Basal ganglia parkinson's disease

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Basal ganglia parkinson's disease

  1. 1. BASAL GANGLIA & PARKINSON’S DISEASE Pratap Sagar Tiwari, Resident, Internal Medicine
  2. 2. THIS IS NOT PSART OF THE PPT BUT FOR THEONES WHO DOWNLOADED THIS.• Note to those who downloaded this file :• In many of the slides for eg regarding the basal ganglia pathways…..only the illustration was shown in the slide and most of the part was narrated and so this downloaded ppt may not contain the portion of my narrations during the semiar but still much info is hidden in the notes added in each slides.
  3. 3. TOPIC OUTLINES• Basal Ganglia and its components• Dopamine• Basal Ganglia-thalamo-cortical motor circuit• Parkinsonism and Parkinson’s disease• Clinical features/workup/management• Atypical Parkinsons/Secondary• Recent Advances
  4. 4. NERVOUS SYSTEM DEVELOPMENT : ANATOMICAL SUBDIVISIONSPrimary division of Sec. subdivision Final segments neural tubeProsencephalon 1. Telencephalon 1. The cortex, 2. Diencephalon Caudate, Putamen, Globus pallidus 2. Thalamus, hypothalamus, subthalamus, subthalamic nucleiMesencephalon Mesencephalon Mesencephalon (Midbrain), Substantia nigra pars compacta (SNc), Substantia nigra pars reticulata (SNr)Rombencephalon 1. Metencephalon 1. Pons and cerebellum 2. Myelencephalon 2. Medulla
  5. 5. BASAL GANGLIA Picture taken from : http://withfriendship.com/user/boss/basal-ganglia.php
  6. 6. Picture taken from : http://www.macalester.edu/academics/psychology/whathap/ubnrp/dopahypoweb04/josh%20page%202.html
  7. 7. BASAL GANGLIA: COMPONENTS Picture taken from :http://webspace.ship.edu/cgboer/basalganglia.htmlCorpus striatum = striatum (caudate + putamen ) ,Pallidum , Nucleus AccumbentsSubstantia NigraSubthalamic Nucleus
  8. 8. BG COMPONENTS: CAUDATE Begins just behind the frontal lobe and curves back towards the occipital lobe. Involved in learning and memory .[1] Overacticve : OCD Underactive : ADD, depression, aspects of schizophrenia Also involved in PAP syndrome., Huntington DiseaseReference:1. Graybiel AM (2005) The basal ganglia: learning new tricks and loving it. Curr OpinNeurobiol 15:638-644.
  9. 9. BG COMPONENTS: PUTAMENunder & behind the front of the caudate. lies just It appears to be involved in coordinating automatic behaviors and influence various type of learning.A/w Tourette Syndrome. The caudate nucleus is largely separated from the lentiform complex by the anterior limb of the IC.
  10. 10. 1. head of caudate nucelus 2. body of caudate nucelus 3. caudatolenticular gray bridge 4. putamen 5. tail of caudate nucleus 6. external segment of globus pallidus 7. internal segment of globus pallidus 8. amygdaloid body 9. nucleus accumbensMedial surface of basal ganglia
  11. 11. Picture Reference : http://thalamus.wustl.edu/course/cerebell.html
  12. 12. UNDERSTANDING THE PATHWAYS Picture Reference: http://thalamus.wustl.edu/course/cerebell.html
  13. 13. UNDERSTANDING THE PATHWAYSD1 = direct pathway Striatum Gpi / SNr InhibitsD2 = Indirect pathway Striatum & GPe Gpe and STN STN Gpi /SNr Excitatory influences
  14. 14. DOPAMINE: SYNTHESIS Tyrosine L-DOPA Tyrosine Hydroxylase dopa decarboxylase Dopamine
  15. 15. DOPAMINE : DEGRADATION
  16. 16. PARKINSONISM AND PARKINSON’S DISEASE• Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.• The underlying causes of parkinsonism are numerous.• The neurodegenerative condition Parkinsons disease (PD) is the most common cause of parkinsonism as it accounts for ~75% of all cases of parkinsonism
  17. 17. PARKINSON’S DISEASE; ETIOLOGY• Genetic causes• Environmental causes• Oxidation Hypothesis• Alpha-synuclein
  18. 18. GENETIC CAUSES OF PDTable Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (18th ed.).Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372
  19. 19. PARKINSON’S DISEASE : CLINICAL FEATURES. Cardinal features Other motor features Nonmotor features Bradykinesia Micrographia Anosmia Rigidity Masked facies Mood disorders eg Resting Tremor Reduced eye blink depression Gait disturbance/postural Soft voice Sleep disturbances instability Freezing Autonomic disturbances Cognitive impairment/ dementiaTable Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (18th ed.).Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372
