Differential Diagnosis in Neurology

14.2. Bradykinetic Disorders

Parkinson's Disease

• General considerations:
  • Incidence of 4 in 1000 people over the age of 40
  • Affects both sexes approximately equally
  • Prevalence rates vary worldwide, possibly due to exposure to different environmental toxins
  • Prevalence rate increases exponentially with age; at 65, 1–3% of the population is affected
  • Risk factors:
    • Age is the most important
    • Rural living
    • Herbicides (possibly); 2.8–3.1 greater frequency
    • Well water (weak correlation)
    • Industrial or chemical exposure:
      • MPTP
      • Carbon disulfide
      • Carbon monoxide
      • Manganese
    • Smoking may reduce risk; 1.7–2.1
    • Family history of essential tremor, 2.1–2.4
    • Minor head trauma, 3.1–4.2
    • Coffee abstinence, 2.86 (univariate)
    • Relative risk of PD in relatives:
      • Siblings – 6.7
      • Offspring – 3.2
      • Nieces and nephews – 2.7

Genetic Parkinson's Disease

Mendelian PD Genes

• Park 1 – Chromosome 4q21 - alpha synuclein gene; AD
• Park 2 – Chromosome 6q 25.2–27-parkin ; AR
• Park 3 – Chromosome 2p13 ; AD
• Park 5 – Chromosome 4p14-UCHL-1 ; AD
• Park 6 – Chromosome 1p35–36 PINK-1; AR
• Park 7 – Chromosome 1p36-DJ-1; AR
• Park 8 – Chromosome 12q12 – Durdarin/L RRK2; AD
• Park 9 – Chromosome 1p36 ; AR
• Park 10 – Chromosome 1p32 ; AR
• Park 11 – Chromosome 2q36–37 ; AD

Park-1 (alpha Synuclein)

• General considerations:
  • Chromosome 4q21
    • AD; alpha Synuclein
  • Point mutations
    • Duplications; triplication
  • Contursi kindred
    • A53T mutation
    • Clinical features of A53T mutation:
      • Mean age of onset – 45.6 years
      • Cortical dementia approximately 20%
      • Rare tremor at rest
      • Triplication (100% over expression of alpha Synuclein)
        • Age of onset is 34 years
      • Duplication (50% over expression)
        • Age of onset 48 years (39–65)

Park-2

• General considerations:
  • Chromosome 6q25
    • gene is Parkin
    • AR
  • Large gene with a wide variety of mutations
  • The gene product is a E3 ubiquitin ligase (possible substrates are syphilis -1 pae1-R
    • Ubiquitin is pivotal in the ubiquitin proteosome pathway of protein degradation
  • The more mutations in the gene the earlier the onset of disease
  • The most common form of familial PD; worldwide distribution
• Clinical features:
  • Onset less than 21 years or age; some greater than 40 years of age
  • Symmetrical presentation
  • Slow progression
  • Excellent response to levodopa
  • Earlier onset:
    • Psychiatric features
    • Increased reflexes
    • Early dyskinesia

Park-3

• General considerations:
  • AD with reduced penetrance
  • North Germany-South Denmark families
• Clinical features:
  • Cognitive impairment
  • Excellent response to levodopa
• Pathology:
  • SNpc A9 degeneration
  • Positive Lewy body formation

Park-5 (UCHL1)

• General considerations:
  • Ubiquitin carboxy-terminal hydrolase L1 (de-ubiquitin enzyme) involved in the ubiquitin-proteosome degradation pathway
  • AD; incomplete penetrance
  • Possible polymorphic variant that is protective (possibly just Asian families)
• Clinical features:
  • Levodopa responsive
  • Family history is compatible with AD inheritance with incomplete penetrance

Park-6 (PINK1)

• General considerations:
  • Chromosome 1p36; recessive with haploinsufficiency
  • AR early onset PD
  • Mutation seen in 5% of PD patients
  • Homozygous mutation in the PTEN (phosphatase and tensin homologue deleted on chromosome 10) induced kinase-1 (PINK1) gene:
    • Localizes to mitochondria
    • May phosphorylate a mitochondrial protein as part of stress response
• Clinical features:
  • Onset third or fourth decade
  • Slow progression and benign course
  • Levodopa responsive
  • Early onset dystonia; not as frequently seen as with Parkin or DJ-1 mutations

