“multisystem wot -trophy….”

1. “multisystem wot-trophy….” Ben Johnson

2. Overview • Context • RCGP curriculum heading • Neurological diseases in the palliative setting • Illustrate with a case • Multisystem atrophy: symptoms, diagnosis, investigations, management, further developments & prognosis • Conclusion & references

3. Context • Tom, 51 yrs ex-telecoms engineer. Wife, daughter and four grandchildren. • Attends DTU for Multi Systems Atrophy (MSA). • Difficult symptom control. • Due to nature of condition has multiple specialties involved, burden of appointments and polypharmacy. • Referred from DTU 6/2 for planned inpatient assessment and management of multiple symptoms. • Admitted 22/2 to inpatient unit.

4. RCGP Curriculum Headings • 3.3 Ethics and Values Based Medicine • 3.4 Promoting equality and valuing diversity • 3.5 Evidence-based Practice • 6 Genetics in Primary Care • 10.2 Men's health • 12 Care of People with Cancer & Palliative Care • 15.7 Neurological problems

5. Neurological conditions in the palliative setting Motor neurone disease (MND) Multisystem atrophy (MSA) Multiple sclerosis (MS) Hepatocerebral degeneration Progressive Supranuclear Palsy (PSP) Parkinson’s disease Huntington’s disease Dementia eg Alzheimer’s Encephalopathies Epilepsy – post debulking surgery, post radiotherapy, post CVA, due to cerebral metastases Brain Injury

6. Epidemiology

7. Case DTU referral “ MSA diagnosed 2009, co-morbities (chronic joint pain, spondylysis, asthma, low mood), recurrent LRTIs (probable aspiration), dizziness and hypotension leading to falls, nausea/vomting, sweats/pallor (autonomic disturbance due to MSA), fatigue (sleeping most of the day, CPAP for OSA, tablet burden”

8. Main problems on admission PMH OA, ??RA hands, COPD, OSA on CPAP, Fibromyalgia, ??myoclonic jerks, restless legs, erectile dysfunction, bilateral carpal tunnel releases, multiple arthroscopies to knees, elbows, shoulders, neck & back pain, psychology intervention Pain Headaches Mobility Dizziness Swallowing Fatigue Hot flushes Memory Mood Polypharmacy (25)

9. Patient’s story • 1997 RTA at work leading to back pain and ?spondylysis • 1999 Orthopaedic review “unlikely to work again” • 2000 Went back to work for 3/12 but stopped due to back pain • 2000 Problems with falls, nausea & vomiting, dizziness • 2004 fatigue started, respiratory input led to CPAP/BiPAP • 2007 problems with hypotension, started on fludrocortisone. Hot flushes. Had cardiology & endocrine input too. • 2009 Diagnosis on MSA. Swallowing difficulties. • 2010 gastroparesis

10. Examination/Social assessment Physical examination largely unremarkable. P77, BP108/61, BM7, O2 92%A, CN : normal except some fasciculation of tongue PNS: all normal except 4+/5 bilateral for grip strength and hip flexors. Mobilising with x2 crutches AMT : 8/10 (later MMSE 30/30) Depression screen 2/2 Wife works as ODP, one daughter and four grandchildren DLA, Incapacity benefit Carer is wife. No formal help, wife’s sister regularly helps with transport to appointments etc. She is paid for 8hrs/wk to act as a befriender. MSA support group in Salford Insight : progressive, non-curative illness. Not clear about what diagnosis means. Struggles sometimes with mortality and leaving loved ones behind. Sometimes hopeless. No SI for years. Admits to not being an open persons. PPD ideally home but if not practical, Manorlands No spiritual needs. No DNACPR

11. Plan after initial assessment • Medication rationalisation. ?stop tamsulosin, finasteride, glucosamine. Aim to reduce medication load further. Liaise with respiratory team re stopping modafinil since SE include headache • Explore headache symptom further. May ultimately need further neuroimaging. • OT, Physio and complementary therapy input • More support at home and for wife • Multiple co-morbities. Multiple specialties and hospitals involved. Need clarity over diagnosis. • Observe symptom control and review medication accordingly. • Help with advanced care planning • Liaise with community SALT for review at Manorlands

12. Summary of admission • Duration 15 days • Improved somnolence/fatigue • Improved pain reducing fentanyl from 325 to 300. Using less PRNs. Reduce further after elbow surgery at DTU • Headaches vastly improved frequency from 4-5/7 to 1/7. • Sleep clinic review for advice with modafinil and check CPAP settings + ABG • Referral to ED team • Open up discussion between patient and his wife. • Care package options explored • Attempt to clarify “list”of diagnoses and communication with relevant specialties. Medication reviewed reducing modafinil, stopping quinine, carbocisteine, finasteride, tamsulosin. Reduced opiate dose. OT & Physio review. Exercise programme, aids. SALT review with community follow up Mood better. Review venlafaxine dose in community. Consider referral to rehab services and further psychological assessment in the community. Exploration of MSA diagnosis. Advanced care planning including preferred priorities of care to be picked up by CNS in community. Introduction to inpatient setting and usefulness in managing chronic, progressive disease

13. Aim of study • To describe the existing access to SPC services for people with LTNC, and to identify current gaps in service provision. • To identify the views of consultants in the specialities of palliative medicine, rehabilitation and neurology regarding their own and other specialities’ roles, access to services and any gaps. • To determine how their services should interact to meet the needs of people with LTNC.

