Atypical parkinsonism

ATYPICAL PARKINSONISM- PARKINSON PLUS SYNDROMES- AN UPDATE

1. ATYPICAL PARKINSONISM DR.SARATH MENON.R, MD(Med.),DNB(Med.),MNAMS DM RESIDENT DEPT. OF NEUROSCIENCES AIMS,KOCHI

2. OUTLINE Classifications Red flag signs AP- syndromic approach Diagnostic criteria Phenotypic spectrum Atypical AP or mimickers Investigations Novel biomarkers Treatment Future trends

3. INTRODUCTION Common problem in neurology outpatient departments Wide variety of sporadic / heredodegenerative syndromes Aetiologies vary widely 80-85% -IPD Differentiation from other syndromes Very important in prognostication and management

4. AKINETIC RIGID SYNDROMES - CLASSIFICATION Primary (Idiopathic) Parkinsonism Multisystem Degenerations . Heredodegenerative Parkinsonism Secondary (Acquired, symptomatic) Parkinsonism

5. Primary Parkinsonism Parkinson’s Disease - Sporadic Parkinson’s Disease - Hereditary

6. Multisystem Degenerations ( Parkinsonism Plus ) Progressive Supranuclear Palsy Multiple System Atrophy (Shy-Dragger syn.) SND (MSA P) OPCA (MSA C) Corticobasal Degeneration Diffuse Lewy Body Disease Lytico-Bodig disease (Parkinsonism Dementia ALS -Complex of Guam) Progressive pallidal Atrophy Parkinsonism dementia Complex Pallido pyramidal Degenerations

7. Heredo Degenerative Hereditary Juvenile Dystonia Parkinsonism (AR Parkin Mutation) Dopa - Responsive Dystonia Huntington’s Disease Wilson’s Disease Hereditary Ceruloplasmin Deficiency Frontotemporal dementia with parkinsonism Mitochondrial Cytopathies with Striatal Necrosis PKAN ( Neurodegeneration associated with brain Iron accumulation; Hallervorden - Spatz Disease)

8. Spinocerebellar Degenerations ( Eg : MJD) Gerstmann - Straussler - Scheinker Disease Familial Progressive Subcortical Gliosis Familial Basal Ganglia Calcification Lubag (X Linked dystonia - Parkinsonism) Ceroid Lipofuscinosis Neuroacanthocytosis Hereditary Haemochromatosis . Neuroferritinopathy Aceruloplasminemia

9. Secondary Parkinsonism Infectious Post- encephalitic HIV; SSPE; Prion diseases Drugs Dopamine Receptor Blocking drugs, Reserpine , Tetrabenazine , Alpha Methyl Dopa , Lithium, Flunarizine , Cinnarizine . Toxins MPTP, Carbon monoxide, Manganese, Mercury, Carbon disulfide,Cyanide , Methanol . Vascular -Multi infarct; Binswangers disease. Trauma -Pugilistic Encephalopathy. Parathyroid abnormalities; Hypothyroidism; Brain Tumors Paraneoplastic NPH Psychogenic.

10. Idiopathic pd UK Brain Bank Criteria bradykinesia and at least one of the following: rest tremor, rigidity, or postural instability.

11.   Red Flags Symmetric bradykinesia and rigidity Absence of tremor Prominent myoclonus Limb apraxia Alien limb phenomena Impaired down gaze Facial dystonia Early loss of postural reflexes L- dopa induced facial dyskinesias Ataxia Stridor Early dysphagia Spasticity Early dementia or hallucinations Early and prominent dysautonomia

12. major syndromes PSP MSA CBGD DLBD

13. PATHOPHYSIOLOGY Accurate diagnosis is necessary to understand pathogenesis Two proteins mainly Alpha synuclein Pre synaptic protein Aggregates in cell body & neurons – lewy body & lewy neuritis- PD & DLBD glial cytoplasmic inclusion in MSA

14. Taupathy 4 repeat tau accumalates NFT & in glia Psp - astrocytic tufts CBD- astrocytic plaques

15. Progressive supranuclear palsy Steele et al—1964 5% of parkinsonian pts Prevalence—4.9 / 100,000 Incidence 1.7 (50-59yrs) to 14.7(80-89yrs) Commonly misdiagnosed as PD Insidious onset No pathologic proven cases have begun before the age of 40.

