CASE 1

A 43-year old HIV positive male came to your clinic with his male friend seeking consult
because of slowly enlarging lateral neck mass. He narrates that before the mass was noted, he
had on and off cough with episodes of low-grade fever and night sweat. He earlier sought
consult at the local health center and was advised to have his sputum examined for tuberculous
bacilli. He, however, did not return to the health center to follow up his sputum examination
results. He also noted that he was slowly losing weight and that he easily gets fatigued.
Pertinent physical examination findings show bilateral lateral neck masses measuring 3.0 x 3.0
x 3.0 cm on the right and 3.0 x 2.0 x 2.0 cm on the left. Complete blood count and peripheral
blood smears reveal he has mild microcytic, hypochromic anemia. The patient was advised to
undergo the following: sputum examination, fine needle aspiration biopsy of bilateral neck
masses and CD4+ count

1. If the patient’s sputum turns out to be positive for tuberculosis, how would his immune
system deal with the infection?

Alveolar macrophages are presumably the first group of cells which encounter
Mycobacterium tuberculosis​. In these cells, the bacteria is able to replicate unchecked
due to its ability to inhibit phagosomal maturation, and resist lysosomal acidification.
Mycobacterium tuberculosis​ also induces p38 mitogen activated protein kinase (MAPK)-
dependent binding of activating transcription factor 2 (ATF2) and
extracellular-signal-regulated kinase (ERK)-dependent binding of FosB to the TNF alpha
promoter region thus stimulating TNF alpha production which mediates M.
tuberculosis-induced apoptosis (Kumawat,2010). However, studies have shown that
M.tb may potentially have the capacity to inhibit this apoptosis. ​Mycobacterium
tuberculosis ​continues to proliferate in the pulmonary alveolar macrophages and air
space, resulting in bacteremia. Antigen presenting cells present mycobacterial peptide to
CD4 T cells via MHC class II, which provide cytokine and chemokine signals to activate
innate immune cells and recruit cytotoxic lymphocytes and other cells to the disease site.
It is important to note that coinfected activated macrophages increases HIV replication.
Multiple pathogen associated molecular patterns of ​Mycobacterium tuberculosis
are recognized by innate immune receptors such as TLR2. Stimulation of TLR2 by
mycobacterial ligands promotes production of IL-12 by dendritic cells. This results in the
differentiation of TH1 cells. In this case, HIV depletes the specific and nonspecific T cells
resulting in a reduced immune response. In addition, HIV preferentially infects and
depletes IL-2-producing CD4+ T cells. The activation of CD8+ cells are also reduced due
to depleted CD4+.
Nonetheless, TH1 cells release IFN-γ which is a critical mediator in containing
M.tb infection. IFN-γ functions to control M.tb infections through stimulation maturation of
the phagolysosome in infected macrophages, stimulation of expression of inducible nitric
 oxide synthase, producing nitric oxide (NO) and reactive nitrogen intermediates,
mobilizing antimicrobial peptides such as defensins against the bacteria, and inducing
autophagy. These mechanisms all result in the degradation of ​Mycobacterium
tuberculosis.​
Moreover, IFN-γ also activates macrophages to differentiate into “epithelioid
histiocytes” that aggregate to form granulomas in lung tissue. It was determined that
granulomas within HIV+ patients contain less CD4+ cells due to decreased availability
which contributes to decreased containment of infection (Diedrich and Flynn, 2011). It is
also important to note that granuloma formation may be absent in late stages of HIV.
Due to immunosuppression, the ongoing immune response progresses into caseation
necrosis.

Sources:
Diedrich, C. R., & Flynn, J. L. (2011, April). HIV-1/Mycobacterium tuberculosis
Coinfection Immunology: How Does HIV-1 Exacerbate Tuberculosis? Retrieved from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3067569/
Kumawat, K., Pathak, S. K., Spetz, A., Kundu, M., & Basu, J. (2010, April 23). Retrieved
from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857058/

2. If the patient’s fine needle biopsy results turns out suggestive of a proliferative
lymphocytic lesion, how will the immune system deal with the abnormal cells?

Within the macrophages, the Mtb may stimulate either TCD4+ cells by an expression of
the antigen associated to MHC class II or TCD8+ cells by an expression of the antigens
associated with molecules of MHC class I. Activation of TCD4+ cells lead to the
secretion of IFN-gamma, which activates the macrophages and leads to increased
production of nitrous oxide (NO) and destruction of bacteria. TCD8+ cells participate in
the protection mechanism through cytotoxicity, thereby destroying the infected
macrophages.

