Introduction
The pentavalent vaccine (PV), which prevents against diphtheria, tetanus, whooping
cough, haemophilus influenzae type B infection and hepatitis B, was introduced in
the Brazilian childhood vaccination schedule in 2012, and is generally administered
to infants aged 2, 4 and 6 months.[1]
According to the “Handbook for the Epidemiological Surveillance of Adverse Events
after Vaccination” (Manual de vigilância epidemiológica de eventos adversos pós-vacinação),[1] published in 2014 by the Brazilian Ministry of Health, mild local and systemic adverse
effects are common, usually between 48 and 72 hours after immunization. Symptoms such
as low or moderate fever (in 4.1% to 58.8% of the cases), drowsiness (in 28% to 48.8%
of the cases), loss of appetite (in 2% to 26.5% of the cases), vomiting (in 1.1% to
7.8% of the cases), irritability (in 2.6% to 85.8% of the cases), and persistent crying
(in 0 to 11.8% of the cases) are some examples.[1]
[2]
They mainly occur in children under three months of age and are usually treated according
to guidelines, with medication administration. It may also be necessary to change
the vaccine formulation in future immunizations to prevent new events.[2]
Despite the fact that its safety has been extensively tested, severe adverse effects
may occur on rare occasions, which, if not treated properly, can cause lasting damage,
such as severe postvaccination neurological complications: encephalitis, meningitis,
myelitis, optic neuritis, Guillain-Barré syndrome (GBS), narcolepsy, and parkinsonism.[3]
Such adverse effects are also observed after the administration of several other vaccine
preparations, such as Bacille Calmette-Guérin (BCG), influenza hemagglutinin 1 and
neuraminidase 1 (H1N1), H. influenzae, the human papillomavirus (HPV), and diphtheria, tetanus and pertussis (DTP).[3]
There are no specific studies on the complications after the administration of the
PV; however, there are studies[1]
[4] which mention the occurrence of complications after the administration of the in
the DTP and tetravalent vaccines (DTP + H. influenzae type B conjugate).
Severe postvaccination complications include hypotonic hyporesponsive episodes (1/1,750
cases), convulsive crises (1/5,266 cases), apnea, anaphylactic reactions, and postvaccinal
encephalopathy (0 to 10.5 cases per million doses administered).[1]
[4]
Among the serious post-vaccination complications, those involving central nervous
system (CNS) manifestations will be highlighted, as well as a discussion about the
immunological mechanisms possibly involved in its genesis.[5]
[6]
[7]
[8]
Since the most frequent adverse effects after vaccination are mild and sometimes nonspecific,
they could be confused with the symptoms observed in the early stages of acute intracranial
hypertension (AIH, such as irritability, crying, drowsiness etc.), especially in infants
with compensated hydrocephalus of which the parents and pediatricians are unaware,
causing undesirable diagnostic delays.[9]
[10]
[11]
Although there are privileges regarding the protection of the CNS from unwanted immune
processes, in the case herein reported, we noted that there was decompensation of
a preexisting and previously unknown neurosurgical condition, potentially harmful
if not treated, emphasizing the need for a better understanding of the inflammatory
postvaccine response over the blood-cerebrospinal fluid barrier (BCSFB).[12]
[13]
[14]
The present article aims to report a case of acute obstructive hydrocephalus in an
infant after immunization with the PV, and to discuss the possible mechanisms related
to the immune response and BCSFB dysfunction.
Case Report
A male infant aged 6 months and 22 days was brought by his parents to the emergency
room 3 days after the immunization presenting irritability, crying, profuse vomiting,
and apparent visual loss.
His mother reported that the symptoms had already occurred on the first day after
the application of the PV. He started with irritability and a high fever (38.5° C),
which was controlled with the use of antipyretics.
The infant was previously healthy. He had no comorbidities, no history of allergic
or vaccine reactions, presented neuropsychomotor development that was adequate for
his age group, had been exclusively breastfed until the sixth month of life, and his
vaccination booklet was up to date.