14. Multisystem Atrophy : overview • Multiple system atrophy (MSA) is a rare neurodegenerative disorder, caused by cell loss in certain areas of the brain and the spinal cord, leading to a variety of symptoms affecting especially the functions of the autonomic nervous system and the motor system. • These are characterised by Parkinsonian features of varying severity, cerebellar ataxia and autonomic (particularly urogenital) dysfunction. • It is sporadic, of adult onset and progressive. • Most patients with MSA develop the disease when older than 40 years and the mean age at onset is between 50 and 70 years.

15. Multisystem Atrophy : overview • The aetiology is not fully understood although recently, α-synuclein has been found to have an important role. • Novel treatment options are being investigated but currently management options are very limited. There is no cure. • Terminology : MSA is referred to as MSA-P type if Parkinsonian features predominate. The terms striatonigral degeneration or Parkinsonian variant are sometimes used in these cases. MSA-P accounts for about two-thirds of cases. MSA-C type describes disease where cerebellar symptoms predominate. This may also be described as sporadic olivopontocerebellar atrophy. MSA-C accounts for about one third of cases. The term Shy-Drager syndrome, which was used to describe MSA with predominant autonomic dysfunction, is not now used, as almost every patient is affected by autonomic or urinary dysfunction.

16. Multisystem Atrophy : presentation • The most common presentations are urinary dysfunction (83%), postural hypotension (75%) and cerebellar ataxia (64%). • Patients may also present with Parkinsonian symptoms, often with a poor or temporary response to levodopa therapy, or cerebellar dysfunction. • Corticospinal tract dysfunction may occur but is not usually a major presentation. • When the disorder presents with non-autonomic features, imbalance caused by cerebellar or extrapyramidal abnormalities is the most common feature. • Constipation may also occur. • There may possibly be mild intellectual impairment, particularly in older patients with greater physical disability. • Other neuropsychiatric problems may include depression, insomnia, daytime sleepiness, restless legs, hallucinations and dementia.

17. Multisystem Atrophy : diagnosis The diagnosis of MSA is based mainly on clinical features. Most patients do not receive the correct diagnosis during their lifetime because of the difficulty in differentiation from other disorders, particularly Parkinson's disease and pure autonomic failure. Definite diagnosis can only be made postmortem. However, major and additional features have been identified which support a possible diagnosis.

18. Multisystem Atrophy : diagnosis

19. Multisystem Atrophy : diagnosis

20. Differential diagnoses • Parkinson's disease is the main differential; about 10% of patients diagnosed with Parkinson's disease are actually found to have MSA on autopsy. Features that suggest MSA over Parkinson's disease include: • Rapid progression of symptoms. • Poor response to levodopa. • Autonomic features are more pronounced. • Rigidity and bradykinesia are out of proportion to the tremor. • Speech may be severely affected. • Aspiration, inspiratory gasps and stridor may be present. Other diagnoses to consider include: Pure autonomic failure. Progressive supranuclear palsy . Multi-infarct dementia. Multiple sclerosis. Neuroacanthocytosis Neurosarcoidosis Neurosyphilis

21. Investigations • Autonomic function testing:bladder function assessment often detects early abnormalities consistent with neurogenic disturbance. Initially, detrusor hyperreflexia and abnormal urethral sphincter function predominate; these are later followed by increased residual urinal volume (as detected by bladder ultrasound). Other autonomic abnormalities include: • Diminished respiratory sinus arrhythmia. • Abnormal response to Valsalva manoeuvre (no blood pressure recovery in late phase II and/or no overshoot in phase IV). • Diminished response to isometric exercise (hand grip). • Diminished response to cold pressor stimuli. • Iodine-123 (I-123) metaiodobenzylguanidine (MIBG) scintigraphy: • Thought to be useful for differentiation between Parkinson's disease and MSA early after onset of autonomic dysfunction. • Patients with Parkinson's disease have significantly lower cardiac uptake of I-123 MIBG than patients with MSA and controls. • MRI and proton magnetic resonance: • Brain imaging may be normal in MSA. Localised brain degeneration may be detected by MRI techniques. • The slit hyperintensity of the lateral margin of the putamen in T2-weighted MRI is a characteristic finding in patients with MSA, involving the extrapyramidal system. • Fluoride 2-(F18)fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) imaging: • Can be used for differentiation between MSA and Parkinson's disease. • The caudate-putamen index (difference in the uptakes in the caudate and putamen divided by the caudate uptake) is lower in patients with MSA than in patients with Parkinson's disease. • Histology: • Neuropathologic changes consist of a high density of glial cytoplasmic inclusions in association with degenerative changes in certain brain structures, e.g. putamen, caudate nucleus, globuspallidus, thalamus, pontine nuclei, cerebellar Purkinje's cells and autonomic nuclei of the brainstem. • Glial cytoplasmic inclusions: can be stained by the Gallyas silver technique and are a hallmark of MSAs.