The apoptosis-regulating proteins, Fas, Fas ligand (FasL), Bcl-2 (anti-apoptotic protein)
and Bax (pro-apoptotic protein), play a vital role in the regulation of apoptosis and the
immune response. The expression of these proteins is exploited by mycobacteria to
evade the immune response and persist in the host. Mycobacterial-infected cells, by
virtue of increased Bcl-2 and reduced Bax expression, can evade activation-induced
apoptotic cell death.

Th1 cells also play a role in the defense against TB due to the ability of IFN-γ to activate
macrophages and stimulate phagocytosis, phagosome maturation, production of reactive
nitrogen intermediates, and antigen presentation. Th17, in addition, mediates pleiotropic
 activities that involve induction of proinflammatory genes (cytokines, chemokines, and
metalloproteinases) and antimicrobial peptides, modulation of extracellular matrix,
stimulation of granulopoiesis, recruitment, and activation of neutrophil granulocytes.
Therefore, the main functions of Th17 cells are protection against extracellular
pathogens and mediation of the inflammatory response, particularly during autoimmune
and chronic inflammatory diseases.

3. If the CD4+ count is low, how was the virus able to cause death to this type of T cell.

The mechanism underlying the death of CD4+ T cells can be explained mainly by
the increased pyroptosis among infected CD4+ T cells that release inflammatory
cytokines (most especially proinflammatory cytokine IL-1​β)​. These cytokines affect
normal, uninfected CD4+ T cells, triggering pyroptosis among the cell population. The
immune activation and inflammation in an HIV-infected individual contribute to the
replication of the virus and increased incidence of chronic conditions but more
importantly, these phenomena contribute to the induction of immune dysfunction with
associated decrease in CD4+ T cell count - both infected and normal CD4+ T cells.

HIV uses our cellular machineries to replicate and infect cells. It uses several
enzymes such as reverse transcriptase and integrase to replicate within the host cell,
specifically the CD4+ T cell. In an infected and untreated patient, virus replication is
invariably persistent. Reverse transcription, integration and virus spread are much more
efficient in activated cells. This activated state in HIV infection result in cascade of
processes that lead to intense immune activation leading to CD4+ T cell dysfunction and
depletion.

Several mechanisms have been proposed regarding the mechanisms for the
dysfunction and death of infected CD4+ T cells. One mechanism involves the aberrant
intracellular signalling events secondary to the loss of plasma membrane integrity due to
viral budding. Additionally, accumulated unintegrated viral DNA and activation of
DNA-dependent protein kinases during viral integration results to autoimmunity. The HIV
envelope proteins such as gp120 are also important in both humoral and cell-mediated
immune response. Interference of cellular RNA processing and syncytia formation
contribute to the T-cell dysfunction and depletion.

All of these events are thought to induce a form of cell death known as apoptosis.
The aberrant cellular activation associated with HIV infection is correlated with a
heightened state of apoptosis. In one way or another, the above mechanisms can trigger
Fas-dependent and Fas-independent pathways of apoptosis. The Fas-dependent
pathway is known for upregulating Fas and Fas ligand. Fas-independent pathways can
be extrinsic (utilizing death receptors) or intrinsic (by downregulation of antiapoptotic
proteins such as Bcl-2). More recently, the role of pyroptosis has been linked to the
 bystander effect of HIV replication and CD4+ T cell destruction. Inflammosomes are
multiprotein complexes that recognize microbial products in cytoplasms of infected cells.
Inflammosomes activate proinflammatory enzyme caspase-1 that cleaves the precursor
form IL-1​β to its active form​. IL-1​β which is a proinflammatory cytokine, along with many
other cytokines, initiate the inflammatory pathways resulting to pyroptosis.

All the mechanisms listed above will trigger the apoptotic and pyroptotic
pathways. In HIV, the infected cells become destructed and release
inflammosome-generated IL-1​β that attaches to receptors of inflammatory cells including
normal CD4+ T cells. This is the characteristic “​by-stander effect​” in HIV infection,
wherein even normal CD4+ T cells, CD8+ T cells and B cells die secondary to
stimulation of proinflammatory cytokine released by infected CD4+ T cells. This explains
how the virus causes CD4+ cell death resulting to low overall CD4+ T cell count.

