Diagnosis, Etiology, and Treatment of PACNS

1 Primary Angiitis of the Central Nervous System: A Review

Abstract
Primary angiitis of the central nervous system is an idiopathic autoimmune disease. The
cause of this disorder is unknown but the following are theorized; underlying infection, exposure
to environmental toxins and Aβ protein. Diagnosis of this disease is a tedious and difficult
process. Due to the unspecific symptoms and lack of exclusive laboratory tests, diagnosis is most
commonly made through a process of elimination. A swift diagnosis and treatment are vital for a
positive prognosis. Treatment is most commonly in the form of dual therapy utilizing both
glucocorticoids and cyclophosphamides, followed by maintenance therapy consisting of some
sort of steroid, or a combination of steroids. In extremely rare cases remission is achieved but is
followed by relapse, leading to the question of whether or not another disease is causing the
angiitis. This paper investigates the diagnostic tools available to physicians, possible origins of
the disease as well as treatments.
Introduction
Vasculitis is the inflammation of blood vessels, acting indiscriminately towards blood
vessels found anyplace in the body. It is important to note that chronic inflammation can
ultimately lead to necrosis of the given blood vessels (FAUCI, 1978). Typically, vasculitis can
be treated quite easily through a course of anti-inflammatory agents, however, the location of the
inflammation is important when not only treating, but also diagnosing. Primary angiitis of the
central nervous system (PACNS) is a rare disease affecting 2 people per million each year and
perhaps, even more, go unnoticed (von Geldern et al., 2012). Primary angiitis of the central
nervous system affects blood vessels found in the brain and central nervous system and can
strike at any age, but is most commonly seen in 40-60 year old patients (Coronel-Restrepo et al.,
2013; Lukas et al., 2005). The angiitis typically associated with PACNS affects both small


arteries and veins (200-300 micrometers), and typically has three morphological types
granulomatous, necrotizing and lymphocytic. This type of inflammation is thought to be caused
by a pre-existing infection (viral or fungal), though no definitive cause has been established
(Alba et al., 2011). Primary angiitis may not simply be due to a single cause, but rather a
collection of circumstances such as infection, environmental factors, stress as well as genetic
susceptibility.
Primary angiitis of the central nervous system was first considered a separate clinical
entity in 1959 by Cravioto and Feigin, since then only 46 cases have been published (Hajj-Ali
and Calabrese, 2013). What makes PACNS so peculiar is its exceptionally low incidence rate
and how the disease is restricted to the cerebral vasculature without any evidence of
inflammation systemically (Coronel-Restrepo et al., 2013). A diagnosis of PACNS is
exceptionally difficult due to the non-specific signs and symptoms. Typically analytical,
neuroimaging and histopathological data are used in conjunction to not only diagnose PACNS
but to eliminate mimics (Alba et al., 2011).
This paper examines the tools used to diagnose PACNS, the possible causes of PACNS, a
disease that mimics PACNS and ultimately a treatment specific for the underlying problems
associated with PACNS. I will begin by discussing the possible diagnostic tools that physicians
use to diagnose and eliminate the possibility of other disorders, weighing the advantages and
disadvantages associated with a given procedure. Next, I will discuss what could lead to PACNS
and how the body could be exasperating the situation by its own natural immunological
response. Finally, I will discuss treatments that are currently available and are considered to be
the standard protocol when it comes to the treatment of PACNS. In addition, I will examine


alternative drugs that are more specific for PACNS as well as less toxic substitutes for typical
treatment.
Diagnosis of PACNS
Primary angiitis of the central nervous system is a disease that requires immediate
intervention in order to avoid lasting damage and dysfunction. Diagnosing PACNS is difficult
due to unspecific symptoms including; stroke, headache, encephalopathy, seizures and
myelopathies (Berlit, 2010). Clinical features of 16 patients diagnosed with PACNS was
recorded and 14 of 16 patients (88%) reported headaches, in addition, 10 of 16 patients (63%)
presented myelopathies (Hajj-Ali et al., 2002). Interestingly enough a majority of the patients
(88%) described headaches as their first symptom, often times labeling it as the worst of their life
(Hajj-Ali et al., 2002). Due to the lack of specified laboratory tests for PACNS, a diagnosis of
PACNS is most commonly achieved by the elimination of mimic disorders. The most effective
form for diagnosing PACNS comes through the standard protocol described below, as well as the
experience of the physician when it comes to the treatment of PACNS.
The first step when it comes to a diagnosis PACNS is to eliminate potential mimics, for
example; infection, systemic vasculitis, malignancy, drug abuse and hypercoagulability states
(Alba et al., 2011). In order to eliminate these forms of mimics, cerebrospinal fluid is collected.
Although CSF analysis will not provide a definitive identification of PACNS, it is crucial to
exclude the possibility of an underlying infection or malignant disease, in which a treatment for
such a disease could prove fatal to the PACNS patient (Hajj-Ali, 2010). Cerebrospinal fluid
analysis of PACNS patients typically exhibits an increase of white blood cell count (pleocytosis)
in addition, an elevated protein count is observed: abnormalities found in CSF is present in 80-
90% of patients (Salvarani et al., 2007). More importantly, the presence of interleukin 6 (IL-6) as


