Management of Neurological Conditions at End of Life

Erwin B. Montgomery Jr. MDProfessor of Neurology

McMaster University, Hamilton ONMedical Director

Greenville Neuromodulation Center, Greenville PA USA

Faculty/Presenter Disclosure

Faculty: Dr. Erwin Montgomery Relationships with commercial interests: • Grants/Research Support: FHC In. • Speakers Bureau/Honoraria: Book Royalties• Consulting Fees: None • Other: None

Greenville Neuromodulation Center

• Non-profit corporation in the Commonwealth of Pennsylvania dedicated to the advancement of neuromodulation therapies, such as Deep Brain Stimulation, through research, technology development, education and training

Conflict of Interest Disclosure

• Dr. Montgomery is an inventor on a number of patents and author of a number of textbooks related to neuromodulation and Parkinson’s disease

• Consultant to FHC, Inc. a for profit company supplying equipment, materials and systems for intraoperative neurophysiological monitoring during Deep Brain Stimulation lead implantation surgery

Caveats• If Off-label, experimental or investigational drugs, biologics,

devices, or diagnostics are mentioned, they will be identified as such

• Dr. Montgomery is new to Canada and is learning Canadian policies, rules, and regulations. Much of what is discussed is in the context of experiences in the United States.– Knowledge of good medical care knows no boundaries

but implementation is a different matter.• Dr. Montgomery makes no claims as to the correct spelling

of any word in the presentations.

Learning Objectives

• Recognition that the holistic care at end of life is extraordinarily complex and challenging; far beyond the expertise of most neurologists. Only by working together with other disciplines can the extraordinary range of concerns be met.

Learning Objectives• Focus on Parkinson’s disease• Common particularly in the elderly• Prevalence of parkinsonism (per 100 population) for the age

groups– 65 to 69 = 0.9– 70 to 74 = 1.5– 75 to 79 = 3.7– 80 to 84 = 5.0– 85 to 89 = 5.1

• Likely an underestimate, false negative rate ~29%

– de Rijk MC, et al. Prevalence of parkinsonism and Parkinson's disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson's disease. J Neurol NeurosurgPsychiatry. 1997 Jan;62(1):10-5.

Learning Objectives

• Focus on Parkinson’s disease• Common particularly in the elderly• Highlight specific issues centered on

– Motoric• Mobility

– Non-motoric• Dysphagia• Cognitive problems• Emotional problems

Parkinson Syndrome• Idiopathic Parkinson’s disease vs. Atypical Parkinsonism

– Idiopathic Parkinson’s disease (74% of patients)• 97% respond to levodopa therapy

– Response becomes complicated over time» Difficult pharmacokinetics and

pharmacodynamics• Shorter duration of effects• Increased adverse effects, such as dyskinesia

Parkinson Syndrome• Atypical Parkinsonism (26% of patients)

• Neurodegenerative– MultiSystems Atrophy (MSA)– Progressive supranuclear Palsy (PSA)– 24% will respond to levodopa but not robust or

sustained• Non-degenerative (lower body Parkinsonism)

– Vascular (infarct) Parkinsonism– Normal Pressure Hydrocephalus

Drug Induced Parkinsonism• Amisulpride• Amoxapine (Asendin )• Chloractil/Largactil• Chlorpromazine hydrocloride• Clopixol• Denzapine• Depixol• Domatil/Sulpitil/Sulpor (Sulparex is discontinued)• Dozic/Haldol/Serenace• Flupenthixol• Fluphenazine hydrochloride • Haloperidol • Melleril• Methotrimeprazine/Levomepromazine • Metoclopramide Reglan• Modecate/Moditen/Motival (includes nortriptyline)• Nozinan• Olanzapine Zyprexa• Oxypertine Oxypertine• Pericyazine Neulactil

• Perphenazine Fentazin, • Pimozide Orap• Piportil• Pipotiazine • Prochlorperazine• Prochlorperazine (Compazine, Stemzine,

Buccastem, Stemetil, Phenotil)• Promazine• Promazine hydrochloride • Risperidone Risperdal• Solian• Stelazine• Stemetil• Sulpiride• Thioridazine • Trifluoperazine• Triptafen (Perphenazine+amitriptyline)• Zoleptil• Zotepine • Zuclopenthixol acetate