  20. 20. PARKINSON’S DISEASE : CLINICAL FEATURES. Cardinal features Other motor features Nonmotor features Bradykinesia Micrographia Anosmia Rigidity Masked facies Mood disorders eg Resting Tremor Reduced eye blink depression Gait disturbance/postural Soft voice Sleep disturbances instability Freezing Autonomic disturbances Cognitive impairment/ dementiaTable Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (18th ed.).Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372
  21. 21. DEMENTIA IN PARKINSONS DISEASE • The prevalence of dementia in Parkinson disease ranges from 20-40%. 1 • Hoops et al found that in dementia in Parkinson disease, the Montreal Cognitive Assessment (MoCA) is superior to the MMSE for screening for mild cognitive impairment or dementia. As a screening instrument, MoCA was better than MMSE (64% versus 54% correct diagnoses).2References:1. Weintraub D, Comella CL, Horn S. Parkinsons disease--Part 3: Neuropsychiatric symptoms. Am J Manag Care. Mar 2008;14(2 Suppl):S59-692. Hoops S, Nazem S, Siderowf AD, Duda JE, Xie SX, Stern MB. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology. Nov 24 2009;73(21):1738-45.
  22. 22. PARKINSON’S DISEASE: WORKUP• Positron emission tomography (PET) and single-photon emission CT (SPECT) may show findings consistent with Parkinson disease but these are not easily available. and olfactory testing may provide early evidence of Parkinson disease but is not routinely needed.• A sustained response to dopamine medications helps confirm the diagnosis.• When an erroneous diagnosis of Parkinson disease is made, the most likely correct diagnoses are essential tremor and the atypical parkinsonisms (MSA, PSP, CBD).• In patients with an unusual presentation, diagnostic testing may be indicated to exclude other disorders in the differential diagnosis. Such tests may include serum ceruloplasmin, or lumbar puncture. Next: Diagnostic criterias
  23. 23. UKPDS BRAIN BANK CRITERIA1 • Step 1 – Diagnosis of a parkinsonian syndrome: bradykinesia + • Rest tremor/ Rigidity/ Postural instability • Step 2 – Exclusion criteria for PD • Hx of strokes, HI, antipsychotic/DA depleting drugs, encephalitis, 1+ relatives, neg response to Ldopa, other neuro signs, tumour/hydroceph on imaging • Step 3 – supportive criteria for PD: 3+ of: • Unilat onset, rest tremor, progressive, persistent assymetry, excellent response to Ldopa, severe Ldopa induced chorea, Ldopa reponse over5 yrs, clinical course>10 yrsReference:1. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. A clinico-pathological study of 100 cases.JNNP 1992;55:181-184.
  24. 24. PARKINSON’S DISEASE: MANAGEMENT• Dopaminomimetic therapy should be initiated as soon as the patients symptoms begin to interfere with quality of life.• The aim of all dopaminomimetic strategies is to restore dopamine transmission in the striatum.This is accomplished byI. stimulating postsynaptic receptors (directly with dopamine agonists),II. increasing dopamine precursor availability (levodopa),III. blocking the metabolism of levodopa in the periphery and in the brain, and blocking the catabolism of dopamine at the synapse.
  25. 25. COMMON TREATMENT STRATEGYTable Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (17h ed.).Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2008; 372
  26. 26. PHARMACOLOGICAL THERAPY LevodopaTyrosine L-DOPA Tyrosine Hydroxylase dopa decarboxylase Carbidopa Doesn’t Dopamine cross BBB
  27. 27. • Levodopa-induced motor complications consist of fluctuations in motor response and involuntary movements known as dyskinesias .• With continued treatment, however, the duration of benefit becomes progressively shorter . This loss of benefit is known as the wearing-off effect.• At the same time, many patients develop dyskinesias. These tend to occur at the time of maximal clinical benefit and peak plasma concentration (peak- dose dyskinesia).• In more advanced states, patients may cycle between "on" periods complicated by disabling dyskinesias and "off" periods in which they suffer severe parkinsonism.