well as white blood cells are indicative of inflammation located someplace in the body (Hirohata
et al., 1993). Cerebrospinal fluid analysis is an unspecific diagnostic procedure for PACNS but
provides the capability of eliminating varying types of infections and malignancies.
Quantitative data such as CSF analysis is important for the exclusion of other diseases,
but PACNS is characterized by the inflammation of blood vessels and therefore requires the use
of qualitative procedures. Magnetic resonance imaging (MRI) is the method of choice when
diagnosing PACNS because it allows for the visualization of such inflammation and lesions.
Magnetic resonance imaging typically demonstrates damage of parenchymal brain tissue, the
result of chronic inflammation and the subsequent necrosis that follows (Néel and Pagnoux). In
proven cases of PACNS, MRI had a sensitivity of about 97%, confirming its efficacy in the role
of diagnosing (Hajj-Ali and Calabrese, 2013). Post-treatment (glucocorticoids and
immunosuppression) MRI shows a substantial decrease in both number and size of irregularities
(Campi et al., 2001).
Figure 1: (A) MRI shows inflammation within the anterior cerebral artery. (B) Resolution of previously seen
inflammation is seen after treatment. (Hajj-Ali and Calabrese, 2013).


In a study of 18 patients conducted by Pomper et al (1999), a total of 74 vasculitic lesions were
recorded via MRI. Each patient presented roughly an average of four lesions, of which 14 (78%)
displayed bilateral lesions and 13 (72%) showed subratentorial lesions (one side) Lesion
frequencies were found in the following; 20 in the subcortical white matter, 16 in the deep gray
matter, 16 in the cortical gray matter, nine in the deep white matter and nine in the cerebellum
(Pomper et al., 1999). This study shows the variability of blood vessels affected by PACNS,
therefore, making a diagnosis that much more difficult.
Angiograms are another form of imaging used to diagnose PACNS. Angiograms are not
the most definitive way of diagnosing PACNS but they are used to support the diagnosis
(Birnbaum and Hellmann, 2009). Angiograms are x-rays that use dyes to monitor blood flow
through blood vessels, providing information regarding changes in blood vessel shape (Birnbaum
and Hellmann, 2009). However, it does not provide any additional information concerning a
cause or mechanism that results in the abnormal finding (Birnbaum and Hellmann, 2009). The
fact that there is a wide range of non-inflammatory vasculitic anomalies that result in similar
findings, angiograms are very limited in its specificity (Birnbaum and Hellmann, 2009). Though
PACNS typically affects small blood vessels, angiograms have also shown abnormalities in
larger vessels (Salvarani et al., 2007). Though angiograms do not offer a definitive diagnosis of
PACNS, they are yet another tool at a physicians disposal when trying to diagnose this rare
disease.
Considered to be the gold standard, brain biopsies are used when trying to diagnose
PACNS. Typically a biopsy will not be given until all other diagnostic procedures have been
exhausted, due to the invasive nature of such a procedure (Hajj-Ali, 2010). The importance of
where a brain biopsy is performed correlates directly with the success of correctly diagnosing


PACNS. In order to achieve the most accurate diagnostic result, biopsies are conducted in parts
of the brain that tested positive for abnormalities (lesions) via MRI (Alba et al., 2011). Miller et
al found that 78% of biopsies conducted on an area of the brain that exhibited an abnormality
resulted in a correct diagnosis of PACNS, while not a single blind biopsy revealed PACNS
(Miller et al., 2009).
Due to the lack of specific tests for PACNS, infections, and malignant diseases must be
ruled out prior to the identification of PACNS. A correct diagnosis of PACNS is achieved
through the tedious process of eliminating mimic diseases. Therefore diagnosing PACNS
requires a battery of tests and procedures to ensure a correct diagnosis of the mysterious and
largely unknown disease.
Infections and PACNS
The body’s natural response to foreign invaders is to initiate an inflammatory response,
resulting in the recruitment of immunological cells in order to combat the infection (Chaplin,
2010). Normally when the infection is no longer present the response subsides and returns to
normal. However, PACNS is characterized by the chronic inflammation of blood vessels found
within the central nervous system (CNS), ultimately resulting in necrosis (death of tissue). Three
histopathological patterns are associated with PACNS, presented in descending frequency;
granulomatous inflammation (occurring 58% of the time), lymphocytic infiltration (28%) and
acute necrosis (14%) (Miller et al., 2009). What is causing this immunological response in the
CNS and why does it persist?
The human body features a feedback system in which hormonal messengers are used in
order to indicate an infection and mount an attack. The reaction begins with hormonal
messengers called cytokines: cytokines can be further broken down into their two main subtypes;