Park-7 (DJ-1)

• General considerations:
  • Chromosome 1p38; multiple mutations:
    • Recessive segregation patterns
• Clinical features:
  • Young age of onset
  • Slow progression
  • Focal dystonia (common)
  • Psychiatric manifestations

Park-8 (Dardarin or LRRK2)

• General considerations:
  • Chromosome 12q; AD:
    • GLY20 19 Ser + 6 other mutations
  • Mutated gene includes a MAPKK class (mitogen-activated protein kinase) domain:
    • Putative importance is apoptotic pathway
    • Increased representation sporadic (1.6%) and familial PD (4.6%)
• Clinical features:
  • Onset in sixth decade; (35–78)
  • Levodopa responsive
  • Asymmetric
• Pathology:
  • Brainstem Lewy bodies (LB)
  • Diffuse LB
  • Parkin like A9 SNpc nigral degeneration

Park-9

• General considerations:
  • AR
• Clinical features:
  • Patients present as parkinsonism
• Neuropathology:
  • SNpc A9 involvement (substantia nigra)
  • Globus pallidus and pyramidal tract degeneration

Familial Parkinsonism

• General considerations:
  • Prominent parkinsonism is a feature of many disorders:
    • Tau-associated disease
    • Trinucleotide repeat disorders
    • Hallervorden–Spatz disease
    • Wilson's disease

Tau-Associated Parkinsonism

• General considerations:
  • Neurofibrillary tangles consist of insoluble fibrillar aggregates of hyper phosphorylated Tau protein
  • Tau H1 haplotype of the Tau gene is associated with progressive supranuclear palsy (PSP) and corticobasal degeneration; may be a risk factor for PD

Frontotemporal Dementia Parkinsonism (FTD-P14)

• General considerations:
  • AD; chromosome on 17
  • Coding or splice site mutations in the Tau gene are causative:
    • Coding mutations cause decreased binding of Tau protein to microtubules
    • Splice site mutations destabilize a stem-loop structure that regulates alternate splicing of exon 10 that increases four repeat isoform
    • Parkinsonism is associated with exon-10 missense mutations or mutations that affect exon-10 splicing
    • PSP and CBD patients also have excess four-repeat Tau isoforms

Clinical Variants of FTD-17 PD

• Disinhibition–Dementia–Parkinsonism–Amyotrophy Complex (DDPAC)
  • Presents with personality and behavioral changes
  • Rigidity, bradykinesia, loss of postural reflexes
  • Amyotrophy of extremities
  • Rapidly progressive (mean survival of 13 years)
  • Pathology:
    • Atrophy and spongiform degeneration in the frontotemporal cortex
    • Neuronal loss and gliosis in the amygdala, substantia nigra pars compacta (A9) and anterior horn cells
    • No Lewy bodies

Pallido-Ponto-Nigral Degeneration (PPND)

• Clinical features:
  • Dementia
  • Dystonia
  • Increased reflexes
  • No amyotrophy

Familial Progressive Subcortical Gliosis

• General considerations:
  • AD; chromosome 17q 21–22
• Clinical features:
  • Dementia
  • Personality change
  • Extrapyramidal signs and symptoms
• Pathology:
  • Prion protein accumulation in the frontal and temporal lobes

Atypical Parkinsonism

• Described in
  • Kii peninsula of Japan
  • Guadeloupe Islands of Western Pacific
  • Guam

• General considerations:
  • Tau pathology and neurofibrillary tangles is seen in all
  • Tau pathology of Kii peninsula and Guam:
    • Alzheimer type
    • Guadeloupe has Tau pathology similar to that of PSP
  • Midbrain Tau pathology occurs in Niemann-Pick disease type C:
    • Failure of upgaze
    • Juvenile parkinsonism

Trinucleotide-Repeat Disorders

• General considerations:
  • Syndromes:
    • Huntington's disease (HD)
    • Spinocerebellar atrophies
    • Dentantanto-Rubro-Pallido-Luysian Atrophy ( DRPLA)
    • Kennedy's syndrome
  • Associated with:
    • Cerebellar ataxia
    • Cognitive dysfunction
    • Chorea
    • Anterior horn cell disease depending on the specific disorder
  • In general, they code for a polyglutamine repeat sequence that leads to intracellular inclusions