16. Tauopathy-4-repeat t, 4R tauopathy ). always sporadic, few familial cases- - MAPT ( microtubuli associated protein t) gene mtn. Mitochondrial dysfunction & oxidative stress - pathophysiology of PSP

17. Postural Instability & EP Features :  Falls—backward Poor postural reflexes Rigidity –axial Dysarthria —spastic, Hypophonic ataxic Frontal release signs Pseudobulbar palsy L-DOPA UNRESPONSIVENESS

18. Reduced blink rate and closure of eyelids due to eyelid dystonia or levator inhibition ( apraxia of eyelid opening) square wave-jerks on doll’s eye maneuver, there is improved range, as vestibulo -ocular reflex is preserved Subcortical -type dementia Typical facies - “surprised look”

19. NINDS–SPSP diagnostic criteria for psp Possible PSP Mandatory inclusion criteria: gradually progressive disorder onset age 40 or later Either vertical supranuclear palsy or both slowing of vertical saccades postural instability with falls within a year of disease onset no evidence of other diseases that could explain the foregoing features, as indicated by exclusion criteria

20. Mandatory exclusion criteria : recent history of encephalitis alien limb syndrome cortical sensory deficits focal frontal or temporoparietal atrophy hallucinations or delusions unrelated to dopaminergic therapy cortical dementia of Alzheimer type prominent, early cerebellar symptoms unexplained dysautonomia

21. Supportive features : symmetrical akinesia or rigidity proximal more than distal abnormal neck posture especially retrocollis poor or absent response of parkinsonism to levodopa early dysphagia and dysarthria early onset of cognitive impairment including two or more of: apathy, impairment in abstract thought, decreased verbal fluency, utilisation or imitation behaviour , or frontal release signs

22. Probable PSP Mandatory inclusion criteria gradually progressive disorder onset age 40 or later vertical supranuclear palsy prominent postural instability with falls within a year of disease onset no evidence of other diseases that could explain the foregoing features, as indicated by exclusion criteria

23. Definite PSP Mandatory inclusion criteria: clinically probable or possible PSP and histopathological evidence of typical PSP

24. phenotypic spectrum of progressive supranuclear palsy typical PSP phenotype- Richardson syndrome PSP-p = PD at least at the initial stages, with asymmetric parkinsonism, rest-tremor, better levodopa response, longer mean survival pure akinesia with gait freezing (PSP-PAGF) corticobasal syndrome (PSP-CBS), frontotemporal dementia (PSP-FTD), progressive nonfluent aphasia no clinical sign to predict PSP pathologic abnormality accurately in the non-RS phenotypes

25. investigations clinical diagnosis MRI- midbrain atrophy Superior cerebellar peduncle atrophy. “morning glory flower sign” and the “hummingbird sign” are quite specific but show low sensitivity (50% and 68.4%, respectively ( DATscan ) is abnormal in PD and all AP syndromes

26. differentiate with PD, [123]meta- iodobenzylguanidine (MIBG) and 123I-iodobenzamide (IBZM) SPECT may be useful MIBG is abnormal in PD because of postganglionic sympathetic denervation , but is typically normal in PSP. IBZM SPECT assessing the postsynaptic receptors is abnormal in PSP and normal in PD IBZM SPECT is abnormal in all APs and therefore cannot differentiate between PSP and other AP Novel diagnostic approaches and biomarkers - csf tau protein - neurofilament light chain

27. pathology Neurofibrillary tangles are present in these areas. Tufted astrocytes ( Gallyas -positive) -hallmark feature of PSP that differentiates other 4R tauopathies such as CBD ( astrocytic plaques