those who promote pro-inflammatory responses and those that induce an anti-inflammatory
response (Berger, 2000). The most common type of inflammation in patients diagnosed with
PACNS is granulomatous inflammation, which is the collection of white blood cells (Alba et al.,
2011). T lymphocytes are a type of white blood cell that are characterized by containing large
quantities of cytokines that are initially produced in response to some sort of infection (Berger,
2000). Inflammation is the result of a release of pro-inflammatory cytokines (TNF, IL, IFN)
(Coutinho and Chapman, 2011). These molecules cause vasodilation, allowing lymphocytes to
migrate in the blood vessels and resulting in inflammation.
An autoimmune disease (AD) is typically initiated by an infectious agent, whether it be
viral, bacterial or parasitic (Kivity et al., 2009). Most times it is not a specific infection that
results in an AD but rather the “burden of infections” beginning early in life (Kivity et al., 2009).
A property of the immune system is its capability of identifying "self" and "nonself", resulting in
an attack on "nonself" substances while not inflecting self-harm (Kivity et al., 2009). Primary
angiitis of the central nervous system is a disease in which the ability to recognize “self” is
disrupted, causing an attack on brain tissue as if it were a foreign substance (Kivity et al., 2009).
There are several infections believed to induce PACNS: varicella-zoster virus (VZV),
Ebstein-Barr virus, cytomegalovirus, as well as human immune-deficiency virus (HIV) (Alba et
al., 2011). The fact that these infections are viral in nature is important for several reasons; they
have the ability to remain dormant, are often times hard to test for and lastly have access to brain
tissue. Primary angiitis of the central nervous system is mostly seen in patients between the ages
of 40-60 years old indicating a possible re-infection of the particular virus (Coronel-Restrepo et
al., 2013). If in fact, PACNS were due to an infection it would indicate that the virus re-emerges
after years of dormancy. The recurrence of the virus would result in an immune response,


recruiting T-helper cells to combat the infection and initiate other cellular processes (Chaplin,
2010). The initiation of T-helper cells and the processes that follow results in pro-inflammatory
cytokines (INF-γ, IL, TNF) resulting in the angiitis associated with PACNS (Alba et al., 2011).
The process by which pre-existing viruses can cause a new immune response is known as
bystander activation (Kivity et al., 2009). When tissue that contains the virus is damaged they
release the viral specific antigen, resulting in the activation of lymphocytes that were not
contributed to the primary response of the virus. This secondary response of lymphocytes results
in cytokine-related inflammation, eventually leading to the death of neighboring cells via chronic
inflammation (Kivity et al., 2009).
Although infections are screened for during the diagnostic stage, many viruses have the
capability of remaining dormant and largely innocuous to tests and imaging. The fine balance
between “self” and “nonself” recognition is how the immune system works and can become
disrupted. Due to the complicated mechanisms in which the immune system works it is difficult
to draw a comparison between the responses associated with the re-emergence of a dormant virus
and an idiopathic disease such as PACNS. Further research into the process by which viruses can
re-emerge and the bodies response would prove valuable in determining whether or not a
PACNS patient is at risk of a relapse or not.
Cerebral Amyloid Angiopathy Mimics PACNS
Primary angiitis of the central nervous system and amyloid beta-related angiitis (ABRA)
are regarded as two separate diseases, but have strikingly similar properties (Scolding et al.,
2005). Amyloid beta protein often time goes completely unnoticed unless specifically tested for
with the appropriate antigen (Scolding et al., 2005). Amyloid beta related angiitis presents
virtually identical symptoms, results in the indicative lesions/necrosis and often times goes


