Parkinson’s Disease THERAPY IN NEUROLOGY COURSE, 2015 MOVEMENT DISORDERS

Antes de iniciar tratamiento Esté seguro del diagnóstico En autopsias hasta 20 % otras causas. En cada consulta replantearse el dx, a veces sólo el tiempo hace aparentes otros Dx ( PSP, MSA )

Características clínicas a favor de PK: Inicio unilateral o asimétrico. Tremor clásico de reposo. Beneficio sostenido con levodopa y desarrollo eventual de fluctuaciones y disquinesias. No historia de exposición a medicamentos bloqueen DA un año antes del inicio de sx.

Características atípicas de PK: No respuesta a levodopa. Caidas tempranas. Rápida progresión ( Signo silla de ruedas ) Signos bulbares tempranos. Demencia temprana, delirios, alucinaciones. Disautonomía temprana y prominente. Signos no esperados en PK : apraxia, ataxia, piramidal, etc. Sacadas verticales lentas /parálisis mirada superior.

Tratamiento temprano PD A 65 year executive secretary is seen for a 9mo history of tremor of the dominant right hand. All movements with the right hand are slower and she tends to drag the right foot. The following activities take more time and effort:writing, typing, dialing the phone, applying makeup, getting dressed, and preparing food. Others have asked why she limps and she finds this embarrassing. The exam confirms features of PD. How should she be treated?

Tratamiento temprano del PD : considerar Qué tanto le afecta los síntomas personal /profesional ? Edad Comorbilidad ( sueño ) Sensibilidad efectos secundarios. Costo

Se debe postponer levodopa para evitar fluctuaciones futuras ? Levodopa vs agonista como tx inicial ( levo es más probable que produzca DK y fluctuaciones ). Sin embargo a 5 a son leves y no discapacitantes. Considerar el beneficio clínico de levodopa /efectos sec de los agonistas.

Levodopa No postponer si síntomas son problemáticos. No justificación para LEVODOPAPHOBIA Iniciar levodopa 100/25 mg ( tid ) Discutir expectativas de tx ( puede que tremor no resuelva o necesite altas dosis ) No ventaja con levodopa de liberación extendida.

No beneficio y aumento de DK si se inicia con carbidopa/levodopa/entacapone Puede ser horario de cada 4 horas, sin comidas ( no necesario al inicio ) Muchos pacientes no necesitan levodopa HS. Mayores de 70 A levodopa como primera opción ( pocas fluctuaciones motoras )

Agonistas Ej bromocriptina, pramipexole Ideal paciente joven con sx leves. Menos eficaz que levodopa. Ventaja : dosificación ej 1 o bid. Vigilar por ICD ( impulse control disorders ) En pacientes con somnolencia o insomnio observar.

Otras opciones Amantadine Inhibidor MAO-b ( no probado efecto neuroprotector )

Manejo fluctuaciones motoras. A 66 year old man with a 5 year history of PD can now feel when it is time to take levodopa as he starts to shuffle, is slower, and has return of tremor. He takes carbidopa/levodopa 25/100, 2 tablets at 7am, noon and 6pm.

La primera fluctuación motora es fin de dosis ( end-of-dose wearing off ). Antes de un ajuste si al paciente esa pérdida de efecto no le preocupa no se hacen cambios ( ej un retorno del tremor antes de la sgte dosis ).

Opciones Disminuir intervalo entre tomas ( es mejor al inicio no aumentar dosis ) Agregar agonista, inhibidor MAO ( selegelina, rasagalina ) o inhibidor COMT ( entacapone ). Considerar apomorfina.

Síntomas al despertar: distonía y aquinesia A 61 year old woman with a 12 year history of PD notices that when she first gets out of bed in the morning that her foot turns in and is painful. This makes it very difficult to ambulate. About 30 min after taking levodopa it resolves.

