Parkinsonism

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"Parkinson disease"[MeSH Terms] AND "diagnosis"[MeSH Terms]

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Parkinsonism

Definition

Parkinsonism is a clinical syndrome - not a single disease - characterized by four cardinal signs forming the acronym TRAP:

Tremor at rest
Rigidity
Akinesia/Bradykinesia
Postural disturbances (instability)

Two additional features often complete the picture: flexed posture and freezing (motor blocks). The most common cause of idiopathic parkinsonism is Parkinson Disease (PD), but the syndrome has many other etiologies.

Bradley and Daroff's Neurology in Clinical Practice, p. 2314

Causes / Differential Diagnosis

1. Parkinson Disease (PD)

The most common cause. Subdivided into:

Sporadic (majority, ~90%)
Genetic forms:
- Autosomal dominant: SNCA (alpha-synuclein), LRRK2 (most common genetic cause in Ashkenazi Jews and North Africans)
- Autosomal recessive: PARK2/parkin (up to 50% of early-onset cases), DJ1, PINK1
- Risk-modifying: glucocerebrosidase gene (higher dementia rates, faster motor progression)

2. Secondary (Atypical/Parkinsonism-Plus) Syndromes

Condition	Key Distinguishing Features
Progressive Supranuclear Palsy (PSP)	Supranuclear gaze palsy, early falls, axial > limb rigidity, poor L-dopa response; "hummingbird sign" on MRI
Multiple System Atrophy (MSA)	Early dysautonomia, cerebellar signs, "hot cross bun" sign on MRI pons
Corticobasal Degeneration (CBD)	Asymmetric apraxia, alien limb, cortical sensory loss, negligible L-dopa response
Dementia with Lewy Bodies (DLB)	Cognitive fluctuations, visual hallucinations, REM sleep behavior disorder
Vascular Parkinsonism	"Lower body" parkinsonism, broad-based shuffling gait, symmetrical, poor L-dopa response, abnormal MRI in 90-100%

3. Drug-Induced Parkinsonism

A common and reversible cause. Implicated drugs:

Dopamine receptor blockers: neuroleptics, metoclopramide, prochlorperazine
Dopamine-depleting drugs: tetrabenazine, reserpine
Others: cinnarizine, flunarizine, alpha-methyldopa, lithium

4. Toxic Causes

MPTP (converted to MPP+, inhibits mitochondrial complex I, destroys substantia nigra dopaminergic neurons)
Manganese, carbon monoxide, mercury
Copper (Wilson disease)

5. Other Causes

Infectious: encephalitis lethargica, HIV encephalitis
Vascular: lacunar strokes (especially with hypertension, diabetes, hyperlipidemia)
Structural: normal pressure hydrocephalus, tumors, head trauma
Metabolic: Wilson disease, Fahr disease (bilateral basal ganglia calcification), Hallervorden-Spatz syndrome
Goldman-Cecil Medicine, p. 3756-3790

Pathophysiology of Parkinson Disease

Loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) → depleted dopamine in the neostriatum (especially the putamen)
Clinical motor features appear only after ~60% of dopaminergic neurons have degenerated
Hallmark pathology: Lewy bodies - cytoplasmic inclusions of aggregated alpha-synuclein protein
Braak staging: disease may begin in the olfactory bulb and lower brainstem before ascending to the SNpc, explaining early non-motor symptoms (anosmia, REM sleep behavior disorder, constipation)
Proposed mechanisms: oxidative stress (MPTP model), mitochondrial dysfunction, protein misfolding/aggregation, excitotoxicity, neuroinflammation
Environmental risk factors: pesticides, heavy metals, traumatic brain injury
Goldman-Cecil Medicine, p. 3730-3740

Clinical Features

Premotor / Prodromal Phase

Non-motor features precede motor symptoms by years:

REM sleep behavior disorder (RBD) - high predictive value
Anosmia (loss of smell)
Constipation and autonomic dysfunction
Depression/anxiety

Motor Symptoms

Feature	Description
Resting tremor	4-6 Hz "pill-rolling" tremor; present at rest, diminishes with movement; accentuated by stress; affects only 1 in 5 patients with classic form
Rigidity	Increased muscle tone throughout passive movement; "cogwheel" (tremor superimposed) or "lead pipe" (without tremor); activated by contralateral limb movement
Akinesia/Bradykinesia	Slowness, reduced amplitude, fatigue; manifests as hypomimia (masked facies), hypophonia, drooling (sialorrhea), micrographia, reduced arm swing, shuffling gait, freezing of gait
Postural instability	Late feature; stooped posture, propulsion, retropulsion; assessed with the "pull test"

Motor symptoms are typically asymmetric at onset - this asymmetry often persists.