unnoticed during laboratory tests, I propose the possibility of a connection between PACNS and
the accumulation of amyloid beta-protein.
Amyloid beta related angiitis is the deposition of an insoluble protein (amyloid) within
the blood vessels of the CNS, ultimately leading to lesions and necrosis (Yamada, 2015). The
accumulation of Aβ protein is a normal occurrence, affecting approximately 30% of the healthy
elderly population and 90% of the elderly with Alzheimer’s disease (Scolding et al., 2005).
Accumulation of Aβ protein is believed to be the result of a disproportional ratio of production
and clearance (Schenk et al., 2012). Lesions and hemorrhages due to Aβ protein occur when the
buildup of the protein becomes severe. Amyloid beta-protein is naturally occurring throughout
the body, however when Aβ protein coagulates it produces an inflammatory response and can,
therefore, lead to necrosis (Annweiler et al., 2008). Paradoxically, it is believed that the process
of amyloid development is the main problem, rather than the final product (Bieschke, 2013).
Blood vessels carrying higher concentrations of Aβ protein are more susceptible to the
inflammatory response caused by Aβ protein (Scolding et al., 2005).
Primary angiitis of the central nervous system and amyloid beta-related angiitis (ABRA)
present similar symptoms; encephalopathy, seizures, and headaches (Scolding et al., 2005).
Another commonality between PACNS and ABRA is their exclusivity of inflammation,
localizing only in the CNS (Scolding et al., 2005). The cerebrospinal fluid analysis reveals
elevated protein and pleocytosis in both diseases. In addition, both diseases exhibit similar
neuroimaging results, which is vasculitic inflammation resulting in tissue damage.


Figure 2: (A) Typical inflammation associated with PACNS, localizing to the anterior cerebral artery. (B)
Inflammation related to Aβ protein. These two MRI images show the similarities between PACNS and ABRA.
(Hajj-Ali and Calabrese, 2013; Sakurai et al., 2014).
Primary angiitis of the central nervous system and ABRA are separate clinical entities,
but the possibility that the two are related cannot be ruled out. Inflammation of blood vessels
results in an increase of permeability, allowing for different types of cells, proteins, and other
molecules to enter (Scolding et al., 2005). Thus, it is plausible that chronic inflammation could
allow for a leakage of Aβ protein and the subsequent accumulation (Scolding et al., 2005). On
the contrary, it is also possible that Aβ protein is a consequence of chronic inflammation and the
angiitis associated with PACNS is exacerbated when Aβ protein leaks in due to increased
permeability (Scolding et al., 2005).
Primary angiitis of the central nervous system has no known origin, the possibility of a
dual immunological response (Aβ protein) and the subsequent inflammation it produces cannot
be ruled out. Patients diagnosed with PACNS should undergo specific immuno-histochemical
(Scolding et al., 2005) tests to determine whether or not Aβ protein is present and contributing to


their disease. Amyloid beta related angiitis not only demonstrates analogous symptoms but also
reacts to treatments such as glucocorticoids and immunosuppressant's almost identically to
PACNS: the result, a possible misdiagnosis of PACNS (Yamada et al., 1996). In patients with
PACNS that relapse, it is possible that the initial immune response (T-helper cells and pro-
inflammatory cytokines) associated with PACNS was taken care of, however, the inflammation
connected to the accumulation of Aβ protein remains untreated, therefore a relapse linked to Aβ
protein coagulation is inevitable. The strikingly similar properties of PACNS and ABRA
warrants further research into the possible connection between the two diseases.
Environment Factors can Induce PACNS
The human body can be considered to be one giant chemical reaction; therefore genetic
regulation and expression can become disrupted given the appropriate chemicals and
circumstances. The correlation between environmental toxins and general disease has been well
documented (White and Birnbaum, 2009). Autoimmune diseases have risen worldwide within
recent years: the correlation between the increase of ADs and new technology, industries,
chemicals and the resulting pollution (organic solvents and dioxins) is difficult to ignore
(Vojdani, 2014) The relationship between increased manufacturing, resulting in more organic
solvents (OSs) and dioxins as well as a spike in ADs worldwide does not appear to be
coincidental.
Organic solvents have the ability to alter the conformation of one's genome, resulting in
the disruption of gene expression (epigenetics) (Costa, 2010). Dioxins are considered to be
xenobiotics, which are simply foreign substances that are not native to the body (Bigazzi, 1997).
Xenobiotics cannot normally bind to proteins when first introduced to the body, rather once
converted to reactive metabolites they have the ability to bind to tissues and induce an immune