28. rx no effective symptomatic or neuroprotective treatments A trial of levodopa (up to 1 g/d) and amantadine (up to 450 mg/d) Botulinum toxin injections can be used to treat levator inhibition. Serotonin reuptake inhibitors (SSRIs) may be used for apathy with no clear benefit. A small study with Coenzyme Q10- no RCT study Recent large, double-blind studies with GSK-3b inhibitors ( Tideglusib , Davunetide ) have failed to show any clinical effect. Tideglusib reduced the rate of brain atrophy in one study. Supportive measures such as physiotherapy, walking aids, speech therapy and PEG

29. Multiple system atrophy :    Sporadic neurodegenerative disorder clinically any combination of parkinsonian , autonomic, cerebellar , or pyramidal signs Pathologically– cell loss, gliosis , and glial cytoplasmic inclusions in several CNS structures. MSA is an a- synucleinopathy usually a sporadic disease; however, rarely, familial cases - mutations in COQ2 gene

30. Epidemiology :  prevalence of MSA in four studies ranged from 1·9 to 4·9 cases per 100 000 people. similar to those of other well-known neurodegenerative disorders such as Huntington’s disease and motor neuron disease. no single environmental factor shown to increase or to reduce risks of MSA

31. Clinical presentation :  affects both men and women the sixth decade of life progresses with a mean survival of 6–9 years. substantial variation of disease progression with survival of more than 15 yrs. main features – autonomic failure Parkinsonism cerebellar ataxia pyramidal signs in any combination.

32. Two major motor presentations distinguished clinically– Parkinsonian features predominate in 80% of patients (MSA-P subtype), cerebellar ataxia is the main motor feature in 20% of patients (MSA-C subtype). Both similar survival times. patients with MSA-P have a more rapid functional deterioration than those with MSA-C

33. MSA-P-associated parkinsonism :  progressive akinesia and rigidity jerky postural tremor and tremor at rest. orofacial or craniocervical dystonia associated with a characteristic quivering high-pitched dysarthria . Postural stability is compromised early on in the disease course recurrent falls at disease onset are unusual in contrast to psp .

34. 90% of the MSA-P pts- unresponsive to levodopa in the long term. 50% have levodopa -induced dyskinesia affecting orofacial and neck muscles, without motor benefit. fully developed clinical picture of MSA-P evolves within 5 years of disease onset, allowing a clinical diagnosis during follow-up.

35. Msa –p red flags Early instability Rapid progression Pisa syndrome,camptocormia,contractures Bulbar dysfunction Respiratory dysfn - stridor,insp sighs Emotional incontinence 2/6 – probable MSA-P – additional criteria

36. MSA-C :  gait ataxia limb kinetic ataxia scanning dysarthria , cerebellar oculomotor disturbances. Most patients develop additional non- cerebellar symptoms and signs may be indistinguishable from other patients with idiopathic late onset cerebellar ataxia

37. Dysautonomia :  urogenital and orthostatic dysfunction. Early erectile dysfunction is nearly universal in men with MSA Female- genital insensitivity urinary incontinence or retention are common early in the course or as presenting symptoms

38. Consensus statement for the clinical diagnosis of MSA clinical domains, features criteria used in the diagnosis of MSA

39. Autonomic and urinary dysfunction :  Features 1. Orthostatic hypotension 2. Urinary incontinence or incomplete bladder emptying Criteria Reduction of least 30mmHg or in diastolic blood pressure by at least 15 mm Hg after 3 min of standing urinary incontinence (persistent, involuntary partial or total bladder emptying, accompanied by erectile dysfunction in men) or both

40. Parkinsonism :  A. Features 1. Bradykinesia 2. Rigidity 3. Postural instability (not caused by primary visual, vestibular, cerebellar , or proprioceptive dysfunction) 4. Tremor (postural, resting or both) B. Criteria Bradykinesia plus at least one of features 2–4