Non-Motor Symptoms (Progressive)

Pain and sensory disturbances
Dysautonomia: orthostatic hypotension, urinary urgency, erectile dysfunction
Neuropsychiatric: depression, anxiety, hallucinations, dementia
Cognitive impairment / Parkinson disease dementia (PDD)
Sleep disturbances: RBD, restless leg syndrome
Goldman-Cecil Medicine, p. 3804-3862

Diagnosis

Diagnosis of PD remains clinical (no definitive biomarker):

Bradykinesia plus at least one of: resting tremor, rigidity, or postural instability
Asymmetric onset, L-dopa responsiveness (supports PD)
Genetic testing should be considered in early-onset disease, family history, or patient preference

Imaging:

MRI brain: primarily to exclude structural/vascular causes; often normal in PD
DaTscan (dopamine transporter SPECT): reduced presynaptic dopamine uptake in PD and most parkinsonian syndromes; normal in drug-induced parkinsonism and vascular parkinsonism
PSP: "hummingbird sign" on sagittal MRI, "morning glory sign" on axial
MSA-C: "hot cross bun" sign in pons; MSA-P: striatal changes on MRI

Red flags against PD (suggesting atypical syndrome):

Early falls, early dysautonomia, symmetric onset, absent tremor, poor L-dopa response, rapid progression, gaze palsy, cerebellar signs

Management

Pharmacological - Parkinson Disease

Drug Class	Examples	Mechanism
Levodopa/carbidopa	Sinemet, Stalevo	Gold standard; L-dopa converted to dopamine; carbidopa inhibits peripheral decarboxylation
Dopamine agonists	Pramipexole, ropinirole, rotigotine	Direct D2/D3 receptor agonists; used as monotherapy in younger patients
MAO-B inhibitors	Selegiline, rasagiline, safinamide	Inhibit dopamine breakdown; mild symptomatic benefit; possible neuroprotective effect
COMT inhibitors	Entacapone, tolcapone	Reduce L-dopa degradation; used to smooth fluctuations
Anticholinergics	Trihexyphenidyl, benztropine	Useful for tremor, especially in young patients; avoid in elderly
Amantadine		NMDA antagonist; antiparkinsonian + antidyskinetic properties
Adenosine A2A antagonist	Istradefylline	Adjunct to L-dopa; reduces "off" time

Motor Complications (Wearing-off and Dyskinesias)

"Wearing off" (end-of-dose deterioration): managed by more frequent dosing, COMT inhibitors, MAO-B inhibitors, dopamine agonists
Peak-dose dyskinesias: reduce individual L-dopa dose, add amantadine
Apomorphine (subcutaneous): fast-acting dopamine agonist rescue for "off" episodes

Advanced/Surgical Therapies

Deep Brain Stimulation (DBS) of subthalamic nucleus or globus pallidus interna: best for patients with motor fluctuations and dyskinesias refractory to medications; strong evidence from RCTs
Focused ultrasound subthalamotomy: emerging non-invasive surgical option
Continuous subcutaneous foslevodopa-foscarbidopa infusion and duodenal levodopa-carbidopa intestinal gel (LCIG): for advanced disease with motor fluctuations

Non-Pharmacological

Physiotherapy: gait training, balance exercises (aerobic and resistance training shown to improve walking and balance in systematic review, 2025)
Speech therapy: hypophonia, dysphagia
Occupational therapy
Vagus nerve stimulation (noninvasive): emerging evidence (systematic review, 2025 - PMID 40057881)

Treatment of Non-Motor Symptoms

Symptom	Treatment
Depression/anxiety	SSRIs (avoid anticholinergic antidepressants)
Hallucinations (PD)	Reduce dopaminergic drugs; clozapine, quetiapine, pimavanserin (5-HT2A inverse agonist; FDA-approved for PD psychosis)
Orthostatic hypotension	Midodrine, fludrocortisone
REM sleep behavior disorder	Melatonin (first-line), clonazepam (second-line)
Dementia	Rivastigmine (AChEI, only one FDA-approved for PDD)

Important caution in DLB: Typical antipsychotics are contraindicated (severe neuroleptic sensitivity, increased mortality). Dopamine agonists more likely to worsen hallucinations.