response (Vojdani, 2014). Xenobiotics can either suppress or stimulate immune responses
(Bigazzi, 1997). In the case of PACNS, xenobiotics are most likely stimulating the immune
response, leading to chronic inflammation and consequently death of brain tissue.
Organic solvents (OSs) and dioxins are chemical compounds that are prevalent in
commercial activities and it has been found that that OS/dioxin exposure can lead to ADs
(Barragán-Martínez et al., 2012). The immune system has an amazing capability, that is its
ability to distinguish between “self from nonself” (Vojdani, 2014). When the body can no longer
identify “self”, the result is an over activity of self-antigens resulting in autoimmunity (Vojdani,
2014). Primary angiitis of the central nervous system is an autoimmune disease (AD) and is
characterized by the loss of immune tolerance and is facilitated through T or B cell activation,
ultimately leading to the necrosis of blood vessels and tissues (Barragán-Martínez et al., 2012).
Though it cannot be directly correlated, epigenetic changes due to OSs likely play a role in the
development of autoimmunity.
One of the most interesting aspects of epigenetics is how twins for example (who possess
the same genome) can develop completely different diseases; the most likely culprit, epigenetics.
In a recent study it was found that when one monozygotic twin was diagnosed with an immune-
mediated disease, there was less than a 40% chance that the other twin would develop the same
disease (Selmi et al., 2004). This trend suggests an apparent environmental factor that may have
the ability to alter one's genome, resulting in a change of gene expression and consequently AD.
It is difficult to determine whether or not environmental factors play a role in PACNS, however,
there is strong evidence that supports how toxins and more specifically dioxins can induce or
suppress immune responses (Kuchroo et al., 2012). Dioxins were created primarily though
natural events such as forest fires and volcanic eruptions, however, within the past two-hundred


years, human activity has resulted in a greater production of these toxic chemicals (White and
Birnbaum, 2009). Dioxins have had a huge impact on humans, natural environments, and food
supplies, therefore, the effects have been widely studied (White and Birnbaum, 2009). Through
the stimulation of T-helper 1 (Th1) cells, dioxins have the ability to activate the inflammatory
response without affecting the genomic pathway (Vojdani, 2014).
T-helper cells upregulate cytokine activity, and are part of the adaptive immune system
(Kuchroo et al., 2012). Such cytokines include; tumor necrosis factor (TNF), interleukins (IL)
and interferon gamma (IFN-γ) (Vojdani, 2014). Though the mechanism in which angiitis is
brought upon is reasonably understood, how dioxins interact with the processes is not.
Cerebrospinal fluid analysis of patients diagnosed with PACNS confirms the presence of IL-6 as
well as pleocytosis (Hirohata et al., 1993). These findings are important due to the fact that the
angiitis is the result of a Th1 mediated response, resulting in the recruitment of cytokines (TNF,
IL, IFN-γ) and white blood cells (Hirohata et al., 1993). Therefore the underlying pathogenesis
of PACNS could lie within the uncontrolled adaptive immune response caused by dioxins
(Vojdani, 2014).
Though dioxins seem to be the scapegoat for many unknown diseases why then do more
people not get diagnosed with PACNS? This conundrum may be as simple as genetically pre-
determined risk (Bigazzi, 1997). The genetic factor associated with disease explains why not all
persons exposed to a certain xenobiotic will demonstrate a particular disease (Bigazzi, 1997).
Furthermore, genetic susceptibility could be the reason as to why it is so difficult to replicate
diseases in animal models (Bigazzi, 1997). It is possible that xenobiotics/dioxins are catalysts
that initiate an autoimmune response and that once the process begins the body does not know
how to respond and results in the hyperactivation of its own adaptive immunity. Studies that


research potential environment factors in patients with PACNS should be conducted in order to
determine if there were certain toxins that patients with PACNS were exposed to. The body is
one large chemical reaction and therefore the introduction of xenobiotics, dioxins, and organic
solvents can result in devastating consequences.
Stress and PACNS
Though stress may not be a direct cause of PACNS it certainly has the capability to
exacerbate the inflammatory response. In a recent study, it was found that up to 80% of patients
with ADs reported uncommon emotional stress prior to the inception of the disease (Shoenfeld et
al., 2008). The association between stress and disease onset is a vicious one, as stress leads to the
disease but in return the disease causes stress, therefore amplifying the effects that much more
(Shoenfeld et al., 2008). There are two different subsets of stress internal and external (Shoenfeld
et al., 2008). Internal stress is connected to the processes that occur within the body. During
PACNS the body is working harder than it has to, combatting what it thinks is a foreign invader.
On the contrary, external stressors can either be work related or family related. Stress is the
body’s response to an unfamiliar or uncomfortable situation, where molecules are secreted to
cope with the given situation. Neuroendocrine hormones are released during times of stress and
can lead to deregulated, distorted or increased cytokine production and therefore lead to AD
(Shoenfeld et al., 2008). Whether it is an increase of cytokine production, altered function or a
deregulation, these effects associated with the body’s response to stress all possess the capability
of producing or exacerbating an autoimmune disease.
Treatment of PACNS
Primary angiitis of the central nervous system requires swift and aggressive treatment in
order to avoid permanent damage and dysfunction (Alba et al., 2011). What makes PACNS so


