CNS Degenerative Disorders and Brain Neoplasms: An Encyclopedic Study Guide

Historical and Conceptual Overview of Dementia

• Etymology and Historical Distinctions

  • The term "dementia" originates from the Latin demens, meaning "out of one’s mind."

  • In 600 AD, St. Isidore established specific clinical distinctions:

    • Insania (Insanity): Characterized as mania and melancholia.

    • Amentia: Described as congenital silliness.

    • Dementia: Defined as a slow-developing condition.

• Manifestations of Dementias

  • Characterized by the progressive loss of cognitive (intellectual) function.

  • Associated with the loss of short-term memory, emotional instability, and confusion.

  • Represents a significant loss of frontal lobe function.

  • Progressive dementia leads to neural degeneration and atrophy of the cortex, diencephalon, and basal nuclei.

Differential Diagnosis: Delirium versus Dementia

• Determining Cause

  • The specific cause of dementia can often only be definitively determined on post-mortem examination.

• Comparison of Brain Dysfunction States

  • Delirium:

    • An acute state of brain dysfunction.

    • The onset is usually abrupt.

    • The autonomic nervous system is overactive.

    • It is common in critical care units, post-surgically, or during withdrawal from CNS depressants such as alcohol or narcotics.

  • Dementia:

    • Involves the progressive failure of many cerebral functions.

    • The onset is usually gradual.

    • Related to hypoxic damage to the brain tissue.

    • Progressive dementias produce nerve cell degeneration and brain atrophy.

    • Age serves as the greatest risk factor.

  • Pseudo-Dementia: A condition that mimics dementia symptoms but originates from other causes.

Alzheimer’s Disease: Progression and Clinical Manifestations

• Deterioration Stages

  • The progression of manifestations follows a specific sequence of deterioration:

    1. Mood

    2. Cognitive function

    3. Functional autonomy

    4. Behavior

    5. Moticity

• Clinical Presentation of Mood and Cognitive Change

  • Mood Lability: Fluctuations occur without apparent reason, accompanied by irritability, hostility, restlessness, and depression.

  • Cognitive Function Losses:

    • Amnestic Losses: General memory loss.

    • Agnosia: Inability to interpret sensory information.

    • Language Problems: Forgetting words or inappropriate word substitution.

    • Disorientation: Loss of sense regarding time and place (e.g., being unsure of the current year).

    • Judgment: Poor or decreased judgment leading to bad decisions.

    • Abstract Thinking: Difficulty handling complex or abstract concepts.

• Behavioral and Executive Manifestations

  • Behavior: Disorientation, misplacing items, general confusion, and unpredictability.

  • Aimless Wandering: Purposeless movement through environments.

  • Hyper-orality: A tendency to put objects in the mouth.

  • Executive Losses: Difficulty in performing familiar tasks and a notable loss of initiative.

Alzheimer’s Disease: Pathologic Findings and Biomarkers

• General Correlation

  • There are no clear pathological findings that correlate perfectly with clinical findings.

• Senile Plaques

  • Involve the amyloid precursor protein (APP) which converts to $\beta\text{-amyloid}$.

  • $\beta\text{-amyloid}$ ($Ab$) enhances the action of free radicals to destroy neurons.

  • Bielchowski Stain Findings: Used to identify neuritic plaques in Alzheimer’s patients and diffuse plaques in the elderly.

  • Caveats:

    • Some patients clinically diagnosed with dementia have few plaques.

    • Some individuals with many plaques do not exhibit dementia.

    • $80\,\%$ of people who are $80\,\text{years old}$ show ‘diffuse’ plaques, often without Alzheimer's Disease (AD) or any form of dementia.

• Neurofibrillary Tangles (NFTs)

  • Tau protein normally functions to stabilize cellular microtubules.

  • Abnormal tau causes ‘tangles’ which alter the shape of the neuron and impair the movement of substances down the axon.

  • In a diseased neuron, the microtubules disintegrate and the tau protein molecules form tangled clumps.

• Anatomical Progression and Atrophy

  • Pathology Pathway: Entorhinal cortex $\rightarrow$ Hippocampus $\rightarrow$ Temporal Lobe $\rightarrow$ Parietal Lobe $\rightarrow$ Frontal Lobe.

  • Brain Structure Changes:

    • Extreme shrinkage of the cerebral cortex.

    • Extreme shrinkage of the hippocampus.