Motoric• Motor manifestations

– Affects any movement– Slowness or absence of movement

• Kinesia paradoxica– Can create misunderstanding of the patient

• Tremor– Not consistent between and within patient

• Rigidity• Gait and postural abnormalities

Levodopa

• Short plasma half-life (90 minutes)• Early “third spacing” in the brain can prolong

effects but buffering diminishes with disease duration and severity

• Dosing interval begins to approach plasma half-life in advanced disease

Levodopa• First address peak-dose effect• Questions I ask to help assess the peak-dose effect are:

– 1. Is there much change in the symptoms during the day? If there are no fluctuations and the patient’s symptoms are bothersome, then it is likely the patient’s peak-dose effect is sub-therapeutic and the individual doses are insufficient. If there are times where the symptoms are sufficiently controlled, then the dose just prior to those times may be sufficient. If there are no fluctuations and the patient’s symptoms are not bothersome or limiting, then the size of each dose may be sufficient and the dosing interval is not too long as to cause a wearing-off effect.

– 2. How is the patient when the patient is at his or her best compared to when the patient is at his or her worst? If there is no difference and the patient’s symptoms are not satisfactorily controlled, then the peak-dose likely is insufficient.

– 3. Does the patient have involuntary movements, can’t sit still or is moving around too much? This suggests that the patient is experiencing dyskinesia which would suggest that the dose just prior to when these involuntary movements are noted may be too large.

Levodopa• Second, dosing interval

• 1. Is there much change in the symptoms during the day? If there are no fluctuations and the patient’s symptoms are not bothersome or limiting, then the size of each dose may be sufficient and the dosing interval is not too long as to cause a wearing-off effect.

• 2. How is the patient when the patient is at his or her best compared to when the patient is at his or her worst? If there is not difference and the patient’s symptoms are not satisfactorily controlled, then the peak-dose likely is insufficient.

• 3. How does the patient or caregiver know when it is time to take the subsequent dose of medication? If the patient knows because the symptoms are returning, then the dosing interval may be too long. If the patient knows by looking at the clock or a timer, then fluctuations are less likely.

• 4. Can the patient or caregiver tell when it is time for the patient to take the next dose of medication? Assuming that the peak-dose effect for each dose is optimal, then the ability for the patient or caregiver to tell that the next dose is due indicates a dosing interval that is too long, hence wearing off effect. If the patient or caregiver cannot tell and the peak-dose effects are optimal, then the dosing interval is likely optimal.

Maximum dose of levodopa

• That will produces intolerable adverse effects that cannot be circumvented

• In clinical trials for Deep Brain Stimulation, the average dose of levodopa (as levodopa equivalents) for candidates was 2500 mg per day

• A great many patients are undertreated

Levodopa

• Absorbed only in distal jejunum• If taken with meals delays absorption by 28%

and delays peak by 30 minutes• Should be taken ½ hour before or 1 hour after

meals

Levodopa

• Absorbed by enzymatic facilitated transport– Across the gut epithelium and across the blood

brain barrier– Competes with large neutral amino acids from

protein ingestion• Issue of nutritional supplementation

– High carb and fats, low protein

Adjuncts to Levodopa

• Drugs to improve bioavailability of levodopa– Carbidopa (blocks aromatic amino acid decarboxylase)

• Optimal dose at least 100 mg per day– COMT-inhibitors

• Entacapone• Short half-life must be taken with each dose of

levodopa– MAO-B inhibitors

• Selegiline and rasagiline

Adjuncts to Levodopa

• Dopamine agonists– Higher risk of short term adverse effects– Used as levodopa sparing agents

• Minimize long term risks of levodopa such as dyskinesia.