41. Cerebellar dysfunction :  A. Features 1. Gait ataxia 2. Ataxic dysarthria 3. Limb ataxia 4. Sustained gaze-evoked nystagmus Criteria Gait ataxia plus at least one of features 2–4

42. Corticospinal tract dysfunction A. Features 1. Extensor plantar responses with hyper- reflexia Criteria Corticospinal tract dysfunction in MSA: no corticospinal tract features are used in defining the diagnosis of MSA prominent and severe spasticity should raise suspicion for an alternative diagnosis

43. Consensus statement: exclusion criteria for the diagnosis of MSA :  History Symptomatic onset under 30 years of age Family history of a similar disorder Systemic disease or other identifiable causes Hallucinations unrelated to medication DSM IV criteria for dementia Prominent slowing of vertical saccades or vertical supranuclear gaze palsy Evidence of focal cortical dysfunction such as aphasia, alien limb syndrome, and parietal dysfunction Laboratory investigation- Metabolic, molecular genetic and imaging evidence of an alternative cause of features

44. Diagnostic clinical approach   Motor signs Parkinsonism poorly responsive to levodopa Cerebellar ataxia Pyramidal signs Early instability and falls Within 3 years of disease onset Rapid progression (wheelchair sign) despite dopaminergic treatment within 5 years of disease onset

45. Orofacial dystonia or dyskinesias Atypical spontaneous or levodopa induced dystonia dyskinesia mainly affecting orofacial muscles, [resembling risus sardonicus of cephalic tetanus] Axial dystonia - Pisa syndrome ( subacute axial dystonia with a severe tonic lateral flexion of the trunk, head, and neck) early severe camptocormia Disproportionate antecollis -Chin on chest, neck can only be passively and forcibly extended to its normal position with difficulty; despite severe chronic neck flexion, flexion elsewhere is minor.

46. Jerky tremor Irregular myoclonic postural or action tremor of the hands or fingers Dysarthria - - Atypical quivering, irregular and severely hypophonic or slurring high pitched dysarthria , - tends to develop earlier and be more severe than in PD notable dysphagia

47. Non-motor signs Severe dysautonomia Abnormal respiration Nocturnal (harsh or strained, high pitched inspiratory sounds) or diurnal inspiratory stridor , involuntary deep inspiratory sighs and gasps, sleep apnoea snoring increased from premorbid level newly arisen REM sleep behaviour disorder Emotional incontinence

48. “ red flags’’ RBD and autonomic failure- pre motor stage Early falls and postural instability can be seen- look for eye signs & fronto-subcortical dysfunction for PSP L-dopa induced oro facial dystonia - MSA Raynaud phenomenon is a common in MSA Freezing of gait may be prominent, early, and severe, causing diagnostic difficulties -PSP -PAGF phenotype dementia, it is considered a non supporting feature for the diagnosis of MSA frank, prominent, early dementia should lead the clinician to other diagnoses.

49. Investigations Autonomic function tests Cardiovascular function test-within in 2-3 ys Bladder function tests standard urine analysis will exclude infection. The residual volume – usg,cystometry ,UDS

50. imaging MRI Hot cross burn sign- mcp / pons - MSA-c Putaminal rim- MSA-p DAT scan abnormal in all MSA, PSP, and PD MIBG scintigraphy abnormal in PD, normal in MSA IBZM SPECT is normal in PD,abnormal in MSA (but also in PSP and CBD)

51. Novel biomarkers Mollenhauer and colleagues- CSF mean a- synuclein levels , not total t, or Ab42 levels differentiated PD and MSA from neurologic controls (70% sensitivity, 53% specificity) a- synuclein and phosphorylated t/total t could differentiate PD from MSA -sensitivity of 90% & specificity of 71% Flt3 ligand , a cytokine PD and MSA with a sensitivity of 99% and a specificity of 95%.