    • Severely enlarged ventricles.

    • Noticeable widening of the sulci and shrinkage of the gyri compared to a normal brain.

Management and Stabilization of Alzheimer’s Disease

• Symptomatic Treatment

  • No disease-arresting therapies are currently available.

  • Primary goals include maintaining socialization and providing support for family and friends.

  • Pharmacotherapy:

    • Anti-depressants.

    • Anti-cholinesterase: e.g., Rivastigmine.

    • Anti-glutamatergic: e.g., Memantine.

    • Antipsychotic: e.g., Haldol.

• Disease Stabilization Efforts

  • Anti-amyloid: Vaccines targeting amyloid development.

  • Anti-inflammatory drugs: Ibuprofen.

  • Anti-oxidants: Tocopherol (Vitamin E).

  • Trophic Factors: Enhancers of growth factors in the brain.

Lewy Body Disease (LBD)

• Overview and Clinical Presentation

  • The exact cause is unknown; it is considered by some to be a variant of Alzheimer's Disease or Parkinson’s.

  • Fluctuating Cognition: Pronounced variations in attention and alertness.

  • Hallucinations: Recurrent, typically well-formed and detailed.

  • Motor Features: Spontaneous motor features characteristic of Parkinson’s disease.

• Pathology

  • Involves the presence of Lewy Bodies containing $\alpha\text{-synuclein}$.

  • $\alpha\text{-synuclein}$ is a presynaptic neuronal protein of unknown function.

  • These bodies disrupt brain physiology by interrupting the action of acetylcholine (Ach) and dopamine.

  • Distribution is both sub-cortical and cortical.

Cerebrovascular Disease (CVD) and Mixed Dementias

• Cerebrovascular Dementia Patterns

  • Rare in its pure form (approximately $1\,\%$); almost never seen clinically.

  • No specific pathological criteria are established.

  • Patterns include:

    • Multiple small infarcts.

    • Lacunar infarcts (affecting basal nuclei).

    • Hypo-perfusion infarcts (affecting white matter).

• Relationship to Amyloid and AD

  • Chronic ischemia causes $\beta\text{-amyloid}$ production.

  • $\beta\text{-amyloid}$ renders neurons susceptible to oxidation changes via free radicals.

  • $\beta\text{-amyloid}$ and chemical mediators of inflammation (complement and cytokines) exacerbate AD effects by increasing blood viscosity and coagulation.

  • Autopsy statistics:

    • $\frac{1}{3}$ to $\frac{1}{2}$ of autopsied AD patients have cerebral infarcts.

    • $55\,\%$ of non-demented stroke patients possess senile plaques and NFTs.

    • Patients with both AD and CvD experience more severe AD symptoms than those with pure AD.

• Mixed Dementias

  • The coexistence of multiple pathologies usually involving AD, Lewy Body Disease (LBD), and/or CvD.

  • Each pathology adds to the overall effect of dementia.

Parkinson’s Disease (PD)

• Neuroanatomy of the Basal Ganglia

  • Key structures include the putamen, caudate nucleus, globus pallidus (interna and externa), thalamus, substantia nigra, subthalamic nucleus, and red nucleus.

  • The corpus striatum and lentiform nucleus are critical components for motor control.

• Pathophysiology

  • PD is a degenerative disorder of the nigrostriatal pathway.

  • There is a deficiency of dopamine (an inhibitory neurotransmitter) secreted into the basal ganglia.

  • This leads to an imbalance between dopamine and ACh (acetylcholine).

  • Disruption occurs in the extrapyramidal function.

  • Normally, the substantia nigra (SN) provides dopamine to the caudate nucleus (CN) to feedback and modify movement. In PD, the loss of dopamine results in failure of this feedback loop.

• Etiology and Epidemiology

  • Onset usually begins after the age of $40\,\text{years}$.

  • Primary Parkinson’s: No known cause.

  • Secondary Parkinson’s: Caused by drugs (neuroleptics like Haldol), trauma, or infection.

• Clinical Manifestations of Parkinson’s

  • Motor Effects:

    • Progressively moves from unilateral to bilateral symptoms.

    • Tremor at rest, beginning in hands (the ‘pill-rolling’ effect), which abates during movement.

    • Bradykinesia (slowed movement) leading to akinesia (loss of movement).

    • Freezing episodes.