  28. 28. COMMON TREATMENT STRATEGYTable Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (17h ed.).Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2008; 372
  29. 29. DOPAMINE AGONISTS: DOSING Dopamine Agonists Initial Dosing Monotherapy As Adjuncts to LD Pramipexole 0.125 mg tid 1.5–4.5 mg/d 0.375–3.0 mg/d Ropinirole 0.25 mg tid 12–24 mg/d 6–16 mg/d Rotigotine 2 mg/24 h 6 mg/d 2–6 mg/d Bromocriptine 1.25 mg bid to tid 7.5–15 mg/d 3.75–7.5 mg/d Apomorphine sc 2–8 mgDrug Dosing Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (18thed.) .Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372
  30. 30. COMMON TREATMENT STRATEGYTable Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (17h ed.).Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2008; 372
  31. 31. PHARMACOLOGICAL THERAPY Selegiline Tolcapone Rasagiline EntacaponeInhibitors of MAO-B block central dopamine metabolism and increase synaptic concentrations of the neurotransmitter.
  32. 32. MAO-B INHIBITORS /COMT INHIBITORS DRUG DOSING MAO-B Inhibitors Dosage Selegiline 5 mg bid Rasagiline 1.0 mg QAM COMT Inhibitors Entacapone 200 mg with each levodopa dose Tolcapone 100–200 mg tid Adverse effects of Tolcapone : HepatotoxicityDrug Dosing Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (18thed.) .Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372
  33. 33. COMMON TREATMENT STRATEGYTable Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (18th ed.).Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372
  34. 34. TREATING NONMOTOR SYMPTOMS IN PD1 • Sildenafil for erectile dysfunction. • Polyethylene glycol for constipation. • Modafinil for excessive daytime somnolence. • Levidopa/carbidopa should be considered to treat periodic limb movements of sleep in PD. • Methylphenidate may be considered for fatigue.References :1. Zesiewicz TA, Sullivan KL, Arnulf I, et al. Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality StandardsSubcommittee of the American Academy of Neurology. Neurology. Mar 16 2010;74(11):924-31
  35. 35. NEUROPROTECTIVE THERAPY• Neuroprotective therapies are defined as those that slow underlying loss of dopamine neurons.• Currently, no proven neuroprotective therapies exist for Parkinson disease.• MAO-B inhibitors selegiline and rasagiline. coenzyme Q10.
  36. 36. DATATOP (DEPRENYL AND TOCOPHEROL ANTIOXIDATIVE THERAPY OF PARKINSONISM) STUDY.[1] • The Parkinson Study Group evaluated the ability of selegiline and tocopherol to delay progression of clinical disability in early Parkinson disease by randomizing 800 patients to receive selegiline (10 mg/d) or placebo and tocopherol (2000 IU/d) or placebo. • Patients who received placebo required levodopa at a projected median of 15 months from enrollment, while those who received selegiline required levodopa at a projected median of 24 months after enrollment. • Tocopherol had no effect on progression of disability.[18] • Result= Selegiline was shown conclusively to delay the need for levodopa therapy in early Parkinson disease.Reference:1. Effects of tocopherol and deprenyl on the progression of disability in early Parkinsons disease. The Parkinson Study Group. N Engl J Med. Jan 21 1993;328(3):176-8
  37. 37. STUDY ON RASAGILINE :TEMPO[1]• In the TEMPO study, treatment with rasagiline at either 1 or 2 mg daily doses over a 6-month period resulted in improved Unified Parkinsons Disease Rating Scale (UPDRS) scores relative to placebo.• Note: TEMPO= TVP-1012 n Early Monotherapy for Parkinsons Disease OutpatientsReference :1. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. Dec 2002;59(12):1937-43
  38. 38. CO-ENZYME Q10 • In a preliminary study, coenzyme Q10, 1200 mg/d, slowed progression of Parkinson disease disability. Coenzyme Q10 is a scavenger of free radicals.[1]Reference:1. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowingof the functional decline. Arch Neurol. Oct 2002;59(10):1541-50
  39. 39. SURGERY AND OTHERS• Deep Brain Stimulation• Neuroablative Lesion Surgeries• Transplantation• Gene Therapy
  40. 40. DEEP BRAIN STIMULATION • A randomized controlled trial in 255 patients with advanced Parkinson disease found that bilateral DBS was more effective than best medical therapy in improving on time without troublesome dyskinesias, motor function, and quality of life at 6 month.[1] Studies have shown that high-frequency electrostimulation in the ventral lateral nucleus (VL) of the thalamus eliminates tremors in patientsReference :1. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr. Bilateral deep brain stimulation vs best medical therapyfor patients with advanced Parkinson disease: a randomized controlled trial. JAMA. Jan 7 2009;301(1):63-73
  41. 41. NEUROABLATIVE LESION SURGERIES• Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson disease.• Lesion surgeries for Parkinson disease have largely been replaced by DBS.• The 2 most commonly performed neuroablative procedures are thalamotomy and pallidotomy.