Summary Table: Key Differentiating Features

Feature	PD	PSP	MSA	DLB	Vascular
Tremor	Common	Rare	Less common	Common	Rare
Onset	Asymmetric	Symmetric	Symmetric	Symmetric	Symmetric
L-dopa response	Good	Poor	Variable	Moderate	Poor
Falls	Late	Early	Variable	Variable	Early
Cognitive decline	Late (PDD)	Frontal/late	Autonomic > cognitive	Early (fluctuating)	Common
Key imaging finding	Normal/DaT scan	Hummingbird sign	Hot cross bun sign	Normal/DaT scan	Lacunar changes

Sources:

Bradley and Daroff's Neurology in Clinical Practice, pp. 2314-2325, 2808-2821
Goldman-Cecil Medicine, pp. 3720-3960
Recent systematic reviews: aerobic/resistance training in PD (PMID 39787155, 2025); noninvasive vagus nerve stimulation (PMID 40057881, 2025)

What kind of gait is in parkinson

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Gait in Parkinson's Disease

The characteristic gait in Parkinson's disease is called the Parkinsonian-Festinating Gait. It is a distinct, recognizable pattern caused by basal ganglia dysfunction and dopamine deficiency affecting motor control.

Core Features

1. Festination

The hallmark feature. The patient takes increasingly rapid, small, shuffling steps as if trying to "catch up" with their own center of gravity. The word comes from the Latin festinare (to hurry). The cadence starts slow but then quickens involuntarily.

"Patients with Parkinson's disease and festinating gait may find their feet unable to keep up and may thus fall forward."

Harrison's Principles of Internal Medicine, 22e

2. Short, Shuffling Steps

Reduced stride length - steps are very short (marche à petit pas)
Feet barely clear the floor - a low, sliding shuffle
The feet may appear to "stick to the ground" (start hesitation)

3. Stooped / Flexed Posture

Forward flexion of the trunk
Flexed neck, hips, and knees
Narrow stance (in contrast to cerebellar or vascular parkinsonism which are wide-based)

4. Reduced / Absent Arm Swing

The arm on the affected side swings minimally or not at all
Often one of the earliest and most easily observed signs

5. Gait Initiation Difficulty ("Start Hesitation")

Difficulty getting started; feet feel "glued" or "magnetic" to the floor
The patient may shuffle in place before moving forward

6. Freezing of Gait (FOG)

Sudden, involuntary interruption of walking - feet stick to the floor while the body continues to move forward
Triggered by doorways, turning, crowds, narrow spaces
Feet stuck, center of mass keeps moving → forward fall risk
Appears in later stages and does not respond to increasing levodopa doses

7. Propulsion and Retropulsion

Propulsion (festination): The patient accelerates forward and cannot stop - runs forward as if chasing their center of gravity
Retropulsion: When pulled backward (pull test), takes multiple backward steps or falls - due to impaired postural reflexes

8. Turning Difficulty

Turns are made in multiple small steps ("en bloc turning") rather than a single pivot
Turning also commonly triggers freezing

Summary Table (PD Gait vs. Symptomatic Parkinsonism)

Feature	Parkinson Disease	Symptomatic Parkinsonism
Posture	Stooped (trunk flexion)	Stooped or upright
Stance	Narrow	Often wide-based
Initiation	Start hesitation	Start hesitation, magnetic feet
Steps	Small, shuffling	Small, shuffling
Stride length	Short	Short
Festination	Common	Rare
Arm swing	Minimal or absent	Reduced or excessive
Falls	Late, forward (tripping)	Early, backward or unpredictable
Reactive postural responses	Preserved early	Absent early

Bradley and Daroff's Neurology in Clinical Practice, Table 25.2

Why This Gait Occurs

The mechanism stems from dopamine deficiency in the nigrostriatal pathway, impairing the basal ganglia's ability to scale and initiate movement:

Bradykinesia reduces stride length and arm swing
Rigidity makes the trunk and limbs stiff
Loss of postural reflexes impairs balance correction
Freezing is thought to involve non-dopaminergic circuits (cholinergic pedunculopontine nucleus), which is why it doesn't respond to levodopa

Response to Treatment

Gait Feature	Levodopa Response
Short shuffling steps	Good
Stooped posture	Good
Reduced arm swing	Good
Festination	Partial
Freezing of gait	Poor
Postural instability/falls	Poor

Freezing and falls in advanced PD are managed with DBS (subthalamic nucleus or globus pallidus interna), physiotherapy, gait cues (visual/auditory), and walking aids.

