN,

• meprazole and naproxen PRN

Case courtesy: Dr. Kapil Sethi Courtesy: Dr. Kapil Sethi

Initial diagnosis

• Initially diagnosed with adverse effects related

to promethazine and she was given diphenhydramine

• Symptoms worsened with diphenhydramine

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Case summary

 What happened?

After 2 mg of morphine

Courtesy: Dr. Kapil Sethi

The two-insult full story

(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.

Iatrogenic akathisia: one extra pearl

 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)

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Management of RLS

 First line: Gabapentin, benzodiazepines (clonazepam,

temazepam), anticonvulsants

 Second line: Dopamine agonists, ropinirole (0.5–6 mg/d),

pramipexole (0.25–1.5 mg/d), and rotigotine (2-4 mg/d)

 Ropinirole does not undergo renal metabolism and may

be more effective in uremic RLS patients.

 Levodopa is effective but may cause symptom augmentation

presumably from overstimulation of D1 versus D2 spinal dopamine receptors.

 Third line: opioids (oxycodone, oxycodone/naloxone,

propoxyphene)

 Iron replacement when ferritin level is <45 g/L. Iron

supplementation and opiates can counter augmentation.

Winkelman et al, Neurology. 2016 Dec 13;87(24):2585-2593.

Movements in a double amputee

 54-year-old man with history of insulin-

dependent diabetes, hypertension, diabetic/hypertensive nephropathy, and bilateral amputation due to complicated ischemic limbs (November 2013).

 January 2014: post-prandial abdominal

pain and vomiting (diagnosis: mesenteric ischemia).

 February 2014: Movements appeared

Case Courtesy: Andres de la Cerda

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.

Case Courtesy: Andres de la Cerda

Review of prior records

Metoclopramide-induce tardive dyskinesia (copulatory dyskinesia) – Risk factor: nephropathy

Metoclopramide 10 mg q 8 hours given for one month before onset of movements

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PD patient administered promethazine for L-dopa induced nausea

Video received from spouse of PD patient:

“Back from ER but my wife is worse” Clinical pearls

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.

Pitfalls in recognition

Case 10

Difficulty walking

Courtesy: Dr. Don Gilbert, Cincinnati Children’s Hospitals, University of Cincinnati

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Inflammation of the iliopsoas bursae causes the iliotibial band, tensor fascia lata, or gluteus medius tendon to slide back and forth across the greater trochanter. Correcting biomechanical abnormalities and stretching tightened muscles, such as the iliopsoas muscle or iliotibial band, is the goal of treatment.

Don’t forget common non-neurological sources

• f abnormal movement!

Snapping hip syndrome

(coxa saltans, iliopsoas tendinitis, or dancer's hip)

Gilbert DL, Espay AJ, Wu SW .. Neurology. 2018 Aug 7;91(6):276-277

Rhythmic movement: oculomasticatory myorhythmia

 Convergent-divergent

nystagmus

 Concurrent

contractions of the masticatory muscles

 Supranuclear vertical

gaze palsy

Louis ED et al Ann Neurol 1996;40:561 Revilla et al. Neurology 2008;70(6):e25

Definite CNS Whipple’s Disease must

have any 1 of the following criteria:

1.Oculomasticatory myorhythmia 2.Positive tissue biopsy 3.Positive PCR analysis