A physical examination revealed macrocrania (head circumference of 46 cm/greater than
the 97th percentile) not previously reported in childcare consultations, and sensorineural
impairment characterized by drowsiness and frequent vomiting. Signs of meningeal irritation
were present, denoted by a tense anterior fontanelle +/4 + , Kernig sign, and mild
opisthotonus. The discreet presence of the sign of Parinaud drew attention.
At the pediatrician's request, a brain magnetic resonance imaging (MRI) scan was performed
in the emergency room, under sedation and with anesthesiological follow-up. An evaluation
by the neurosurgeon was requested because acute obstructive hydrocephalus with a lesion
suggestive of suprasselar arachnoid cyst was evidenced ([Figure 1]).
Fig. 1 Preoperative cranial magnetic resonance imaging (MRI) scan showing a cystic lesion
in the suprasellar region, obstructing the flow of cerebrospinal fluid (CSF) and causing
obstructive hydrocephalus upstream. (A,C) Axial T1-weighted MRI of the skull. (B) Coronal T2-weighted MRI of the skull.
The lesion had an important extension to the cavity of the third ventricle, obstructing
both the outflow tracts of the lateral ventricles and the opening of the cerebral
aqueduct. The fourth ventricle had usual dimensions.
On magnetic resonance imaging of the brain, no signal alterations were observed in
the brain parenchyma, or uptake by paramagnetic contrast in any of the sequences performed,
and encephalitis could be excluded at first.[15]
With the parents' agreement, an emergency neuroendoscopy was chosen, without previous
collection of cerebrospinal fluid (CSF). Although rare, the risks of further deterioration
of the sensorium due to descending herniation (after the lumbar puncture) or the occurrence
of intraventricular hemorrhage (after the transfontanellar puncture) were considered.[16]
[17]
The CSF collection was performed at the time of ventricular puncture, through the
endoscopic system, in a satisfactory manner. The possibility of placing an external
ventricular shunt (EVS) at the same operative time or later, in case of suspicion
or proof of infectious etiology, was also explained.[18]
The infant underwent general anesthesia, with the head in a slightly flexed neutral
position, eye protection, and a thermal blanket. Cefazolin was administered as a prophylactic
antibiotic.
We opted for the classic access to the right lateral ventricle, opening at the Kocher
point, with trepanation using a number 15 scalpel blade, collecting the powder and
bone micelles to occlude the orifice created. Linear durotomy was performed without
coagulation of the dural edges, using a Karl Storz (Tuttlingen, Germany) Deqc 0° endoscope
for the ventricular puncture.[19]
[20]
[21]
[22]
Upon entering the right ventricular cavity, a large cystic lesion occluding the foramen
of Monro was evidenced. The cyst had several cotton-wool spots on its surface ([Figure 2]). Protein materials could also be observed floating inside the ventricular cavity,
which led us to assume a probable inflammatory reaction as an origin for the decompensation
of the condition.[11]
[23]
[24]
Fig. 2 Intraoperative view of the arachnoid cyst (C) occupying the ventricular cavity and covered by cotton-wool spots (A). Foramina of Monro (B).
The cyst was fenestrated using microscissors and, when entering it, the floor of the
third ventricle was visualized in detail. This was open and displaced by the lesion,
as well as the various arterial and venous structures and pituitary stalk.
The lower portion of the Arachnoid Cyst was opened towards the Carotid Cistern with
Fogart Balloon number 2. After its communication, the lesion collapsed onto the floor
of the third ventricle, also providing the permeability of the cerebral aqueduct.
A meticulous closing of the planes was carried out, occluding the burr hole with the
powder and bone fragments collected.[21]
[25]
An additional contralateral approach was chosen with caution. When entering the left
lateral ventricle, it is possible to observe the total opening of the ipsilateral
foramen of Monro. The cyst was completely collapsed, and was not submitted to resection,
for we chose to interrupt the surgical procedure at this time. The same synthesis
procedure was performed on the right side.
The patient was sent awake and responsive along with the mother to the Pediatric Intensive
Care Unit, where, one day later, he was discharged to the ward without symptoms.[26]
The analysis of the cerebrospinal fluid collected during the operation was performed.