Fragile X-Mental Retardation Tremor Ataxia Disorder

• General considerations:
  • Permutations of the FMR1 gene (55–200 repeats; full expansion of the trinucleotide repeat is greater than 200 CGG repeats in the 5-untranslated part of the gene
  • Rare in women with one normal X-chromosome
• Clinical features:
  • Postural tremor
  • Ataxia
  • Autonomic dysfunction
  • Cognitive dysfunction
  • Parkinsonism
• MRI evaluation:
  • Increased signal in the middle cerebellar peduncles

Parkinsonism in Autosomal Dominant Spinocerebellar Ataxias

SCA 3/Machado Joseph Disease and SCA2

• General considerations:
  • 18F-dopa PET scans have demonstrated basal ganglia hypometabolism
  • SCA2 parkinsonism symptoms are more common in Chinese than Caucasian patients
  • SCA 3 parkinsonism is more common in Afro-Caribbean patients
• Clinical features:
  • Responsive to L-dopa

Parkinsonism in Juvenile Variant of Huntington's Disease (Westphal)

• General considerations:
  • Chromosome 4p16.3
  • Large CAG repeats
  • 90% are of paternal lineage
• Clinical features:
  • Presents in teens
  • Akinetic rigid syndrome
  • Seizures

X-Linked Dystonia Parkinsonism (PYT3)

• General considerations:
  • Primarily found in Filipinos from the Panay Islands; also found in some non-Filipinos
  • Known as Lubag
  • Possible missense mutation in exon 4 of the X-chromosome in Lubag patients
  • Rare in female carriers
• Clinical features:
  • Presents with a mixed movement disorder
  • Blepharospasm or limb dystonia
  • Symptoms generalize within the first decade
  • Forty percent of patients have Parkinsonism
  • Poorly responsive to L-Dopa
  • Severe masseter dystonia

Rapid-Onset Dystonia Parkinsonism (DYT12)

• General considerations:
  • Encodes the alpha 3 subunit of the sodium-potassium pump
• Clinical features:
  • Rapid onset of symptoms; progresses over hours
  • Initiated by physical and emotional stress
  • Present with cranial and limb dystonia
  • Dysarthria and dysphagia
  • Parkinsonism
  • Not L-dopa responsive

Parkinsonism in Dentantanto-Rubro-Pallido-Luysian Atrophy (DRPLA)

• General considerations:
  • AD; chromosome 12 p 13.3
• Clinical features:
  • Cerebellar ataxia
  • Parkinsonism
  • Myoclonus
  • Dystonia
  • Seizures

Parkinsonism Features of Wilson's Disease

• General considerations:
  • AD; chromosome 13q 14–21
• Clinical features:
  • Onset 6–40 years of age; neurologic symptomatology in the early twenties
  • Presentation is psychiatric, neurologic or as liver disease
  • Severe dysarthria
  • Wing-beating tremor
  • Postural abnormalities
  • Dystonia
  • Parkinsonism
  • Kayser–Fleisher ring in the cornea (accumulation in Descemet's membrane)
    • Present in all patients with neurologic disease
  • Rare chorea
  • No sensory symptoms
  • Depression, personality changes, emotional lability with cognitive decline
• Laboratory evaluation:
  • Increased urinary copper excretion (> 100 μg/ 24 hr)
  • Low plasma ceruloplasmin (<15 μg/dl)
• MRI evaluation:
  • Ventricular dilatation
  • Cortical atrophy
  • Basal ganglial lesions (caudate and primarily in the putamen)

AD Lewy Body Positive Familial Parkinsonism with Atypical Features

• General considerations:
  • AD; Lewy bodies
• Clinical features:
  • Late onset with dementia
  • Amyotrophy of extremities
  • Depression and hypoventilation
  • Ataxia
  • Seizures

Parkinsonism Features of Huntington's Disease

• General considerations:
  • Chromosome 4p 16.3:
    • Gene is 1T 15 (expanded CAG repeats)
    • Encodes Huntingtin disease
• Clinical features:
  • Age of onset is related to the number of repeats
    • Juvenile onset greater than 50 repeats.
  • Normal people less than 27 repeats
    • A few patients have intermediate repeat number of 29–35
  • Presents with neurological or psychiatric features
    • Rarely both simultaneously
  • Change in personality
  • Chorea (choreatic eye movements)
  • Lurching gait
  • Impersistence of sustained movement (inability to hold the tongue out; milkmaids hand)
  • Slow and hypometric saccades (vertical >than horizontal plane); convergence paresis; inability to initiate saccades
  • Orolingual apraxia
  • Parkinsonism (bradykinesia)
  • Increased reflexes and clonus
  • Juvenile Westphal variant:
    • Akinetic rigid syndrome with seizures