22. (A) Axial T2 image showing the classic “hot cross bun” sign in the pons; axial (B) and coronal (C) T2 images depicting a hyperintense rim bordering the lateral margin of both putamina (white arrows); (D) sagittal T2 sequence disclosing pontine and cerebellar atrophy, the latter also evident in A. Right side of images is left side of patient in A, B, and C.

23. Management Currently, no therapy can reverse or halt progression of the disease. Management is symptomatic and targets Parkinsonism and autonomic failure. The extrapyramidal and cerebellar aspects of the disease are debilitating and difficult to treat. Orthostatic hypotension is often the problem that brings the patient to the doctor and is associated with reduced physical activity (and the consequent deconditioning and problems associated with this) so management of this is a particularly important aspect of patient care. Nondrug • Orthostatic hypotension: • Mechanical manoeuvres such as leg-crossing, squatting, abdominal compression, bending forward, and placing one foot on a chair can be effective to prevent episodes of orthostatic hypotension. • Wearing an external support garment that comes to the waist improves venous return and preload to the heart during standing (but loses effectiveness if the patient also wears it while supine). • Tilted sleeping with the head elevated can help. • Postprandial hypotension: • Small and more frequent meals prevent a blood pressure drop after eating. • Intake of water half an hour before meals, or drinking coffee, can counteract postprandial hypotension. • Supine hypertension: • Patients should not lie down during the day. • Tilted sleeping with the head elevated is helpful to lower supine hypertension during the night, decrease nocturia and prevent orthostatic hypotension in the morning. • Exercise of muscles of the lower extremities and abdomen (aqua-aerobics is particularly useful but not swimming, which causes polyuria) and postural training. • Speech and language therapy may help with the swallowing and communication difficulties associated with stridor. • A high-fibre diet ± laxatives for constipation. • Occupational therapy can be of significant help.

24. Management Drugs • Orthostatic hypotension: • Fludrocortisone: • Traditionally, this has been the mainstay of therapy. • Disadvantages include possible hypokalaemia, hypomagnesaemia and excessive fluid accumulation. • Most patients have supine hypertension, even when receiving no therapy. This limits the degree to which upright blood pressure can be increased with fludrocortisone. • Midodrine and short-acting sympathomimetics: • Midodrine avoids the electrolyte abnormalities associated with fludrocortisone. • Supine hypertension often limits the dose and therefore effectiveness of treatment. • Recombinant erythropoietin: • Increases the functional capacity of patients, particularly if there is associated mild anaemia, which is common. • Recombinant erythropoietin has been shown to correct anaemia and improve standing blood pressure. • Other agents that are much less often used include non-steroidal anti-inflammatory drugs, antihistamines, somatostatin analogues, caffeine, and yohimbine. • Movement disorder: • Usually treated with levodopa, dopaminergic agonists, anticholinergic agents, or amantadine, but effectiveness may be very limited. • However levodopa is effective in 40-60% of patients with predominant Parkinsonian features.

25. Future developments • Drug therapy • At the moment, no neuroprotective treatment is available. But there are potential drug candidates that have been considered: • Growth hormone therapy: experimentally, growth hormone therapy appears to slow progression of the disease but not significantly. • Minocycline: this is a tetracycline with neuroprotective efficacy in transgenic MSA mice which has shown some promise in the early stages of the disease in laboratory studies. • Rasagiline: this is a monoamine oxidase B inhibitor which appears to have disease-modifying effects and is soon expected to enter phase 3 trials. • Rifampicin: this has been shown to have the property of preventing α-synuclein aggregation and so is also being considered as a therapeutic candidate. Neurotransplantation • Striatal grafting has been discussed as a therapeutic option to 'turn MSA into Parkinson's disease' by recovering dopaminergic response in experimental models. However, early trials on mice models have given rise to a number of problems and much more work has yet to be done in this area.

26. Prognosis Most patients have a poor prognosis with an average survival rate of 9 years following disease onsetalthough there can be substantial variation. Poor prognostic factors include: • Older age at onset. • Female gender. • Early autonomic failure. • Shorter intervals between clinical milestones (e.g. frequent falling, cognitive disability, unintelligible speech, dysphagia. etc.). Bronchopneumonia and sudden death are common terminal events.

27. Conclusion This case is a good example of a patient with a palliative neurological condition. It illustrates : • morbidity and “co-morbidity,” • involvement of multiple specialties and the need for co-ordination and communication (as recognised by NCPC Neurology Study) • polypharmacy (benefits vs side effects of interventions) • depression in chronic disease • exploration of patient and carer goals • need for early advanced care planning • inpatient setting for symptom control. It also introduced me to a condition I knew little about.

28. Resources • http://www.ncpc.org.uk/site/Neurological-conditions • http://www.patient.co.uk/doctor/Multiple-System-Atrophy.htm • http://www.neurology.org/content/71/15/e38.full • Gpnotebook.com • http://www.msatrust.org.uk/