    • Gait Disturbances: Festinating gait (short, accelerating steps) and propulsive-retropulsive gait.

  • Postural Effects:

    • Hypertonia (muscle rigidity): Described as ‘lead pipe’ or ‘cogwheel’ phenomenon.

    • Stooped, hyper-flexed posture.

    • Loss of automatic movements and disequilibrium.

  • Emotional and Intellectual Effects:

    • Flat affect (mask-like facies).

    • Depression.

    • Progressive dementia.

Pharmacotherapeutics for Parkinson’s Disease

• Bromocriptine Mesylate (PO)

  • Classification: Direct-acting dopamine receptor agonist.

  • Mechanism: Stimulates production of more dopamine.

  • Indications: Early or late stages.

  • Adverse Effects: Ataxia, dizziness, headache.

  • Duration: $4\text{--}8\,\text{h}$.

• Levodopa-Carbidopa (PO)

  • Classification: Dopamine replacement.

  • Mechanism: Most common dopamine therapy.

  • Contraindications: Primary angle glaucoma, malignant melanoma.

  • Adverse Effects: Confusion, palpitations, hypotension, urinary retention.

  • Duration: $5\,\text{h}$.

• Selegiline (PO)

  • Classification: Indirect-acting dopamine receptor agonist.

  • Mechanism: Prevents MAO (Monoamine oxidase) from breaking down dopamine.

  • Indications: Adjunctive drug used with Levodopa-carbidopa.

  • Contraindications: Use of opioids.

  • Duration: $1\text{--}3\,\text{days}$.

• Amantadine HCL (PO)

  • Classification: Dopamine modulator.

  • Mechanism: Stimulates release of dopamine from storage sites in presynaptic fibers and blocks reuptake.

  • Indications: Early stages when neurons are intact; within the first year of diagnosis.

  • Adverse Effects: Dizziness, insomnia, hallucinations.

• Entacapone (PO)

  • Classification: COMT inhibitor.

  • Mechanism: Blocks COMT (the enzyme breaking down catecholamines) peripherally; prolongs Levadopa duration.

  • Indications: Adjunctive drug with Levodopa-carbidopa.

  • Adverse Effects: GI upset, dyskinesia, orthostatic hypotension.

Multiple Sclerosis (MS)

• Overview and Epidemiology

  • A CNS demyelinating disorder restricted mainly to white matter.

  • Characterized by multiple areas of degeneration and sclerotic lesions.

  • Onset is usually between $20\text{--}50\,\text{years}$.

  • Prevalent in northern latitudes and white populations.

  • Incidence: Approximately $110\text{--}140\,\text{cases}$ per $100,000\,\text{people}$ above the $37^{th}‑\text{Parallel}$, and $57\text{--}78\,\text{cases}$ per $100,000$ below it.

• Pathogenesis and Pathophysiology

  • Suspected involvement of the Epstein-Barr Virus (EBV).

  • Women are affected more than men ($Ratio = 2:1$).

  • Process: Initial inflammation and edema resolve, leaving diffuse plaques. These plaques coalesce, and in late stages, gliosis occurs.

  • Axonal Impact: Action potentials are disrupted. Conduction can sometimes be restored by an increase in the density of sodium channels in acutely demyelinated axons, but chronic demyelination leads to degenerated or transected axons.

  • Short-Circuiting: Loss of myelin leads to non-synaptic transmission.

• Clinical Forms of MS

  • Relapsing-Remitting MS: The most common type. Patients show symptoms but seem to recover. The cycle of symptoms-to-recovery continues over time.

  • Primary Progressive MS: Gradual worsening of symptoms without periods of recovery.

  • Secondary Progressive MS: Begins with periods of recovery but transitions into a stage of gradual worsening without recovery.

• Clinical Manifestations

  • Often preceded by a precipitating event: trauma, infection, or pregnancy.

  • Symptoms: Diffuse pain, fatigue, paresthesia, and visual disturbances (diplopia).

  • Motor/Neurological: Feeling of ‘heaviness,’ ataxia, dysarthria, and bowel/bladder control problems.

  • Mental Health: Depression, inattentiveness, and forgetfulness.

Pharmacotherapeutics for Multiple Sclerosis

• Fingolimod (PO) and Glatiramer Acetate

  • Classification: Immunosuppressants.

  • Mechanism: Suppress T lymphocyte cells to prevent their involvement in the immune response.