Adams and Victor's Principles of Neurology, p. 683
Harrison's Principles of Internal Medicine 22e, p. 1736
Bradley and Daroff's Neurology in Clinical Practice, pp. 4035-4048

Adrenal gland hormones

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Adrenal Gland Hormones

The adrenal gland has two anatomically and functionally distinct parts - the outer cortex and the inner medulla - each producing completely different types of hormones.

Costanzo Physiology, 7e - Fig. 9.21

PART 1: ADRENAL CORTEX

The cortex produces steroid hormones from cholesterol as the common precursor. It is divided into 3 zones - each producing different steroids (mnemonic: GFR → Salt, Sugar, Sex from outside to inside).

Zone	Location	Hormone Produced
Zona Glomerulosa	Outermost	Mineralocorticoids (aldosterone)
Zona Fasciculata	Middle (widest, ~75%)	Glucocorticoids (cortisol)
Zona Reticularis	Innermost	Androgens (DHEA, androstenedione)

"The zona fasciculata contains all of the enzymes required to convert cholesterol to cortisol... The zona glomerulosa produces aldosterone because it contains aldosterone synthase."

Costanzo Physiology, 7e

1. Glucocorticoids - Cortisol

Main hormone: Cortisol (hydrocortisone)

Regulation:

Hypothalamus → CRH → Anterior pituitary → ACTH → Adrenal cortex → Cortisol
Cortisol exerts negative feedback on both hypothalamus (inhibits CRH) and pituitary (inhibits ACTH)
Diurnal pattern: Peak just before awakening (~8 AM); lowest around midnight
Rate-limiting enzyme: Cholesterol desmolase (stimulated by ACTH)

Actions of Cortisol:

System	Effect
Carbohydrate metabolism	Raises blood glucose (stimulates gluconeogenesis, inhibits glucose uptake - anti-insulin)
Protein metabolism	Catabolic - increases protein breakdown in muscle, bone, and connective tissue
Fat metabolism	Stimulates lipolysis; redistributes fat (central obesity, buffalo hump, moon face in excess)
Anti-inflammatory	Inhibits phospholipase A2 → blocks prostaglandins and leukotrienes; stabilizes lysosomal membranes; inhibits cytokines
Immune	Suppresses T-cell function, reduces eosinophils and lymphocytes
Cardiovascular	Maintains vascular tone and cardiac output ("permissive" effect on catecholamines)
Bone	Decreases osteoblast activity → osteoporosis in excess
Kidney	Weak mineralocorticoid activity; increases GFR
Stress response	Key hormone of the stress response ("fight or flight" support)
Development	Promotes fetal lung surfactant synthesis (important in prematurity)

Deficiency (Addison's Disease - primary adrenal insufficiency):

Hypoglycemia, weakness, weight loss, nausea/vomiting
Hypotension, hyperkalemia, metabolic acidosis (from aldosterone loss)
Hyperpigmentation - due to elevated ACTH (which contains α-MSH fragment)

Excess (Cushing's Syndrome): Central obesity, moon face, buffalo hump, striae, hypertension, osteoporosis, hyperglycemia, immunosuppression

2. Mineralocorticoids - Aldosterone

Main hormone: Aldosterone

Regulation:

Primary regulator: Renin-Angiotensin-Aldosterone System (RAAS)
- Low BP / low Na+ → kidney releases renin → angiotensin I → angiotensin II → stimulates zona glomerulosa → aldosterone
Also stimulated by: hyperkalemia (direct effect on zona glomerulosa), ACTH (minor)
NOT significantly regulated by ACTH (unlike cortisol)

Actions of Aldosterone:

Acts on principal cells of the collecting duct of the kidney
Increases Na+ reabsorption (retains water → raises blood pressure and ECF volume)
Increases K+ excretion (hypokalemia in excess)
Increases H+ excretion (metabolic alkalosis in excess)
Also acts on colon, salivary glands, sweat glands (similar Na+/K+ exchange)

Excess (Hyperaldosteronism / Conn's Syndrome): Hypertension, hypokalemia, metabolic alkalosis, suppressed renin

Deficiency: Hypotension, hyperkalemia, metabolic acidosis, salt-wasting

3. Adrenal Androgens

Main hormones: DHEA (dehydroepiandrosterone) and androstenedione (19-carbon steroids)