difficult to successfully treat is the amount of time it takes to correctly diagnose in addition to the
lack of clinical studies performed. Administering treatment without ensuring the possibility of
another disease could prove fatal due to complications. There have not been any clinical studies
researching possible treatments for PACNS due to the rare nature of the disease rather
management is based solely on observational data as well as clinical experience with PACNS.
After diagnostic and laboratory tests are administered and a diagnosis of PACNS is confirmed,
treatment for PACNS typically consists of glucocorticoids (Alba et al., 2011). Dual therapy of
glucocorticoids and immunosuppressant’s are utilized when the severity of the disease worsens
(Hajj-Ali and Calabrese, 2013).
No standard protocol for the treatment of PACNS exists, instead of treatment is based on
observational and experience with the disease. Treatment typically begins with glucocorticoids in
order to alleviate the initial inflammation. Glucocorticoids work by inhibiting vasodilation as
well as decreasing leukocyte (white blood cells) activity (Coutinho and Chapman, 2011).
Glucocorticoids are administered at a high dosage (1 mg/kg/day) and are reduced within the
course of 6 months (Hajj-Ali et al., 2002). In the case, that inflammation does not resolve or a
relapse occurs, a dual therapy of glucocorticoids and immunosuppressant’s are administered.
In an assessment carried out by Hajj-Ali et al (2002). 16 patients with atypical PACNS
(non-aggressive) recovered after treatment with glucocorticoids alone, indicating that
immunosuppressant’s (cytotoxic drugs) may not be necessary for less aggressive forms of
PACNS. However when PACNS is aggressive and glucocorticoids are not enough to attain
disease control, immunosuppressants are utilized (Hajj-Ali, 2010). In conjunction with
glucocorticoids, immunosuppressant’s such as cyclophosphamide (intravenous or oral) are


employed (Hajj-Ali, 2010). Cyclophosphamide works by reducing the number of lymphocytes in
addition to B and T cells (Marder and McCune, 2004).
Two forms of cyclophosphamide delivery exist, pulse and continuous. Pulsed therapy
delivers cyclophosphamide at a dose of 15 mg/kg for about 3 to 6 months whereas the dose for
continuous oral therapy is reduced by as much as 50% (Mukhtyar et al., 2009). Pulse therapy is
the most common approach when treating PACNS due to its lesser toxicity than continuous
therapy in addition to its similar results in achieving remission (Groot, 2001). Analysis of pulse
therapy has shown that it is just as likely to result in remission when compared to continuous oral
therapy but it is also less toxic (Groot, 2001). However, pulse therapy may result in a higher
relapse rate (Groot, 2001).
Due to the negative effects associated with glucocorticoids and immunosuppressants,
measures should be taken in order to prevent osteoporosis and infections (Hajj-Ali, 2010). Such
prophylaxis measures can be taken in the form of supplements such as bisphosphonates, calcium
and vitamin D (Hajj-Ali, 2010). In addition, patients receiving cyclophosphamide should be
given Mesna, a drug that binds to acrolein ( a toxic byproduct of cyclophosphamide) rendering it
non-toxic (Reinhold-Keller et al., 2004). During the course of treatment, it is of utmost
importance to monitor disease activity via MRI in order to spot any signs of disease progression
(Hajj-Ali, 2010). When reading an MRI it is crucial to decipher between damage caused by the
disease as opposed to present disease activity (Hajj-Ali, 2010). It is most important to determine
whether or not any new lesions are present (Hajj-Ali, 2010).
Unlike many other diseases PACNS does not have a specific treatment, rather the course
of management is based on other vasculitic diseases and the response they have to certain drugs.
Cyclophosphamides result in a high level of toxicity and therefore a large effort has been