4. Assuming the result of the FNAB showed numerous clusters of epithelioid macrophages,
which pathway will the role of macrophages proceed to ? (tissue destruction or tissue
repair). Explain.

Macrophages are activated via the classical and alternative pathways. The former is
implicated in microbial killing and the latter in tissue repair. Activated macrophages
develop abundant cytoplasm, such that they resemble epithelial cells, and are hence
called epithelioid macrophages, which can fuse together to form giant cells.

Classical activation of macrophages is initiated by the release of IFN-Ɣ by Th1 cells,

resulting to enhanced killing via the production of ROS, NO and lysosomal enzymes and
inflammatory stimulation via cytokine secretion (including IL-1, 12 and 23), leading to
leukocyte recruitment, which in turn enhances T cell and macrophage activation and
recruitment.

In infections involving microbial agents which are hard to eradicate, granuloma formation
takes place. Macrophages become activated and surround the offending agent, inducing
hypoxia and free radical injury, and would be subsequently rimmed by lymphocytes and
fibroblasts. In the case of Mycobacterium tuberculosis infection, the resultant tissue
damage grossly manifests as a central area of necrosis with a granular, cheesy
appearance (i.e. caseous necrosis).

CASE 2
This is the case of patient DZ, an 86-year-old female, Filipino, from Quiapo, Manila,
Roman Catholic, widow, and a grade school graduate. She is a known hypertensive for 20
years, highest BP: 200/100 mmHg and usual BP of 160/100 mmHg. Maintained on Amlodipine
5mg/tab OD, Losartan 50mg/tab OD, Simvastatin 10mg/tab ODHS, ASA 80mg/tab OD,
Carvedilol 6.25mg/tab BID, Spironolactone 75mg/tab OD. Said to be compliant to all
medications except for ASA due to abdominal discomfort. Had easy fatigability (2 flights of
stairs), 2 pillow orthopnea, and occasional chest pain 6/10, non-radiating.

Chief complaint:​ Left-sided body weakness.

History of Present Illness:

1-day PTA: had sudden onset of left-sided body weakness (upper and lower extremities) with no
associated fever, vomiting, nausea, headache, dizziness, blurring of vision, slurring of speech,
and loss of consciousness. Persistence of symptoms prompted consult.

Past Medical History​: (-) DM, prior surgeries, known allergies, thyroid, liver, or kidney
diseases, PTB, s/p CVD (OMMC, 2004); (PGH, 2007).

Family History: ​(+) Hypertension, CAD, CVD (maternal side), (-) DM, known thyroid, liver, or
kidney diseases.

Personal and Social History: ​Non-smoker, non-alcoholic beverage drinker, denies illicit drug
use. Stays at home, eats 3x a day (preference: rice 2-3 cups/day, fatty foods, and vegetables),
sleeps for 6-7 hours at night, uninterrupted.

Laboratory and Ancillary Tests

PT 14.5

% Activity 90.3

INR 1.09

aPTT 27.4

WBC 6.4x10​3​/dL

Lymphocytes 33.8%

Monocytes 8.6%

Neutrophils 57.6%

RBC 4.35x10​6​/uL

HGB 13.7 g/dL

HCT 40.5%

MCV 93.3 fL
 MCH 31.5 pg

MCHC 33.8 g/dL

RDW CV 13.1%

PLT 169x10​9​/L

BUN 3.08

CREA 92.9

ALT 26.5

AST 37.5

Sodium 131.0

Potassium 3.3

Chloride 100.5

12 Lead ECG: No visible P waves, irregularly irregular QRS complex, deep S in anterior leads,
PVCs

Guide Questions:
1. Explain the mechanisms involved in the transition from homeostasis towards an altered
state in this patient.

The patient is a known, diagnosed case of hypertension for 20 years. Her

homeostatic state had already been altered from that point onward (essentially making
this altered state her new homeostatic state). Her maintenance medications together
with several adaptations by the body helped her maintain this homeostatic state until the
body can no longer adapt. When this happened, cellular injury occurred (manifested by
the signs and symptoms seen in the patient).

Due to her old age, the arteries are already less elastic and less compliant, which
made it harder for the heart to pump blood to the other parts of the body. Additionally,
her diet consisting of mostly fatty foods increased the risk of developing plaques that are
deposited into the arteries, leading to narrowing of the arterial lumen. This increased the
total peripheral resistance, which also made pumping blood harder. Blood pressure is
then subsequently increased.