52. rx Symptomatic PD - L-dopa/ dopa agonists- cranio cervical dystonia postural hypotension Amantidine - gait disturbances Orthostatic hypotension- high salt, fludrocortisone,midodrine Urinary dysfunction - UDS- characterise nature - Neurogenic bladder- Oxybutinin or Tolderotidne Erectile dysfunction - - sildenafil - intracavernosal inj. Or penile implants

53. Emotional incontinence SSRI/TCA RCT – Rasagiline and rifampicin - no effects Promising studies IVIG Intrarterial /IV autologous stem cells Future Alpha synuclein targeting antibodies

54. Corticobasal degeneration : sixth to eighth decades of life, onset of symptoms at mean age 63 years (SD 7·7) . sporadic disease 4–6% of parkinsonism,

55. Clinical presentations Five initial presentations The most common presentation (55%) -“useless arm” ( ie , a rigid, dystonic , akinetic , or apraxic arm), gait disorder (27%) prominent sensory symptoms isolated speech disturbance behavioural disturbance

56. Clinical features Motor Limb clumsiness (asymmetric) Bradykinesia / Akinesia (asymmetric) Rigidity (asymmetric) Tremor (action/postural) Myoclonus Limb dystonia (asymmetric) Blepharospasm Choreoathetoid movements Speech abnormalities Gait disorder

57. Higher cortical functions Apraxia (limb more common than orofacial , eyelid-opening) Dementia Alien-limb phenomenon Aphasia Frontal-lobe-release signs Cortical sensory abnormalities   Depression apathy Anxiety Irritability Disinhibition Delusions Obsessive compulsive disorder

58. Diagnostic criteria for corticobasal degeneration Inclusion criteria (one of A or B) A) Rigidity (easily detectable without reinforcement) and one cortical sign : apraxia (more than simple use of limb as object; absence of cognitive or motor deficit sufficient to explain disturbance) cortical sensory loss (preserved primary sensation, asymmetric) alien-limb phenomenon (more than simple levitation) B) Asymmetric rigidity, dystonia (focal in limb; present at rest at onset), focal reflex myoclonus (spreads beyond stimulated digits

59. Exclusion criteria Early dementia (will exclude some patients with corticobasal degeneration) Early vertical gaze palsy Rest tremor Severe autonomic disturbances Sustained responsiveness to levodopa Lesions on imaging studies indicate another pathological process

60. Proposed criteria for the diagnosis of corticobasal degeneration Core features Insidious onset and progressive course No identifiable cause ( eg , tumour , infarct) EPS – one of the follow -focal or asymmetric appendicular rigidity -lacking prominent and sustained l- dopa response -focal or asymmetric appendicular dystonia   Cortical dysfunction - at least one of the following : focal or asymmetric ideomotor apraxia alien-limb phenomena cortical sensory loss visual or sensory hemineglect constructional apraxia focal or asymmetric myoclonus apraxia of speech or nonfluent aphasia

61. Supportive investigations Variable degrees of focal or lateralised cognitive dysfunction, with relative preservation of learning and memory on neuropsychometric testing Focal or asymmetric atrophy on CT or MRI imaging, typically in perifrontal cortex Focal or asymmetric hypoperfusion on SPECT or PET, typically maximal in parietofrontal cortex with or without basal ganglia involvement

62. Neuropathological criteria Core features Focal cortical neuronal loss Substantia nigra neuronal loss Cortical and striatal Gallyas /tau-positive neuronal and glial lesions, especially astrocytic plaques and threads, in both white and grey matter Supportive features Cortical atrophy, commonly with superficial spongiosis Ballooned neurons, in atrophic cortices Tau-positive oligodendroglial coiled bodies

63. phenotypic spectrum of corticobasal degeneration Classic CBD phenotype- CBS CBD- present with FTD,RS,PPA,PCA AD,PSP,FTD present with CBS Symmetrical bilateral CBS- AD pathology/RS Early onset PSP – CBD pathology For which proposed clinical criteria applied

64. Investigations Imaging asymmetric frontal, and parietal cortical atrophy becomes evident with dilatation of the lateral ventricle EEG – -normal at first - show asymmetric slowing that is maximum over the hemisphere contralateral to the more affected limb   Dopamine transporter SPECT- abnormal - differentiate them from those with Alzheimer’s and Pick’s diseases (in whom this scan is typically normal) early in the course of the disease.