Opciones de manejo (Síntomas al despertar: distonía y aquinesia ) Levodopa CR al acostarse ? ( no efecto tan prolongado ) Si se despierta a miccionar levodopa CR o regular lo más cercano a la hora de despertarse. Tomarse una levodopa regular apenas se despierte ( en agua carbonatada se absorbe más rápido ) Apomorfina Toxina botulínica.

Manejo de las disquinesias inducidas por levodopa A 71 year old man with a 15 year history of PD has dyskinesias which usually start as soon as levodopa kicks in and include head bobbing, tongue protrusion, facial grimacing and truncal twisting. He is taking carbidopa/levodopa 25/250 every 3-4 hours, rasagiline and pramipexole 0.5mg tid.

Puntos a aclarar de las disquinesias A menudo incomodan más a los demás que al mismo pcte. Si no es problemático no tratar. Siempre solicitar que el paciente haga un diario con las horas de aparición. Si se confunde con tremor acentuado esperar a ver una crisis en la oficina.

Manejo disquinesias problema. Reducir dosis de levodopa. Y de ser posible intervalo. Aumentar agonista. Suspender inhibidores de la MAO-B o de la COMT.

Manejo DK Asociar amantadina. ( a menudo con efecto dramático y largo tiempo ). Antagonista receptores de NMDA. Considerar Estimulación cerebral profunda ( Gpi )

Estimulación profunda ( cuando considerar ) Tremor discapacitante y refractario a t xy /o fluctuaciones motoras a pesar de tx óptimo Debe mantenerse ON con la levodopa. Cognitivo/psiquiátrica estable. Levodopa intestinal gel : una alternativa potencial.

Puntos a considerar con DBS El dx debe ser PK no Pk plus. Realizarse en centros multidisciplinarios y con experiencia. Definir expectativas ( ej balance no mejor, excepto que fuera parte de los periódos OFF ), efecto puede observarse 10 años después pero al progresar la enfermedad el beneficio tiende a no ser evidente.

Marcapaso no con la eficacia esperada – considerar -: Dx Colocación Parámetros de estimulación. Medicamentos para PK Comorbilidad como depresión.

Falls in Parkinson’s disease  Try to determine when/why falls happen  Often seen in setting of executive dysfunction with impulsivity, decreased insight and impaired judgment  Optimize motor fluctuations (minimize off time)  Check for orthostatic hypotension

 Economize medications (TCAs, benzodiazepines)  Physical therapy/Tai Chi  Home safety: bars in bathroom, remove throw rugs, banisters on stairs, lighting at night, etc.  Educate patient: avoid carrying things while walking, hand on banister, etc.  Walker (my preference is UStep but others with 4 wheels are fine); hiking poles; laser cane  Knee pads

U step walker

Laser cane

Manejo síntomas no motores

Orthostatic hypotension Be alert to presentations of OH other than traditional near-syncope  fatigue  cognitive impairment  falls  coat hanger sign  Look for OH  First try to eliminate any causal or contributing medications especially DA agonists, TCAs, antihypertensives

Non-pharmacologic measures: increase water/salt intake; avoid standing quickly; avoid large meals and alcohol; avoid hot baths or showers; support hose (impossible for most patients with PD to use); keep the head of the bed propped up; recognize the earliest symptoms and sit or use an isometric exercise

Medications which can be considered o fludrocortisone o midodrine o droxidopa o Be sure to use last dose early to avoid supine hypertension overnight

Sialorrhea o Drooling is a common problem in PD. For most patients it is an annoyance but for some,particularly with advanced PD, it can be problematic. Pooling of saliva in the mouth can interfere with talking and poses a risk for aspiration. There are relatively few proven therapies for treatment of drooling. o Options: anticholinergics (intraorally vs systemic) o I typically try oral atropine drops (1% ophthalmic solution) with fair success o Local injection of botulinum toxin into salivary glands is what I have found most beneficial