Due to increase blood pressure, the afterload that the heart needs to overcome
became higher. Since a pressure gradient needs to be maintained in order for the heart
 to pump blood out of the heart, the myocardial cells adapted through hypertrophy to
increase the force of contraction needed. However, due to this, the impulse sent to the
myocardial cells during normal contraction does not fully reach the cells enough to elicit
simultaneous contraction of the heart, leading to atrial fibrillation.

In response to this, the body adapted through the action of the baroreceptors that
monitor the change in blood pressure. Blood pressure is subsequently brought back to
normal levels. However, due to persistently increased blood pressure, the baroreceptors
are also persistently firing at an increased rate, and the body adapted by increasing the
blood pressure set point.

The prolonged increased BP led to a more turbulent blood flow that may damage
the arterial walls. This may activate the coagulation pathway through the exposure of the
endothelial cells. This cascade of events will lead to an increased risk of forming a
thrombus.

The anti-hypertensive maintenance medications taken by the patient helped in

maintaining her homeostatic state. However, due to non-compliance with ASA (which
are also platelet aggregation inhibitors), the risk of forming a thrombus increased.
Coupled with the 20-year history of hypertension of the patient, there is an increased risk
of forming a large thrombus that may become dislodged into smaller pieces that could
then travel through the bloodstream and occlude the smaller vessels (embolus). Such is
what happened to the patient.

The dislodged thrombus reached and occluded the small arteries of the brain,
which led to ischemia of the parts of the brain they supplied. This subsequently led to
ischemic stroke, which presented in the patient as left-sided body weakness, which is
the new altered state of the patient. Since the patient presented with left-sided body
weakness, the occluded blood vessel could probably be the right middle cerebral artery.

2. Explain the cellular/histologic and pathophysiologic basis of the patient’s condition on

admission.

Occlusion of the right middle cerebral artery, particularly at its trifurcation,

resulted in the reduction of blood flow to the right lateral hemispheric cortex, which gave
rise to left hemiparesis. This is an example of focal cerebral ischemia, which when
sustained, leads to infarction of the area supplied by the occluded vessel.

Focal cerebral infarction may occur either via necrotic or apoptotic pathway.
Ischemia, which is present in this case, produces necrosis through depletion of glucose
and oxygen, which starves neurons and leads to impaired production of ATP by the cell’s
mitochondria. This results in the malfunction of the ion pumps as well as the
depolarization of neurons, thereby increasing intracellular calcium and glutamate release
 from synaptic terminals. Excess extracellular glutamate then activate the postsynaptic
glutamate receptors which increase neuronal calcium influx, thereby producing
neurotoxicity by ​activating (1) phospholipases which degrade membrane phospholipids;
(2) proteases which break down membrane and cytoskeletal proteins; (3) ATPases
which hasten ATP depletion; and (4) endonucleases that cause chromatin
fragmentation. Degradation of membrane lipids lead to formation of free radicals which
cause further membrane destruction and damage to the cells’ other vital functions.

Free radicals cause catalytic destruction of membranes, triggering cell death and
inducing the formation of inflammatory mediators, which then induce JNK, p-38, NFκB
and AP-1 activation in glial cells, endothelial cells, and infiltrating leukocytes. This
culminates in pro-inflammatory cytokine and chemokine secretion leading to invasion of
leukocytes via up-regulation of endothelial adhesion molecules. Within a few minutes,
core of brain tissue exposed to the most dramatic blood flow reduction, is mortally
injured, and subsequently undergoes necrotic cell death. Necrosis is morphologically
characterized by initial cellular and organelle swelling, subsequent disruption of nuclear,
organelle, and plasma membranes, disintegration of nuclear structure and cytoplasmic
organelles with extrusion of cell contents into the extracellular space.

Generally, one day after the infarct has taken place, shrunken eosinophilic
neurons with nuclear pyknosis are present in the infarct. After 2-3 days, neutrophils start
infiltrating the tissue which is soft and edematous. Blood vessels are also prominent.
Macrophages replace neutrophils by 3-4 days and phagocytose and clear debris in the
infarct at about 1mL per month. Astrocytes join the macrophages a week after and form
dense fibrillary glial meshwork around the dead tissue. While the macrophages dispose
of debris, the infarct slowly evolves into a glial lined cyst which is crossed at points by
delicate glial sheets and small vessels invested with residual lipid and hemosiderin-laden
macrophages.

3. Explain the significance of the tests performed on the patient. Do the available laboratory
and ancillary tests correlate with the patient’s presentation?