MRI Evaluation of Familial Parkinsonism

• Usually normal
• Hallervorden Spatz disease (PANK 2 gene):
  • Low signal in the internal segment of the globus pallidus
  • Axonal vacuolization (Spheroids)
• Fahr's disease:
  • Bilateral calcification of the basal ganglia
  • Calcification of subcortical white matter and the dentate nucleus
• Niemann Pick type C (NPC 1 gene):
  • Diffuse cerebellar atrophy
  • Mild cerebral atrophy
• Huntington's disease:
  • Atrophy of the caudate nucleus ("box car" atrophy)
  • Frontal lobe atrophy
• Wilson's disease:
  • Putamen >caudate T2-weighted lesions
  • Midbrain and occasional thalamic lesions
• Neuroferrotinopathy:
  • T2-weighted lesions in the globus pallidus
• Fronto temporal dementia parkinsonism chromosome 17:
  • Mesial temporal lobe atrophy

Syndromes with Prominent Parkinsonism Features and Known Genetic Loci

• SCA 2 – Chromosome 12
• Machado–Joseph, disease – SCA3 chromosome 14q 24, 3–32
• Hallervorden Spatz disease – 20p 12.3
• Huntington's disease – 4 p 16.3 (Westphal variant)
• Dentato-Rubro-Pallido-Luysian atrophy chromosome 12p13.3
• Wilson's disease – chromosome 13 q
• Fronto temporal dementia – chromosome 17
• Rapid – onset dystonia Parkinsonism Dy 12
• X-linked dystonia Parkinsonism (DYT 3)
• Fragile X-mental retardation tremor ataxia disorder – (FMR1 gene)
• Familial progressive subcortical gliosis (prion disease) – chromosome 17q21–22

Differential Diagnostic Points in Genetic Parkinsonism

• Recessive PD may occur in small families and be misdiagnosed as sporadic. Parental consanguinity is a hint.
• Incomplete penetrance occurs in dopa responsive dystonia
• Male to male transmission excludes X-linked recessive inheritance

Idiopathic Parkinson's Disease

• General characteristics:
  • There must be degeneration of components of the substantia pars compacta (SNpc on A9)
  • Usually it is the ventral tier dopaminergic neurons of SNpc that project to the posterior lateral putamen
  • Lewy body formation
• Clinical features:
  • Cardinal signs:
    • Akinesia – bradykinesia
    • Tremor at rest (4–6 Hz)
    • Rigidity (negri's signs; cogwheel in type)
    • Autonomic dysfunction
    • Cognitive decline in approximately 30% of patients

Brady and Akinesia

• Most distressing symptoms to patients. When severe the patient is frozen.
• Suffer "freezing" episodes; they are unable to change motor programs rapidly and freeze when turning or going through a doorway
• An akinetic patient may initiate movement rapidly if frightened
• Patients at the end of effective therapy with L-Dopa and other agonists experience "off" episodes during which bradykinesia, akinesia and fatigue makes any form of movement difficult

Tremor

• Occurs at rest (4–6Hz), almost pathognomonic for IPD
• Occurs in the hand with metacarpophalangeal flexion; progresses to involve the entire arm and becomes bilateral. The hand may be involved ("up and down"); the leg may be involved, in extreme case. The tremor may persist during movement as well as at rest.
• Tremor is embarrassing, but does not interfere with activities of daily living
• Responds well early to L-Dopa and trihexyphenidyl

Rigidity

• More in extremities than axial musculature
• "Catching" or cogwheel character (Negr's sign)
• May have stiffness throughout the range of motion of the affected extremity
• Contributes to the flexed-stooped posture of the patient
• Generalized stiffness of the body

Loss of postural reflexes

• Frequent falls with characteristic humeral and hip fractures; unable to extend arms to brace themselves.
• Falling backwards is characteristic of the last portion of a posturally induced movement