65. FDG-PET - Asymmetric reduction in fronto parietal regions

66. rx Anecdotal L-dopa trial ( upto 1 gm/d)/ Amantadine - PD symptoms Valproate , Levetiracetam - myoclonus Botox inj - dystonic hand No trials with ACEI – dementia Palliative rx

67. “ cortico basal degeneration-lookalike” syndromes atypical manifestations of PSP -progressive nonfluent aphasia FTD. Parkinson’s disease multiple-system atrophy Wilson’s disease progressive subcortical gliosis rigid- akinetic type Huntington’s disease atypical Pick’s disease parkinsonism– dementia–amyotrophic-lateral-sclerosis complex prion related disease sudanophilic leukodystrophy neurofilament inclusion disease.

68. Dementia with Lewy bodies Central feature (essential for a diagnosis of possible or probable DLB) Dementia -progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairmen - not occur in the early stages ,usually evident with progression. Deficits on tests of attention, executive function, and visuospatial ability may be especially prominent.

69. Core features (two core features are sufficient for a diagnosis of probable DLB , one for possible DLB) Fluctuating cognition with pronounced variations in attention and alertness Recurrent visual hallucinations that are typically well formed and detailed Spontaneous features of parkinsonism

70. Suggestive features REM sleep behavior disorder Severe neuroleptic sensitivity Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging (If one or more of these is present in the presence of one or more core features , - probable DLB . In the absence of any core features, one or more suggestive features is sufficient for possible DLB. Probable DLB should not be diagnosed on the basis of suggestive features alone.)

71. Supportive features (commonly present but not proven to have diagnostic specificity) Repeated falls and syncope Transient, unexplained loss of consciousness Severe autonomic dysfunction, e.g., orthostatic hypotension, urinary incontinence Hallucinations in other modalities Systematized delusions Depression Relative preservation of medial temporal lobe structures on CT/MRI scan Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity Abnormal (low uptake) MIBG myocardial scintigraphy Prominent slow wave activity on EEG with temporal lobe transient sharp waves

72. A diagnosis of DLB is less likely If -CVA evident as focal neurologic signs or on brain imaging In the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical picture If parkinsonism only appears for the first time at a stage of severe dementia

73. Temporal sequence of symptoms diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). Parkinson disease dementia (PDD) - dementia that occurs in the context of well-established Parkinson disease. In research studies in which distinction needs to be made between DLB and PDD, the existing 1-year rule between the onset of dementia and parkinsonism - DLB continues to be recommended.

74. Clinical management Motor parkinsonism- - Levodopa at low doses & titrate up. - Anticholinergics should be avoided. Neuropsychiatric symptoms.--cholinesterase inhibitors (CHEIs) or atypical antipsychotic

75. “Atypical” atypical parkinsonism Misdiagnosis PD with AP , as well as FTD,AD,PPA Mimickers of Atypical PD Eg : SCAS/ FTAX- mimic MSA Neimann Pick C,CTX,prion d/ s,mitochondrial - mimic AP phenotype Age of onset Tempo of progression Family history Clinical exam + associated features

76. summary Careful clinical examination Expanding phenotypic spectrum of AP & expanding pathological spectrum of classic AP phenotypes – diagnostic challenge AP mimickers Investigations may be supportive, but their sensitivity and specificity are low. There are currently no biomarkers available. There are currently no neuroprotective treatments available. symptomatic and supportive treatments with usually no sustained effect. Further research required

77. Thank you