invested in trying to find similar therapies with less toxicity. A drug that specifically targets the
properties of PACNS should be researched in order to reduce side effects and the toxic nature of
current treatments. Biologic agents have had recent success in treating vasculitic diseases and
prove much less toxic than cyclophosphamides. Primary angiitis of the central nervous system is
linked with high levels of TNF and disrupted B cell activity; biological agents are utilized to treat
these symptoms and have been shown to be quite effective (Chung and Seo, 2009).
An increase TNF is commonly seen in patients with PACNS. Tumor necrosis factor is a
pro-inflammatory cytokine that also activates other immune system cells (Chung and Seo, 2009).
Drugs currently available that target this cytokine are infliximab (Remicade), etanercept (Enbrel)
and adalimumab (Humira) (Chung and Seo, 2009). Remicade and Humira both result in the
programmed cell death (apoptosis) of targeted cells, which in the case of PACNS would result in
further loss of brain tissue. Due to this fact, Enbrel would be the most desired mode of treatment
since it targets the pro-inflammatory initiated by TNF without causing cell death.
Cyclophosphamides are used in order to establish disease control; once remission is
secured they are typically swapped with less toxic immunosuppressants (azathioprine,
leflunomide or mycophenolate mofetil) for maintenance therapy (Yazici, 2008). Maintenance
drugs are typically in the form of a steroid, 1 mg/kg is taken daily (Yazici, 2008). Patients
typically remain on these drugs for at least 24 months and even longer for those who have
encountered relapses (Yazici, 2008). Azathioprine is considered to be the “workhorse” when it
comes to maintenance drugs because it controls PACNS once cyclophosphamide therapy has
relieved the initial immune response (Marder and McCune, 2004).
There are cases of PACNS where relapses have occurred post glucocorticoid treatment,
cyclophosphamide therapy, and maintenance therapy. Though these relapses could quite possibly


be inevitable, there may be an underlying condition that has gone undiagnosed and is the actual
cause of the relapse. Amyloid beta related angiitis is a disease that bears a striking resemblance
to PACNS in both presentation and mode of treatment (Scolding et al., 2005). Laboratory tests
and imaging reveal almost identical results. Clinical presentations were practically
indistinguishable, including but not limited to headaches and seizures (Hajj-Ali et al., 2002;
Scolding et al., 2005). In addition, treatment for both PACNS and ABRA are practically
identical, consisting of glucocorticoids and cyclophosphamides (Alba et al., 2011; Scolding et
al., 2005).
If not specifically tested for with complimentary antibodies, Aβ protein is almost
impossible to distinguish (Scolding et al., 2005). Treatment for PACNS and ABRA are almost
identical and therefore it is not difficult to imagine that Aβ protein could go unnoticed when a
patient is being treated solely for PACNS. For this reasons treatment for PACNS may not be
fully addressing the pathogenicity of ABRA. Treatment for ABRA involves glucocorticoids and
cyclophosphamides. These drugs overlap with PACNS treatment, however, there are new
strategies being developed for the intervention of ABRA.
Natural compounds mainly catechins are found in tea leaves and grape seeds and have
been heavily studied due to their antioxidant properties (Bieschke, 2013). Tea leaves are
comprised of approximately 30% catechins and of that 30% one-third is epi-gallocatechine-3-
gallate (EGCG) (Bieschke, 2013). Epi-gallocatechine-3-gallate has been tested in a mouse model
and has shown positive effects on tumor growth (Bieschke, 2013). In addition, EGCG reduced
the toxicity of Aβ protein in cells by decreasing inhibiting the aggregation of Aβ protein fibrils
(Bieschke, 2013). Treatment for PACNS should include drugs and compounds that target the
formation of Aβ protein and the inflammatory consequences it may have in PACNS patients.


Further research needs to be conducted in order to determine whether or not these natural
compounds (catechins) are effective in treating ABRA in humans.
Conclusion
Primary angiitis of the central nervous system is an idiopathic disease of which little is
known. Diagnosis is extremely difficult due to the unspecific nature of the symptoms associated
with PACNS. New diagnostic techniques are unlikely to be developed therefore it is important to
take note of symptoms that are most commonly associated with PACNS. Such symptoms include
headaches, often times described by patients as the worst headaches of their life (Hajj-Ali et al.,
2002). In addition, cognitive ability as well as motor skills are often times compromised (Hajj-
Ali and Calabrese, 2013). Therefore when PACNS is in question, laboratory tests, as well as
neuroimaging, should be conducted immediately.
Perhaps the first step when considering PACNS is to perform an MRI. Magnetic
resonance imaging is often times very conclusive when it comes to PACNS, with a sensitivity of
97% (Hajj-Ali and Calabrese, 2013). When examining an MRI result, the attending physician
will most likely see some sort of tumor-like growth or lesion(s). In order to determine whether
or not the growth is in fact due to inflammation or another malignant disease, cerebrospinal fluid
should be collected.
Cerebrospinal fluid analysis is a crucial point when diagnosing PACNS because it allows
for the elimination of mimic diseases such as infection, systemic vasculitis, malignancy, drug
abuse and hypercoagulability states (Alba et al., 2011). Typical findings of CSF analysis in
patients with PACNS consists of pleocytosis and increased protein count: abnormalities of CSF
analysis is consistent in 80 – 90% of PACNS patients (Salvarani et al., 2007). Cerebrospinal