Autonomic Dysfunction

• Becomes evident in moderately advanced disease
• Difficulty initiating micturition
• Obstipation
• Sexual dysfunction
• Seborrheic dermatitis
• Postural hypotension (worsens as the illness progresses)

Cognitive Decline

• Depression
• Poor executive function
• Bradyphrenia (inability to process or formulate ideas quickly)
• Decreased short term memory
• Inability to change motor sets
• Some patients suffer concomitant Alzheimer's Disease or diffuse Lewy Body Disease
• Hallucinations from dopamine therapy

Associated Neurological Deficits

• Decreased spontaneous blink and all subconscious movement
• Sleep disruption due to sleep apnea and REM sleep disorder
• Gait ignition failure
• Once the patient is in motion he cannot position his body over its center of gravity so that he festinates and is unable to control progression. The gait is shuffling and has no or decreased associated arm movements
• Failure of upgaze and poor smooth pursuit. The patient utilizes saccadic substitution.
• Hypomimia and hypohemia
• Swallowing dysfunction due to the failure of posterior pharyngeal striated muscles to deliver the bolus of food to the esophagus. There may be concomitant dysfunction of the cricopharyngeal muscles (external esophageal sphincter); cranial nerve IX
• Micrographia (failure to maintain movement) during writing
• Sialorrhea (less spontaneous swallowing)

Differential Diagnosis of Parkinson's Disease

• Parkinsonism as a component of Multiple System Atrophies (MSA)

Multiple System Atrophies (MSA)

General Features of MSA

• A group of neurodegenerative diseases with varying degrees of dysfunction of the following systems:
  • Cortical (cognitive dysfunction)
  • Basal ganglionic function
  • Cerebellar dysfunction
  • Autonomic dysfunction
  • Pyramidal signs
  • Stimulus sensitive myoclonus of hands and face
  • Extreme neck flexion
  • Inspiratory stridor (laryngeal muscle dysfunction)
  • Parkinsonian features have poor response to levodopa
• Differentiated by:
  • Clinical examination
  • MRI , SPECT, and PET scanning
• Rest tremor is slight or absent

Distribution of Signs and Symptoms

• Olivopontocerebellar Atrophy (OPCA):
  • AD, AR, and sporadic forms
  • Sporadic OPCA presents with:
    • Ataxia
    • Dysarthria
    • Cerebellar dysfunction
    • Parkinsonism is mild
    • Approximately 20% respond to levodopa
    • MRI demonstrates:
      • Pontine atrophy – "mattese cross" (prominence of crossing fibers that make up the middle cerebellar peduncle (MCP)
      • Atrophy of the olivary nuclei
      • Atrophy of the mid vermis
      • Some varieties have peripheral neuropathy, retinal degeneration, dorsal column deficits, and cranial nerve dysfunction
      • Primary deficits of cerebellar function in all varieties

Striatonigral Degeneration (SND)

• Severe akinetic rigid syndrome; minimal tremor
• Do not respond to L-Dopa
• Dystonia (particularly in the upper extremity); arm is held upward
• More cognitive defects than idiopathic Parkinson's Disease
• MRI demonstrates atrophy and signal change in the putamen
• Reduced uptake of raclopride with PET and ²³iodobenzamide SPECT is noted in the striatum
• Loss of dopamine receptors in projection zones of A9

Distribution of Signs in MSA

• Approximately 28% have all four major manifestations
• 18% have parkinsonism, corticospinal and autonomic dysfunction
• 11% have parkinsonism and autonomic dysfunction
• 10% have solely parkinsonism
• Parkinsonism was not found in 11% of patients
• Autonomic dysregulation develops in greater than 90% of patients:
  • A poorly levodopa responsive parkinsonian patient with "cold hands" and hypotension suggests MSA
• Autonomic dysregulation is manifest as:
  • Impotence in males
  • Urinary incontinence in women
  • Orthostatic hypotension is the most disabling symptom:
    • Upright hypotension
    • Supine hypertension
    • Heat, exercise, large meals precipitate syncope
    • "coat hanger headaches" just prior to syncope (across the trapezius muscles)
• Wheelchair bound after 4 years; median survival is 9.5 years

