Basal ganglia parkinson's disease

Pratap Sagar Tiwari, Resident, Internal Medicine

BASAL GANGLIA & PARKINSON’S

DISEASE

THIS IS NOT PSART OF THE PPT BUT FOR THE

ONES 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.

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

NERVOUS SYSTEM DEVELOPMENT :

ANATOMICAL SUBDIVISIONS

Primary division of

neural tube

Sec. subdivision Final segments

Prosencephalon 1. Telencephalon

2. Diencephalon

1. The cortex,

Caudate, Putamen, Globus pallidus

2. Thalamus, hypothalamus, subthalamus,

subthalamic nuclei

Mesencephalon Mesencephalon

Mesencephalon (Midbrain),

Substantia nigra pars compacta (SNc),

Substantia nigra pars reticulata (SNr)

Rombencephalon 1. Metencephalon

2. Myelencephalon

1. Pons and cerebellum

2. Medulla

BASAL GANGLIA

Picture taken from : http://withfriendship.com/user/boss/basal-ganglia.php

Picture taken from : http://www.macalester.edu/academics/psychology/whathap/ubnrp/dopahypoweb04/josh%20page%202.html

BASAL GANGLIA: COMPONENTS

Corpus striatum = striatum (caudate + putamen ) ,Pallidum , Nucleus Accumbents

Substantia Nigra

Subthalamic Nucleus

Picture taken from :http://webspace.ship.edu/cgboer/basalganglia.html

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

Disease

Reference:

1. Graybiel AM (2005) The basal ganglia: learning new tricks and loving it. Curr Opin

Neurobiol 15:638-644.

http://en.wikipedia.org/wiki/Caudate_nucleus

BG COMPONENTS: PUTAMEN lies just under & behind the front of the caudate.

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.

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 accumbens

Medial surface of basal ganglia

Picture Reference : http://thalamus.wustl.edu/course/cerebell.html

UNDERSTANDING THE PATHWAYS

Picture Reference: http://thalamus.wustl.edu/course/cerebell.html

UNDERSTANDING THE PATHWAYS

D1 = direct pathway

D2 = Indirect pathway

Striatum

Gpi /SNr

Gpi / SNr

STN

Gpe and STN

Striatum & GPe

Inhibits

Excitatory influences

DOPAMINE: SYNTHESIS

Dopamine

L-DOPA Tyrosine

Tyrosine Hydroxylase

dopa decarboxylase

DOPAMINE : DEGRADATION

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 Parkinson's disease (PD) is

the most common cause of parkinsonism as it accounts for

~75% of all cases of parkinsonism

PARKINSON’S DISEASE; ETIOLOGY

• Genetic causes

• Environmental causes

• Oxidation Hypothesis

• Alpha-synuclein

GENETIC CAUSES OF PD

Table Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine (18th ed.) .Parkinson's Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372

PARKINSON’S DISEASE : CLINICAL FEATURES.

Cardinal features Other motor features Nonmotor features

Bradykinesia

Rigidity

Resting Tremor

Gait disturbance/postural

instability

Micrographia

Masked facies

Reduced eye blink

Soft voice

Freezing

Anosmia

Mood disorders eg

depression

Sleep disturbances

Autonomic disturbances

Cognitive impairment/

dementia


PARKINSON’S DISEASE : CLINICAL FEATURES.

Cardinal features Other motor features Nonmotor features

Bradykinesia

Rigidity

Resting Tremor

Gait disturbance/postural

instability

Micrographia

Masked facies

Reduced eye blink

Soft voice

Freezing

Anosmia

Mood disorders eg

depression

Sleep disturbances

Autonomic disturbances

Cognitive impairment/

dementia


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).2

References:

1. Weintraub D, Comella CL, Horn S. Parkinson's disease--Part 3: Neuropsychiatric symptoms. Am J Manag Care. Mar 2008;14(2 Suppl):S59-69

2. 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.

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

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 yrs

Reference:

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.

PARKINSON’S DISEASE: MANAGEMENT

• Dopaminomimetic therapy should be initiated as soon as the patient's

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 by

I. 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.

COMMON TREATMENT STRATEGY

Table Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine (17h ed.) .Parkinson's Disease and Other Movement Disorders . New York: McGraw-Hill .; 2008; 372

PHARMACOLOGICAL THERAPY

Dopamine

L-DOPA Tyrosine

Tyrosine Hydroxylase

dopa decarboxylase

Levodopa

Carbidopa

Doesn’t

cross

BBB

• 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.