  • Indications: Reduces relapse frequency in remitting-relapsing MS.

  • Contraindications: Kidney/liver failure, hypertension, uncontrolled infection; pregnancy (urgent only); avoid live vaccines.

  • Adverse Effects: Risk for opportunistic infections, headache, hepatotoxicity, flu-like symptoms, back pain, throat constriction, dyspnea, flushing, urticaria, and chest pain.

Amyotrophic Lateral Sclerosis (ALS)

• Etiology and Pathology

  • Etiology is speculative; suspected genetic factors involve a defect on Chromosome $21$. Possible viral triggers include Enterovirus/Coxsackie B.

  • Pathology affects both upper and lower motor neurons.

  • Inflammation is absent; instead, gliosis and sclerosis (scarring) are found.

  • Lower Motor Neuron (LMN) lesions involve denervation and muscular atrophy.

• Pathophysiology

  • Involves a specific interaction of IgG with $Ca^{++}$ ion channels in the axon terminal.

  • Leads to axonal degeneration and secondary demyelination.

• Clinical Manifestations and Prognosis

  • Symptoms: Weakness, muscular atrophy, flaccid and spastic paralysis, loss of speech, swallowing difficulties, and ventilatory failure.

  • Intellectual function remains normal.

  • Prognosis: Usually progresses to death within $3\text{--}5\,\text{years}$.

• Pharmacotherapeutics for ALS

  • Rilutek (Riluzole) (PO):

    • Classification: Benzothiazole.

    • Mechanism: Thought to block voltage-sensitive sodium channels and presynaptic calcium-dependent glutamate release to reduce neuronal loss/excitotoxicity.

    • Indications: Slows progression of ALS.

    • Adverse Effects: Increased BP, numbness/tingling around the mouth, dizziness, GI pain.

  • Radicava (Edaravone) (IV/PO/G-tube):

    • Classification: Antioxidant.

    • Mechanism: Captures reactive oxygen species (unstable molecules) to prevent energy-consumption-related damage to neurons.

    • Adverse Effects: Bruising at injection site ($15\,\%$), abnormal walking ($13\,\%$), headache ($10\,\%$).

    • Administration: PO should be taken on an empty stomach (no food for $1\,\text{hour}$ after).

Brain Tumors

• Primary Tumors (Gliomas)

  • Astrocytomas:

    • Pilocytic Type: Slow-growing; found in optic nerves/chiasma, hypothalamus, basal nuclei, and hemispheres. Not aggressively infiltrative.

    • Diffuse Type: Found in fronto-temporal lobes; moderately infiltrative.

  • Glioblastoma Multiforme: Highly proliferative, invasive, and vascular. Located in cerebral hemisphere white matter (fronto-temporal). Most common brainstem tumor in children.

  • Oligodendrocytoma: Located mainly in frontal lobe white matter; can occur in brainstem, cerebellum, or spinal cord. Relative avascular and usually encapsulated.

  • Ependymoma: More common in children; arise from ependymal cells lining the ventricles. Variable growth rate.

• Non-Glial and Meningeal Tumors

  • Meningioma: Arises from meninges. Slow-growing, compressive, circumscribed, and encapsulated.

• Metastatic Tumors

  • Distribution: Cerebrum ($80\text{--}85\,\%$), Cerebellum ($10\text{--}15\,\%$), Brainstem ($3\text{--}5\,\%$).

  • Primary Sources: Lung, breast, kidney, colon, and skin (melanoma).

  • Dissemination: Blood-borne (there are no lymphatics in the brain).

  • Characteristics: Melanoma has the highest tendency to produce multiple lesions. Multiple tumors are usually metastatic; single ones are primary. Subcortical in location.

• Manifestations and Management

  • Symptoms depend on location, number, growth rate, and edema.

  • Common signs: Increased intracranial pressure (headache, nausea, vomiting), stroke-like symptoms (weakness, speech deficits), and seizures.

  • Treatment: Brain metastases often require aggressive focal treatment (surgery or radiosurgery) because immunotherapy and chemotherapy do not effectively reach them.

  • Medications (Nitrosoureas): Procarbazine, Lomustine, and Vincristine.

    • Mechanism: Alkylation (preventing cancer cell reproduction by attaching alkyl groups to DNA).

    • Adverse Effects: Nephrotoxicity and bone marrow suppression.