fluid analysis is an important stage when diagnosing PACNS not only because it eliminates
mimics but it provides telltale signs of inflammation occurring somewhere in the body.
After clinical evaluations, neuroimaging, and laboratory tests indicate PACNS, the final
step of diagnosis is to perform a brain biopsy. A biopsy of the brain is considered to be the gold
standard when it comes to diagnosis. It allows for the elimination of an alternative diagnosis and
confirms 78% of PACNS cases when taken from a location that presented inflammation on an
MRI (Miller et al., 2009). A brain biopsy is a final step when it comes to the diagnosis of
PACNS, if all other diagnostic approaches do not point to PACNS a brain biopsy should be
avoided due to its invasive nature (Hajj-Ali, 2010).
When PACNS is confirmed treatment should be administered as soon as possible.
Glucocorticoids, in conjunction with cyclophosphamide, are given almost immediately in order
to repress the immune response as well as to control initial inflammation (Hajj-Ali and
Calabrese, 2013). The benefits of pulse cyclophosphamide therapy outweigh continuous oral
therapy; therefore once remission has been secured cyclophosphamide is swapped for
maintenance therapy drugs such as azathioprine, leflunomide or mycophenolate mofetil (Yazici,
2008). In addition to the standard treatment, ABRA should be addressed. Although treatment for
ABRA is mostly consistent with that of PACNS, dexamethasone has been proven to reduce the
inflammation associated with ABRA and could, therefore, treat ABRA in patients diagnosed
with PACNS (Scolding et al., 2005). The relapse that few patients with PACNS experience could
be associated with an undiagnosed case of ABRA. Lastly, new biological drugs that specifically
target the immune response associated with PCNS have proven their efficacy. These drugs are
less toxic than cyclophosphamide and are similarly effective (Chung and Seo, 2009). Further
research needs to occur in order to find a treatment that specifically targets the underlying issue


with PACNS, that is an over-reactive immune response. Tumor necrosis factor, interleukins, and
cytokines are all molecules released during such a reaction and results in a pro-inflammatory
response (Coutinho and Chapman, 2011). Future research should aim to specifically target these
molecules in order to attempt to alleviate the response and therefore reduce inflammation
resulting in necrosis of brain tissue.
Perhaps the most frustrating aspect of PACNS is the fact that the cause is completely
unknown (Hajj-Ali and Calabrese, 2013). Studies have attempted to link PACNS to
environmental toxins, such as dioxins but have failed to prove this relationship (Shoenfeld et al.,
2008). In addition, inflammation is the body’s natural response to a foreign invader (Chaplin,
2010). Therefore researchers have also tried to draw a connection between an underlying
infection and PACNS however during the diagnosis process, countless laboratory tests are
conducted in order to rule out the possibility of an infection. Primary angiitis may not be the
result of a single infection, but rather the burden of infections encountered throughout the course
of one's life (Kivity et al., 2009). This hypothesis would make sense due to the fact that PACNS
is simply an over reactive immune system fighting against itself. It is reasonable to assume that
the countless infections encountered through one's life may have compromised the body's
mechanism for targeting infections.
The possible cause of PACNS that interests me most is ABRA. The presence of Aβ
protein is almost impossible to identify unless specifically tested for. For this exact reason, I feel
that ABRA often goes unnoticed. The symptoms, diagnostic results, and treatment of both
PACNS and ABRRA are so similar I feel that an undiagnosed case of ABRA is easily
overlooked. In the case that this disease would go unnoticed it could ultimately result in relapse
after remission was believed to have been established. Primary angiitis of the central nervous


system is for the most part easily managed by incorporating cyclophosphamides and
glucocorticoids (Berlit, 2010). In the case of a relapse, it is possible that it is not a reoccurrence
of PACNS related responses, but rather a response to Aβ protein. Alpha beta protein related
angiitis mimics PACNS in such a way that it is very likely that Aβ protein accumulation goes
undiagnosed due to its similar nature to PACNS (Scolding et al., 2005). Specific antibody tests
for Aβ protein should be conducted in conjunction with the standard diagnostic procedure for
PACNS (Scolding et al., 2005)s .
In conclusion, even though PACNS is such a rare disease, autoimmune disorders affect
an exorbitant amount of people worldwide. A better understanding of what causes these
autoimmune diseases will allow physicians to treat AD patients more specifically without the
harmful side effects of cyclophosphamides and glucocorticoids (Hajj-Ali, 2010). Research
should be focused on attempting to collaborate data in order to find a common link between
people who present PACNS. Lastly, because PACNS is such a rare and unknown disease, it does
not get the type of publicity associated with cancers and other forms of well-known disorders. In
order to learn more about the causes and treatments for autoimmune disorders, researchers and
scientists must realize that the population is faced with a serious epidemic: not necessarily
PACNS, but AD as a whole.


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