  42. 42. PARKINSONISM :DIFFERENTIALS Atypical ParkinsonismsParkinsons Disease Multiple-system atrophy Genetic Progressive supranuclear palsy Sporadic Corticobasal ganglionic degenerationDementia with Lewy bodies Frontotemporal dementiaSecondary Parkinsonism Other Neurodegenerative Disorders Drug-induced Wilsons disease Tumor Huntingtons disease Infection Neurodegeneration with brain iron Vascular accumulation Normal-pressure hydrocephalus SCA 3 (spinocerebellar ataxia) Trauma Fragile X–associated ataxia-tremor- Liver failure parkinsonism Toxins (e.g., CO, Mn, MPTP, cyanide, Prion diseasemethanol, carbon disulfide) Dystonia-parkinsonism (DYT3) Alzheimers disease with parkinsonism
  43. 43. ATYPICAL PARKINSONISMSConditions FeaturesMultiple-system atrophy MSA is suspected when a patient presents with atypical parkinsonism in conjunction with cerebellar signs ,cst signs and/or early and prominent autonomic dysfunction, usually orthostatic hypotension and poor response to levodopa/carbidopaProgressive supranuclear palsy Progressive supranuclear palsy (PSP) is the most common Parkinson-plus syndrome. Early onset of postural instability, supranuclear gaze palsy, and cognitive dysfunction.Parkinsonism-dementia-amyotrophiclateral sclerosis complex
  44. 44. ATYPICAL PARKINSONISMS Conditions Features Diffuse Lewy body disease Progressive dementia is often the first and predominant symptom. In Parkinson disease, they are mainly observed in the substantia nigra. In contrast, in DLBD they are scattered throughout the cerebral cortex and also are seen in the nigra and other subcortical regions. Its like Alziehmers with extrapyramidal . Corticobasal ganglionic Corticobasal ganglionic degeneration (CBGD) is characterized degeneration by frontoparietal cortical atrophy in addition to degeneration within basal ganglia. Alien limb’ phenomenon. 5 initial presentations, including a "useless" arm (55%), gait disorder (27%), prominent sensory symptoms, isolated speech disturbance, behavioral disturbance.[1]Reference: 1. Rinne JO, Lee MS, Thompson PD, Marsden CD. Corticobasal degeneration. A clinical study of 36 cases.Brain. Oct 1994;117 ( Pt 5):1183-96
  45. 45. HISTORY AND C/F SUGGESTING DX OTHER THAN PARKINSONS DISEASEMSA-p (previously striato-nigral degenerationMSA-c (previously olivopontocerebellar atrophy
  46. 46. THANKYOUReferences:• Table Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrisons principles of internal medicine (18th ed.) .Parkinsons Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372• www.emedicine.com• http://en.wikipedia.org/
  47. 47. PARKINSON OR PARKINSON PLUS ?• An inadequate response to treatmentOther clinical clues suggestive of Parkinson-plus syndromes include the following:• Early onset of dementia ,postural instability• Early onset of hallucinations or psychosis with low doses of levodopa/carbidopa or dopamine agonists• Ocular signs, such as impaired vertical gaze, blinking on saccade, square-wave jerks, nystagmus, blepharospasm, and apraxia of eyelid opening or closure• Pyramidal tract signs not explained by previous stroke or spinal cord lesions• Autonomic symptoms such as postural hypotension and incontinence early in the course of the disease• Alien-limb phenomenon• Marked symmetry of signs in early stages of the disease
  48. 48. ESSENTIAL TREMOR• The most common early sign of PD – in about three-quarters of cases – is a 4–6 Hz, unilateral resting tremor.• The cardinal difference between essential tremor and the tremor of PD is that the former is associated with voluntary movements or postures and is absent at rest, whilst the tremor of PD is present at rest.Other characteristics that may help to distinguish essential tremor from that of PD include:• onset early in adult life when PD is rare• bilateral onset• head and voice tremor• family history• other features of PD are absent• unresponsive to levodopa• alcohol responsiveness• beta-blocker or primidone/gabapentin responsive• positional and kinetic tremor.