Key enzyme required: 17,20-lyase (present in zona reticularis/fasciculata; absent in zona glomerulosa - hence glomerulosa cannot make androgens)

Actions:

Weak androgens; converted peripherally to testosterone and estrogens
In females: main source of androgens - responsible for axillary and pubic hair, libido
In males: minor contribution compared to testicular testosterone
Stimulated by ACTH; also regulated by CRH axis

Excess: Virilization/adrenogenital syndrome (e.g., in congenital adrenal hyperplasia - CAH) Deficiency (in women): Loss of pubic/axillary hair, decreased libido

Biosynthesis Summary (All steroids from cholesterol)

Cholesterol
    ↓ [Cholesterol desmolase - rate limiting, stimulated by ACTH]
Pregnenolone
    ↓
Progesterone
    ↓
    ├─→ [17α-hydroxylase] → 17-OH-Progesterone
    │       ↓ [21β-hydroxylase]
    │   11-Deoxycortisol
    │       ↓ [11β-hydroxylase]
    │     CORTISOL (zona fasciculata)
    │
    ├─→ [21β-hydroxylase, aldosterone synthase]
    │     ALDOSTERONE (zona glomerulosa)
    │
    └─→ [17,20-lyase] → DHEA / Androstenedione (zona reticularis)

Key enzyme deficiency - 21β-hydroxylase (most common CAH):

Blocks cortisol AND aldosterone synthesis
Shunts precursors toward androgen production → virilization
Elevated ACTH (due to no cortisol feedback) → adrenal hyperplasia

PART 2: ADRENAL MEDULLA

The medulla is embryologically derived from neuroectoderm - it is essentially a modified sympathetic ganglion, innervated by preganglionic sympathetic fibers (via nicotinic receptors).

Cells: Chromaffin cells (named for their brown-black color with potassium dichromate staining)

Hormones produced: Catecholamines

Hormone	% Secreted	Receptor Preference
Epinephrine (adrenaline)	80%	α1, α2, β1, β2 (all adrenoceptors)
Norepinephrine	20%	Mainly α1, α2; weak β2
Dopamine	Trace	Dopamine receptors

Biosynthetic pathway (from tyrosine):

Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine
                                              ↑
                              [PNMT enzyme - requires cortisol!]

Key point: PNMT (phenylethanolamine-N-methyltransferase) converts norepinephrine to epinephrine. This enzyme requires cortisol (supplied from the adrenal cortex via venous drainage). This is why pheochromocytomas (tumors away from the cortex) secrete mainly norepinephrine - they lack cortisol exposure for PNMT activation.

Actions - "Fight or Flight" Response:

Effect	Mechanism
↑ Heart rate and cardiac output	β1 receptors
↑ Blood pressure	α1 (vasoconstriction)
Bronchodilation	β2 receptors
↑ Blood glucose	β2 (glycogenolysis, gluconeogenesis)
↑ Blood flow to skeletal muscle	β2 vasodilation
↓ GI motility	α2 and β2
Pupil dilation (mydriasis)	α1
↑ Metabolic rate	β receptors

Tumor - Pheochromocytoma:

Secretes mainly norepinephrine (lacks PNMT activation)
Clinical features: paroxysmal hypertension, headache, palpitations, diaphoresis
Diagnosed by: elevated urinary/plasma metanephrines, VMA (vanillylmandelic acid)
Treatment: α-blocker first (to control BP), then surgery

Quick Summary Table

Hormone	Zone/Source	Regulator	Main Action	Excess	Deficiency
Cortisol	Zona fasciculata	ACTH/CRH	Gluconeogenesis, anti-inflammatory	Cushing's syndrome	Addison's (hypoglycemia, weakness)
Aldosterone	Zona glomerulosa	RAAS, K+	Na+ retention, K+ excretion	Conn's (HTN, hypoK)	Salt-wasting, hyperK, hypotension
DHEA/androstenedione	Zona reticularis	ACTH	Weak androgens	Virilization (CAH)	↓ libido, hair loss (females)
Epinephrine	Medulla	SNS/stress	Fight-or-flight, bronchodilation	Pheochromocytoma	Hypoglycemia risk
Norepinephrine	Medulla	SNS/stress	Vasoconstriction, ↑ BP	Pheochromocytoma	-

Sources:

Costanzo Physiology, 7th Edition, pp. 43-265
Robbins & Kumar Basic Pathology, pp. 2798-2822
Costanzo Physiology (ANS chapter), pp. 1777-1800

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