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 mg

Drug Dosing Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine (18th ed.) .Parkinson's Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372



PHARMACOLOGICAL THERAPY Selegiline

Rasagiline

Entacapone

Tolcapone

Inhibitors of MAO-B block central dopamine metabolism and increase synaptic concentrations of the neurotransmitter.

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 : Hepatotoxicity

Drug Dosing Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine (18th ed.) .Parkinson's Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372



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 Standards

Subcommittee of the American Academy of Neurology. Neurology. Mar 16 2010;74(11):924-31

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.

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 Parkinson's disease. The Parkinson Study

Group. N Engl J Med. Jan 21 1993;328(3):176-8

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 Parkinson's Disease Rating Scale (UPDRS) scores

relative to placebo.

• Note: TEMPO= TVP-1012 n Early Monotherapy for Parkinson's Disease

Outpatients

Reference :

1. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. Dec 2002;59(12):1937-43

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 slowing

of the functional decline. Arch Neurol. Oct 2002;59(10):1541-50

SURGERY AND OTHERS

• Deep Brain Stimulation

• Neuroablative Lesion Surgeries

• Transplantation

• Gene Therapy

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]

Reference :

1. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr. Bilateral deep brain stimulation vs best medical therapy

for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. Jan 7 2009;301(1):63-73

Studies have shown that high-frequency electrostimulation in the ventral lateral nucleus (VL) of

the thalamus eliminates tremors in patients

http://en.wikipedia.org/wiki/Modafinil



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.

PARKINSONISM :DIFFERENTIALS Atypical Parkinsonisms

Parkinson's Disease

Genetic

Sporadic

Dementia with Lewy bodies

Multiple-system atrophy

Progressive supranuclear palsy

Corticobasal ganglionic degeneration

Frontotemporal dementia

Secondary Parkinsonism Other Neurodegenerative Disorders

Drug-induced

Tumor

Infection

Vascular

Normal-pressure hydrocephalus

Trauma

Liver failure

Toxins (e.g., CO, Mn, MPTP, cyanide,

methanol, carbon disulfide)

Wilson's disease

Huntington's disease

Neurodegeneration with brain iron

accumulation

SCA 3 (spinocerebellar ataxia)

Fragile X–associated ataxia-tremor-

parkinsonism

Prion disease

Dystonia-parkinsonism (DYT3)

Alzheimer's disease with parkinsonism

ATYPICAL PARKINSONISMS

Conditions Features

Multiple-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/carbidopa

Progressive 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-amyotrophic

lateral sclerosis complex

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

degeneration

Corticobasal ganglionic degeneration (CBGD) is characterized

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

HISTORY AND C/F SUGGESTING DX OTHER

THAN PARKINSON'S DISEASE

MSA-p (previously striato-nigral degeneration

MSA-c (previously olivopontocerebellar atrophy

THANKYOU

References:

• Table Ref: Powers A.C. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's

principles of internal medicine (18th ed.) .Parkinson's Disease and Other Movement Disorders . New York: McGraw-Hill .; 2011; 372

• www.emedicine.com

• http://en.wikipedia.org/

http://www.emedicine.com/

http://en.wikipedia.org/

http://en.wikipedia.org/

PARKINSON OR PARKINSON PLUS ?

• An inadequate response to treatment

Other 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

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.

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

dysfunction

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.


STEP TWO: FEATURES TENDING TO EXCLUDE PARKINSON’S DISEASE AS THE CAUSE OF PARKINSONISM

• 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


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 years

Three or more required for diagnosis of definite Parkinson’s disease in combination with step 1

DOPAMINERGIC PATHWAYS

mesolimbic transmits D from the ventral tegmental area to the

nucleus accumbens. The VTA is located in the

midbrain, and the nucleus accumbens is in the

limbic system.

schizophrenia

mesocortical transmits D from the VTA to the frontal cortex. schizophrenia

nigrostriatal The nigrostriatal pathway transmits dopamine

from the substantia nigra to the striatum. This

pathway is associated with motor control.

Parkinson disease

Tubero

infundibular

transmits D from the hypothalamus to the

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.

hyperprolactinaemia

http://en.wikipedia.org/wiki/Mesolimbic_pathway

http://en.wikipedia.org/wiki/Mesocortical_pathway

http://en.wikipedia.org/wiki/Nigrostriatal_pathway

http://en.wikipedia.org/wiki/Tuberoinfundibular_pathway



PATHOLOGY

Pathologically, 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 bodies

Neuronal 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.

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.

Health & Medicine

Basal ganglia parkinson's disease