Coagulation studies are done in cases of suspected ischemic stroke to rule out
coagulopathy as the possible cause. It is also necessary before initiating thrombolytic
therapies as it will serve as the baseline and if the desired INR is reached following
administration. A CBC serves as a baseline study and may reveal a cause for the stroke
(eg, polycythemia, thrombocytosis, thrombocytopenia, leukemia), identify evidence of
concurrent illness (eg, anemia), or issues that may affect reperfusion strategies
(thrombocytopenia). Electrolyte measurement is also particularly useful as certain
electrolyte disturbances may present with muscle weakness and mimic stroke such as
 seen in hypokalemia, hyperkalemia, hypercalcemia ,hypernatremia, hyponatremia,
hypophosphatemia, hypermagnesemia.
The measurement of transaminases are used to assess the function of the liver
as diseases of the liver is ​associated with both hemorrhagic and thrombotic processes​. ​It
can also be used to rule out myocardial infarction but it has been replaced by more
modern and specific molecular markers such as Troponin I, CK-MB, and LDH. BUN and
Creatinine measurement can reveal concurrent renal insufficiency which can greatly
influence the clinical outcome of the patient. An ECG is particularly useful as may
demonstrate arrhythmias or reveal evidence of recent myocardial infarction (MI).

Based on the patient’s laboratory results, she has a low potassium level which
can explain the pure motor hemiparesis experienced by the patient which also correlates
with the ECG finding of ​ST segment sagging and T wave depression. She has a low
BUN level which might be explained by her low protein diet of vegetables and fatty
foods. Finally she has a high Creatinine levels which might suggest an impaired
glomerular filtration rate. All reference values are based on Harrison’s.

4. What are the possible outcomes for this patient? Describe the pathophysiologic and
cellular/histologic events that may occur in course of her disease.

Vascular occlusion secondary to thromboembolic disease produces

heterogeneous regions of ischemia in the affected vascular territory. Local blood flow is
limited to any residual flow in the major arterial source plus the collateral supply. Affected
regions with less cerebral blood flow (less than 10 mL/ 100 g of tissue/ min) are referred
to collectively as the core. These cells are presumed to die within minutes of stroke
onset. Zones of decreased or marginal perfusion (cerebral blood flow less than 25 mL/
100 g of tissue/ min) are collectively called ischemic penumbra. Tissue in the penumbra
can remain viable for several hours because of marginal tissue perfusion. The ischemic
penumbra will eventually progress into infarction if no change in flow occurs.

Ischemia causes cell hypoxia and if the supply of oxygen to the cell is reduced,
oxidative phosphorylation ceases. This results to depletion of cellular adenosine
triphosphate. With the decrease in ATP, there is no more energy to maintain ionic
gradients across the cell membrane. The ischemic neuron becomes depolarized and
membrane ion-transport systems fail. Disruption of cellular metabolism also impairs
normal sodium-potassium plasma membrane pumps, producing an intracellular increase
in sodium, which in turn increases intracellular water content due to osmotic pressure.
This cellular swelling is referred to as cytotoxic edema and occurs very early in cerebral
ischemia.
 Cerebral ischemia impairs the normal sodium-calcium exchange protein also
found on cell plasma membranes. The resulting influx of calcium leads to a release of a
number of neurotransmitters, including large quantities of glutamate from synaptic
terminals, which in turn activates N-methyl-D-aspartate (NMDA) and other excitatory
receptors on other neurons. These neurons become depolarized, causing further
calcium influx, further glutamate release, and local amplification of the initial ischemic
insult. The massive calcium influx also activates various degradative enzymes, leading
to the degradation of membrane lipids and mitochondrial dysfunction. Free radicals are
produced by the degradation of membrane lipids and mitochondrial dysfunction. Free
radicals cause catalytic destruction of membranes and likely damage other vital
functions of cells. Arachidonic acid, and nitric oxide are also generated by this process,
which leads to further neuronal damage. There is also progressive loss of glycogen and
decreased protein synthesis. The functional consequences may be severe at this point.
If hypoxia continues, worsening ATP depletion causes further deterioration. The
cytoskeleton disperses, resulting in the loss of ultrastructural features such as microvilli
and the formation of “blebs” at the cell surface. Myelin figures derived from degenerating
cellular membranes may be seen within the cytoplasm (in autophagic vacuoles) or
extracellularly. They are thought to result from unmasking of phosphatide groups,
promoting the uptake and intercalation of water between the lamellar stacks of
membranes. The mitochondria is swollen by now, as a result of loss of volume control in
these organelles. The ER remains dilated. The entire cell is markedly swollen with
increased concentrations of water, sodium, and chloride and a decreased concentration
of potassium. If oxygen is restored, these are reversible.