Diplopia Assuming there is no other cause unrelated to PD (myasthenia, ischemic VI palsy, etc.), then diplopia in PD is usually due to a combination of an exphoria combined with convergence insufficiency It is typically horizontal and worse at near

Treatment options o Keep one eye closed while reading o Prism o Eye patch o Reading glasses with masking tape over one of the lenses

Sleep Disorders

Excessive daytime sleepiness  Inquire about sleep hygiene  Critical evaluation of medications (esp DA agonists)  Consider primary sleep disorder (OSA)  Common in advanced PD especially with dementia  Often difficult to treat  May use Modafanil or Armodafanil (I have not been impressed)  Methylphenidate

Insomnia Remember, insomnia is a symptoms, not a disease  Try to determine cause for insomnia  Important considerations: PD symptoms interfering with initiating or maintaining sleep (tremor, difficult turning, cramps, etc.) which can be improved with adjustment of PD meds (e.g., controlled release levodopa HS) o Depression/insomnia o Nocturia

REM behavioral disturbance Dream enactment  Very common in PD  May precede PD by years or decades  Need history from bed partner  Can cause “falling” out of bed  If infrequent and mild, not in need of treatment  Move potentially injurious objects from around bed  Options: low dose clonazepam (I start with 0.125mg) or melatonin

Depression and anxiety in PD Both are very common in PD and often inadequately recognized and treated o Mood disorders may fluctuate with motor fluctuations  Panic when off  Despondency when off  Hypomania when on

Treatment  Recognition/education  TCAs, SSRIs, SNRIs (relatively limited evidence base and no clear benefit of one vs another)  ECT if refractory or intolerant of meds

Impulse control disorders and dopamine agonist withdrawal syndrome o Approximately 15% of patients with PD will develop an impulse control disorder (ICD) o The most common include gambling, shopping, sexual behavior, eating and hobbyism o They are often challenging to diagnose and are often done surreptiously o They are most closely associated with dopamine agonists and are dose related

Other potential risk factors include male sex, younger age and younger age of onset of PD; prior history of ICD including substance abuse and gambling and impulsive personality traits o Prior to initiating dopaminergic therapy, especially with a DA agonist, patient and their family should be warned about this potential side effect o It is important to screen for ICD at each visit

The treatment of choice for a ICD is gradual reduction/withdrawal of a DA agonist or the presumed offending drug (which can include levodopa and amantadine) o Recognize that withdrawal of a DA agonist can be problematic and this is known as the “dopamine agonist withdrawal syndrome” which includes anxiety and insomnia

Dementia in PD Dementia is common in PD, affecting at least 40% of patients over the course of the disease, with some studies reporting up to 80%. Important to consider remediable causes and not just assume it is PD dementia Education of the patient, caregiver and family When PD is complicated by dementia, it adds a much greater burden to the caregiver. Significant factor in predicting nursing home placement

First step in management is to eliminate as many drugs as possible o Cholinesterase inhibitors can be used. Recent evidence-based reviews demonstrate greatest evidence for rivastigmine with less convincing evidence for donepezil galantamine and Memantine Impart realistic expectations if a cholinesterase inhibitor is used. No proven neuroprotective effect of cholinesterase inhibitors for PDD so if no meaningful benefit, discontinue.

Psychosis in PD Common problem but uncommonly addressed o Patients/caregivers reluctant to bring up o Important to ask about, especially when PD is complicated by cognitive impairment o Includes  Delusions (infidelity [delusional jealousy], paranoia)  Hallucinations: visual (formed), tactile or auditory hallucinations  Illusions

If infrequent with retained insight and not-bothersome, not necessary to treat o If problematic  Eliminate as many meds as possible (I try to use just levodopa in advance PD, especially when there is dementia)  Options  Seroquel (despite limited evidence, generally seen as first choice)  Clozaril (risk of leukopenia but most effective and underutilized)  Cholinesterase inhibitors  Pimavanserin (5HT2A inverse agonist): pending approval