Adjuncts to Levodopa

• Deep Brain Stimulation– No upper age limit

• Issue of biological rather and chronological age

Management of Levodopa-dose limiting adverse effect

• Nausea and vomiting– Supplemental use of carbidopa (Lodosyn)

• 25 mg three times a day• Caution in exceeding 200 mg per day

–May enter the CNS to reduce conversion of levodopa to dopamine

Dysphagia

• Pneumonia– Leading cause of death (30%) in patients with PD

• Dysphagia leading cause of pneumonia• Diagnosis

– 25% silent aspirators– High index of suspicion– Coughing or choking when eating or drinking

Dysphagia• Evaluation• Best positive and NEGATIVE predictive value

– Video Fluoroscopic Evaluation of Speech (VFES)• Modified Barium Swallow)

• Bedside (clinical) evaluation and Fiberoptic Endoscopy Evaluation of Swallowing (FEES)– Cannot demonstrate mechanism(s)

• Important for treatment– Poor negative value– If positive then VFES– If negative then VFES– Why do anything else but VFES?

Abrupt Discontinuation of Dopaminergic Agents

• Neuroleptic-malignant-like syndrome• High fever, altered levels of consciousness, a

marked increase in muscle tone, autonomic disturbance, and elevation of serum creatine kinase (CK)

• Rhabdomyolysis, disseminated intravascular coagulation (DIC), and acute renal failure

• May present as an FUO (fever of undetermined origin)

Abrupt Discontinuation of Dopaminergic Agents

• I.V. levodopa (generally unavailable)• Apomorphine (problem of precipitous hypotension in

patient already at risk)• Transdermal rotigotine (Neupro) patch

– 2 to 6 mg per 24 hrs

Psychosis• Prevention

– Low level illumination• Parkinson’s disease reduces visual acuity

– Reassurance• Don’t discount their fears or concerns• Find ways that the patient will be reassured

– Avoid agitation– If in chronic care facility, personal belongings to reduce

strangeness of environment

Psychosis• Prevention

– Avoid psychoactive agents• Acute psychosis• Psychosis from withdrawal

Psychosis• Use of anti-Parkinson medications

– From most likely to least likely to produce psychosis• Anticholinergics• Amantadine• Dopamine agonists

– Pramipexole– Ropinirole– Rotigotine

• Controlled release carbidopa/levodopa• Immediate release carbidopa/levodopa

Psychosis• Treatment

– Differentiate psychosis from delirium• Marked autonomic dysfunction and depressed levels of

consciousness suggest delirium– Very different differential diagnosis

» Toxic, metabolic and infectious causes

Psychosis• Treatment

– Anti-psychotics• All typical antipsychotics can markedly worsen

parkinsonism• Most atypical antipsychotics with the exception of

quetiapine (Seroquel) and clozapine (Clozaril) will worsen parkinsonism

– Associated with increase risk of sudden death (small)– Clozapine associated with a 1.8% risk of

agranulocytosis• Increased risk of unexplained death in elderly with

dementia

Psychosis• State of confusion

– Capgrass syndrome• Cholinesterase inhibitors • Galantamine -allosteric potentiation of nicotinic

acetylcholine receptors

Depression• Part of the syndrome independent of disability• Confusion between parkinsonism and depression

– High index of suspicion• Depression in elderly presents differently compared to young

– More cognitive problems (pseudodementia)– Bradykinesia particularly mask-like faces versus psychomotor

retardation– Thoughts of death or dying may or may not suggest depression

• Anhedonia perhaps a good marker• Parkinsonism may improve with aggressive treatment of depression

– ECT

Dopamine dysregulation syndrome• Impulse control problems• Gambling• Hypersexual behavior• Hypomania• Dysphoria• compulsive shopping• Compulsive repetitive stereotypic motor behaviors (punding)• Eating disorders • Aggressive behavior

modified Edmonton Symptom Assessment System Scale for PD (ESAS-PD)

• Miyasaki JM, Long J, Mancini D, Moro E, Fox SH, Lang AE, Marras C, Chen R, Strafella A, Arshinoff R, Ghoche R, Hui J. Palliative care for advanced Parkinson disease: an interdisciplinary clinic and new scale, the ESAS-PD. Parkinsonism Relat Disord. 2012 Dec;18 Suppl 3:S6-9. doi: 10.1016/j.parkreldis.2012.06.013. Epub 2012 Aug 3. PubMed PMID: 22867994.

TAKE-HOME MESSAGESParkinson’s disease is common particularly in the elderly and likely to be encountered in the patients in palliative care. Patients may experience motoric and non-motoric symptoms and disabilities. Further the compromised patient is at risk for complications from and due to the treatment of Parkinson’s disease. But many are eminently treatable.