If ischemia persists, irreversible injury and necrosis ensue. Irreversible injury is

associated morphologically with severe swelling of mitochondria, extensive damage to
plasma membranes and swelling of lysosomes. The cells are completely digested and
broken down by the excessive and extreme actions of lysosomes and enzymes. Death is
mainly by necrosis but apoptosis also contributes. The apoptotic pathway is activated by
release of pro-apoptotic molecules from leaky mitochondria. The cell’s components are
progressively degraded.

Ischemia also directly results in dysfunction of the cerebral vasculature, with

breakdown of the blood-brain barrier occurring within 4-6 hours after infarction. Brain and
immune cells produce reactive oxygen species that activate endothelial cells and cause
oxidative stress. Oxidative stress and the induction of the inflammatory cascade leads to
the breakdown of the blood-brain barrier allowing activated blood-borne immune cells
such as neutrophils and T cells to infiltrate and accumulate in the ischemic brain tissue.
Following the barrier’s breakdown, proteins and water flood into the extracellular space,
leading to vasogenic edema. This produces greater levels of brain swelling and mass
effect that peak at 3-5 days and resolve over the next several weeks with resorption of
water and proteins.
 Within hours to days after a stroke, specific genes are activated, leading to the
formation of cytokines and other factors that cause further inflammation and
microcirculatory compromise. Along with the accumulation of activated immune cells
from the periphery, microglia in the brain become activated after cerebral ischemia due
to the increase in extracellular ATP from the depolarization of neurons and glia and the
release through damaged plasma membranes of dying cells. Activated microglia secrete
pro-inflammatory mediators such as cytokines (such as ​TNF-α, interleukin (IL)-1β, IL-6,
and IL-10​) and develop phagocytic and major histocompatibility complex (MHC) class
II-restricted antigen presenting characteristics. Danger associated molecular pattern
molecules (DAMPs) are generated and activate pattern recognition receptors such as toll
like receptors (TLRs). These pattern recognition receptors are found on endothelial cells
and microglia in the brain along with infiltrating leukocytes from the periphery, and
activation of pattern recognition receptors increases cytokine release. Moreover, as
neurons begin to die in ischemia, cell-cell interactions with microglia are lost and further
increases inflammatory signaling. Acutely after ischemia, hypoxia and oxidative stress
induce synthesis of nuclear factor kB, hypoxia inducible factor 1 and many other
transcription factors that increase the expression of pro-inflammatory and
anti-inflammatory cytokines. As cells die and brain tissue damaged, molecular danger
signals further potentiate the inflammatory response by activating more microglia and
infiltrating leukocytes in a feed-forward response producing more deleterious
pro-inflammatory cytokines. This increase in expression of cytokines further increases
the expression of adhesion molecules on endothelial cells that result in additional
recruitment of leukocytes from periphery. These inflammatory changes after ischemia
lead to an increase in neuronal cell death resulting in a larger infarct volume and worse
neurological outcome. Ultimately, the ischemic penumbra is consumed by these
progressive insults, coalescing with the infarcted core, often within hours of the onset of
the stroke.

Infarction results in the death of astrocytes, as well as the supporting

oligodendroglial and microglial cells. The infarcted tissue eventually undergoes
liquefaction necrosis and is removed by macrophages, with the development of
parenchymal volume loss. A well-circumscribed region of cerebrospinal fluid-like low
density, resulting from encephalomalacia and cystic change, is eventually seen. The
evolution of these chronic changes may be seen in the weeks to months following the
infarction.

References
Robbins and Cotrans 9th ed
Rubin's Pathology 7th ed
Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L., Jameson, J. L., & Loscalzo, J.
(2015). Harrison's Principles of Internal Medicine (19th ed., Vol. 2). McGraw-Hill Education.
Timmermans​, W. M. C., V​an Laar​, J. A. M.,​ Van Hagen​, P. M., &​ Van Zelm​, M. C. (2016).
Immunopathogenesis of granulomas in chronic autoinflammatory diseases. ​Clin Transl
Immunology​ 5(​ 12). doi: ​ 10.1038/cti.2016.75.