Shy–Drager Syndrome

• General characteristics:
  • Autonomic dysfunction is the seminal feature
• Clinical features:
  • Onset is between 40–69 years of age
  • Most prominent symptom is postural hypotension (precedes parkinsonism)
  • Forward-flexed rigid stance
  • Lose consciousness and fall due to severe hypotension
  • Iris atrophy (holes in the iris)
  • Dementia
  • Ataxia
  • Bowel, bladder, and sexual dysfunction early in the process of the illness
  • Cold mottled hands (livedo reticularis) at clinical presentation
  • Progression is more rapid than idiopathic Parkinson's Disease

PSP (Progressive Supranuclear Palsy)

• Clinical features of PSP:
  • Parkinsonian patients who respond poorly to levodopa; 1–8% may have PSP pathologically
  • Median age of onset is 64 years of age (50–77)
  • Supra nuclear ophthalmoplegia is seminal:
    • Poor vertical saccades early
    • Downward saccades affected first
    • Hypometria of saccades vertical >horizontal
    • Abnormal smooth pursuit
    • Blepharospasms
    • Apraxia of eye lid opening
    • Ptosis, marked lid retraction
    • Decreased blinking
    • Pseudointernuclear ophthalmoplegia
    • Nystagmus
    • "Square wave jerks" (nystagmus recording)
    • Pathologic lid retraction
    • Poor convergence
    • Poor reading and eye contact
    • Vertical saccades accomplished by moving their eyes in a lateral arc
    • Complete ophthalmoplegia (late)
  • Personality change with frontal lobe dyscontrol
  • Falling, imbalance, gait disorder much earlier than IPD
  • Axial rigidity > appendicular
  • Dysphagia and dysarthria
  • Falling backwards:
  • Rigid hyperextension of the neck; IPD has flexed neck posture
  • Gait abnormalities:
    • Stiff and broad based
    • Knees and trunk extended (IPD stooped with knees flexed; narrow base)
    • Arms slightly adducted; IPD increased flexed carrying angles of the arm
    • Pivot rather than turning en bloc as occurs with (IPD)
  • Absent tremor
  • Characteristic facies:
    • Deep nasolabial folds
    • Wide eyed
    • Staring expression
  • Early they may present with prominent akinesia; gait ignition failure and freezing
  • Rare findings:
    • Limb rigidity >axial
    • Mild tremor at rest
    • Upper limb apraxia, myoclonus, chorea
    • Respiratory dysfunction
  • Arm levitation (more common than the posterior alien hand seen with CBGD)
  • Higher blood pressure than other neurodegenerative disorders
  • Differential Diagnosis of Supra nuclear ophthalmoplegia:
    • Niemann Pick type C
    • Lewy body dementia
    • Fahr's disease
• MRI/CT evaluation:
  • Early midbrain atrophy
• Pathologic changes consistent with PSP may be associated with:
  • Creutzfeldt–Jacob disease
  • Progressive subcortical gliosis
  • MSA
• Differential diagnosis of falling backwards
  • IPD
  • NPH
  • Acquired hepatolenticular degeneration

Corticobasal Degeneration

• General characteristics:
  • Degeneration of:
    • Cortical areas
    • Substantia nigra
    • Basal ganglia
    • Swollen neurons in affected areas (neuronal achromasia)
  • Glial and neuronal accumulation of tau protein
• Clinical features:
  • Equal sex incidence
  • Average age of onset is 60 years of age
  • Six to ten years disease duration
  • Asymmetrical:
    • Rigidity
    • Clumsiness
    • Stiffness
    • Jerking of an arm or leg
    • Limb ideomotor apraxia
    • Postural instability
  • After 2–3 years:
    • Dystonia rigidity and akinesia of the limb
    • Hemimyoclonus
  • Posterior parietal alien limb:
    • Limb moves without voluntary control
    • Patient feels as if the affected limb may not belong to him
    • Affected limb may assume an abnormal posture or levitate
  • Parietal S1 type sensory loss
  • Progression to:
    • Dysarthric
    • Dysphagia
    • Supranuclear gaze palsy
    • Rare cerebellar signs
  • Frontotemporal neurobehavioral disorder may develop
  • Rare aphasia
• Neuroimaging: MRI and SPECT:
  • Asymmetric cortical atrophy:
    • Frontal and parietal lobe
  • Some patients:
    • Focal asymmetrical frontotemporal distribution of atrophy
    • May have generalized atrophy
• Pathology:
  • SNpc; GP, and STN are involved
  • Swollen cortical neurons
  • Tau containing neuropil threads
  • Tau containing astrocytes
  • Filamentous inclusions (tau protein)
  • Affected areas:
    • Rolandic regions
    • Posterior frontal and parietal cortex
    • Late disease:
      • Insular cortex
      • Tip of the temporal lobe