  49. 49. UK BRAIN BANK DIAGNOSTIC CRITERIA STEP ONE: DIAGNOSIS OF PARKINSONISM BRADYKINESIA AND AT LEAST ONE OF THE FOLLOWING: • Muscular Rigidity • 4-6 Hz Resting Tremor • Postural Instability not caused by primary visual, vestibular, cerebellar or Proprioceptive dysfunctionHughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathicParkinson’s disease. A clinico-pathological study of 100 cases. JNNP 1992;55:181-184.
  50. 50. UK BRAIN BANK DIAGNOSTIC CRITERIASTEP TWO: FEATURES TENDING TO EXCLUDE PARKINSON’S DISEASE AS THE CAUSE OFPARKINSONISM• History of repeated strokes/repeated head injury /encephalitis• More than one affected relative• Sustained remission• Strictly unilateral features after 3 years• Supranuclear gaze palsy• Cerebellar signs• Early severe autonomic involvement• Early severe dementia with disturbances of memory, language, and praxis• Babinski’s sign• Presence of cerebral tumor or communicating hydrocephalus on CT scan• MPTP exposure a positive predictive value of 98.6% for the clinical diagnosis of PD
  51. 51. UK BRAIN BANK DIAGNOSTIC CRITERIA STEP THREE: FEATURES THAT SUPPORT A DIAGNOSIS OF PARKINSON’S DISEASE, 3 OR MORE REQUIRED • Unilateral onset • Rest tremor present • Progressive disorder • Persistent asymmetry affecting the side of onset most • Excellent (70 – 100%) response to levodopa • Severe levodopa-induced chorea • Levodopa response for equal to or greater than 5 years • Clinical course of equal to or greater than 10 yearsThree or more required for diagnosis of definite Parkinson’s disease in combination with step 1
  52. 52. DOPAMINERGIC PATHWAYSmesolimbic transmits D from the ventral tegmental area to the schizophrenia nucleus accumbens. The VTA is located in the midbrain, and the nucleus accumbens is in the limbic system.mesocortical transmits D from the VTA to the frontal cortex. schizophrenianigrostriatal The nigrostriatal pathway transmits dopamine Parkinson disease from the substantia nigra to the striatum. This pathway is associated with motor control.Tubero transmits D from the hypothalamus to the hyperprolactinaemiainfundibular pituitary gland. This pathway influences the secretion of certain hormones, including prolactin. "Infundibular" in the word "tuberoinfundibular" refers to the infundibulum out of which the pituitary gland develops.
  53. 53. PATHOLOGYPathologically, the hallmark features of PD are• degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc),• reduced striatal dopamine,• intracytoplasmic proteinaceous inclusions known as Lewy bodiesNeuronal degeneration with inclusion body formation can also affect• cholinergic neurons of the nucleus basalis of Meynert (NBM),• norepinephrine neurons of the locus coeruleus (LC),• serotonin neurons in the raphe nuclei of the brainstem, and• neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system.
  54. 54. DIETERY CONSIDERATIONS• Protein-restricted diets may be useful in patients who are experiencing motor fluctuations with long-term levodopa treatment.• Levodopa is transported into the brain by a carrier protein that also transports large neutral amino acids found in dietary protein.• Consequently, high-protein meals can compete for the transport of levodopa and reduce or eliminate its effects.• A protein-restricted diet can therefore improve the response to levodopa and can be useful in patients with otherwise refractory motor fluctuations.

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