Lewy Body Dementia

• General characteristics:
  • Hallmark is the accumulation of Lewy bodies throughout the cortex to a greater degree than is noted with IPD and aging
  • An alpha synucleinopathy
• Clinical features:
  • Onset is sixth to seventh decade; average age is 68 years
  • Visuo spatial, attentional and problems solving abilities are seen early
  • Fluctuations in cognitive abilities are striking
  • Visual hallucinations are a seminal feature
  • Fluctuations of alertness and Parkinsonian features
  • Associated clinical features:
  • Repeated falls:
    • Syncope
    • Sensitivity to neuroleptics
    • Transient loss of consciousness
    • Auditory and tactile delusions
    • Transient ischemic like episodes
  • Rest tremor, Parkinsonian rigidity and bradykinesia occur but not to the same degree as in IPD

Post-Encephalitic Parkinsonism (1915–1927)

• Sequela of Von Economo's or epidemic encephalitis; also known as encephalitis lethargic
• Rare (almost all patients have died)
• Parkinsonism occurred weeks to years after the encephalitis
• Tremor as prominent as that in IPD
• Oculogyric crises (usually spasm of the superior rectus and inferior oblique muscles; any muscles may be affected)
• Personality and behavioral changes
• Autonomic crises; hypertension, severe hyperhydrosis
• Bulbar palsies
• Ophthalmoplegia
• NFT tangles and neuronal loss in SNpc of A9
• Sleep-wake cycle disruption

Differential Diagnostic Features between MSA and Parkinson's Disease

• Shy-Drager
• SND (Striatonigral degeneration)
• CBGD (Cortico basal ganglionic degeneration)
• Olivoponto cerebellar degeneration
• Lewy body disease

The immediate clues that one is dealing with a system degeneration is the lack of response to levodopa in its parkinsonian feature, a low blood pressure and cold hands.

Shy-Drager syndrome is dominated by autonomic failure. Small clues are iris atrophy (deep anterior chamber of the eye and atrophic iris) as well as cognitive dysfunction. Striatonigral degeneration is predominantly an akinetic rigid Parkinsonian patient that has no tremor at rest more rigidity than an IPD patient and does not respond to levodopa. Occasionally, these patients have levitation of an arm. The difficult diagnostic problems occur between IPD and PSP. The supranuclear gaze palsy (often is associated with eye lid apraxia) falls, and the head is held in extension. It is associated with frequent falls after the onset of illness. The deep nasolabial folds and stare are minor diagnostic features. The hallmark of diffuse Lewy body disease is dementia, visual hallucinations and clear fluctuation of cognitive and parkinsonian features. These patients may develop levitation of an upper extremity.

Corticobasal ganglionic degeneration is suspected when a patient presents with clear asymmetric akinetic rigid state, an alien hand and primary sensory (S1) sensory loss. Pick's disease is demonstrated by an expressive aphasia that is slowly progressive.

Olivopontocerebellar degeneration may have dorsal column dysfunction, retinal disease and cranial nerve abnormalities in addition to clear cerebellar ataxia.

Drug-Induced Parkinsonism

• General characteristics:
  • MPTP (methyl-4phenyl-2,3,6-tetrahydropyridine)
  • Designer drug produced from overheated Demerol specifically destroys dopaminergic cells of SNpc A9
• Clinical features:
  • Irreversible and progressive illness
  • Dramatically rapid onset of parkinsonism
  • Tremor faster than 4–6Hz of IPD
  • Respond to L-Dopa early; side effects develop quickly dependent on the severity of SNpc loss rather than length of treatment
  • Reflexes generally increases
  • May be very similar to IPD

Reversible Drug-Induced Parkinsonism

• Antipsychotic medications:
  • Phenothiazines and butyrophenones
  • Bradykinesia and rigidity
  • No tremor
  • Shuffling gait; increased carrying angles of the arms during walking
• Haloperidol and fluphenazine:
  • High potency
  • Low dose
  • Acute extrapyramidal effects
• Prochlorperazine (Compazine):
  • Antiemetic
  • Acute extrapyramidal effects most often cervical dystonia
• Metoclopramide (Reglan):
  • May cause chronic parkinsonism
  • No tremor
• Reserpine:
  • Parkinsonism
  • Nasal stuffiness
  • Depression
  • G.I. hemorrhage
  • Rarely used now
• Calcium channel blockers:
  • Diltiazem
  • Cinnarizine
  • Flunarizine
• Alpha-methyl dopa (Aldomet):
  • False neurotransmitters

Toxic Causes of Parkinsonism

• Manganese:
  • Manganese miners
  • Welders
  • Clinical manifestations:
    • Severe depression as an early symptom
    • Bradykinesia and akinesia are dominant presentation
    • Loss of postural reflexes
    • Frequent falls
    • Rare tremor
• Post hypoxic:
  • Parkinsonism: delayed onset from the sentinel event
  • Associated with: myoclonus, choreoathetosis and cortical deficits
  • Bilateral GP, destruction with carbon monoxide
• Carbon tetrachloride:
  • Dry cleaning toxic exposure
  • Akinetic-rigid presentation
• Methanol:
  • Suicide attempts (antifreeze; "moonshine")
  • Akinetic-rigid presentation
  • Severe optic neuropathy with hemorrhagic optic neuritis
  • Increased T2 signal on MRI of the striatum
• Mercury:
  • Industrial exposure
  • Akinetic-rigid presentation
  • Choreoathetosis
  • Peripheral neuropathy
  • Minamata Bay Japan large toxic exposure that demonstrated the above features

Movement Disorders Associated with Long-Term Treatment of Parkinson's Disease

• End of dose failure:
  • Return to baseline bradykinesia or akinesia
  • Tremor returns
• Peak dose dyskinesia:
  • Choreoathetosis at period of maximum absorbed concentration of L Dopa
• Early morning dystonia:
  • Awakening with dystonia of the lower extremity (plantar flexion – inversion of the foot)
• "Off periods":
  • Severe bradykinesia-akinesia
  • Occurs suddenly
  • May last 30 minutes to hours
  • Associated with "freezing" (inability to change motor sets); go through a doorway; change directions
• "On periods":
  • Duration of maximum benefit of medications
• "On-off" phenomenon:
  • Periods of benefit from medication associated with sudden episodes of bradykinesia
• "On-off" dystonia
• Dyskinesia-improvement-dyskinesia

Differential Diagnosis of Secondary Parkinsonism

• Hemiatrophy hemiparkinsonism
• Normal pressure hydrocephalus
• Pseudobulbar Palsy
• Lacunar infarctions of the basal ganglia (hypertension; diabetes)
• Binswanger's Disease (atherosclerotic ischemic demyelination)
• Alzheimer's Disease
• Neoplasm
• Vascular malformation
• Infection:
  • HIV
  • Cryptococcus
  • Creutzfeldt–Jakob Disease
• Severe depression
• Head trauma (major)
• Pugilistic (multiple minor)
• Post-hypoxia

Rare Causes of Parkinsonism

• NPH (normal pressure hydrocephalus)
• Third stage syphilis (trombone tongue)
• Vascular parkinsonism:
  • Lacunar infarctions of basal ganglia
  • Gait and balance most affected
  • Lower half Parkinsonism:
    • Vascular disease of the periventricular descending corticospinal fibers that project to leg neurons
• Severe depression (pseudo Parkinsonism)
• Wilson's Disease
• Huntington's Disease:
  • Juvenile akinetic-rigid form
  • Seizures
  • An end-stage phenomenon in the choreic form
• Hallervorden-Spatz Disease (PANK-2)
• Pseudo-bulbar palsy (emotional incontinence)
• Alzheimer's disease (cognitive decline; memory loss, visual spatial domain dysfunction)
• Hemiatrophy/hemiparkinsonism (congential MCA occlusion)
• Neoplasm
• Creutzfeldt–Jakob variant
• Binswanger (atherosclerotic demyelination)
• Repeated head trauma (Pugilistic parkinsonism)
• Hypoparathyroidism (rare; calcified basal ganglia)