No alterations were observed in cellularity (8 cells / 100% lymphocytes) or in glucose
(48 mg/dl), identifying only hyperproteinorraquia (80 mg/dl). Cultures did not demonstrate
bacterial growth. Postoperative cranial tomography and brain MRI showed a significant
reduction in supratentorial ventricular cavities ([Figure 3], [Figure 4]).
Fig. 3 Postoperative cranial computed tomography (CT) scan showing a reduction in ventricular
cavities. (A, C) Axial section of skull CT. (B) Coronal section of skull CT.
The large amount of particulate matter observed in the CSF and on the cystic surface
led to the assumption of a inflammatory reaction, which may or may not be associated
with vaccination. Classic works such as those by Spina-França and Saraiva[27] (1961) and Rocha et al.[28] (1971) have already reported the occurrence of leptomeningeal reactions in infectious
and inflammatory processes and in aseptic causes.
Discussion
The neurosurgical pathologies that affect the sellar and suprasellar regions of children
are varied. They comprise solid, cystic or mixed tumors, are most often histopathologically
benign, but have a recognized potential for invasion of adjacent structures.[29]
Examples of sellar and suprasellar lesions are craniopharyngeomas, pituitary adenomas,
and optic-chiasmatic gliomas. Granulomatous lesions such as histiocytosis X, tumoral
lesions derived from germ cells (germinomas), and cystic lesions secondary to defects
of normal embryogenesis (Rathke cleft cysts) and arachnoid cysts may also be found
more rarely.[29]
Arachnoid cysts are benign lesions usually arising from a duplication of the arachnoid,
but they can also have a rare posttraumatic etiology. They are filled with CSF, and
comprise about 1% of all intracranial lesions. Sellar and suprasellar arachnoid cysts
comprise 9% to 21% of these lesions. They usually predominate in men (with a ratio
of 2:1), and their most frequent location is the middle fossa, representing about
50% of the cases.[20]
[29]
[30]
Carriers of arachnoid cysts are mostly asymptomatic, however, in some patients they
can become clinically manifest. These manifestations can range from simple paroxysmal
headaches to severe cases of symptomatic intracranial hypertension.[31]
Focusing on the specific type of cyst in this report, of suprasellar location and
extension to the cavity of the third ventricle, it is commonly manifested by obstructive
hydrocephalus, visual alterations, endocrine alterations (short stature and delayed
pubertal development), delayed neuropsychomotor development. Less frequently, seizures,
head movement disorders (Bobbing Head Doll) and appendicular (tremors) may occur.[20]
Several pathophysiological theories have been proposed to explain the symptomatology
of these lesions. Some of them are the development of a valve mechanism, in which
there is an imbalance between intracystic CSF inflow and outflow, intracystic CSF
production, and an increase in the intralesional osmotic gradient due to an increase
in the protein content.[29]
There are different types of therapeutic approaches, from fenestrations (open, under
microscopy or endoscopy with or without navigation) to derivations (cyst-peritoneum,
cyst-subdural shunts), and they must be chosen on a case-by-case basis and depending
on the structure of the service.[20]
[31]
[32]
[33]
In the case in question, endoscopic fenestration of the cyst was chosen with satisfactory
results. Furthermore, we believe that the increase in CSF protein content, both in
the intraventricular and intracystic components, may have been the underlying cause
of the decompensation and would be related to the recent immunization of the infant
with cellular DTP, of recognized immunogenic potential, which will be detailed below.
Bordetella pertussis is a gram-negative bacterium that exclusively infects susceptible humans, causing
pertussis, a respiratory disease that, in some cases, presents severe neurological
complications. These are related to the antigenic components of the pathogen, mainly
the pertussis toxin (TP), hemagglutinins, agglutinogens, adenylate cyclase, pertactin
and tracheal cytotoxin.[5]
[34]
[35]
[36]
In particular, PT causes ciliary paralysis of the airways due to exacerbated local
inflammation. This leads to the accumulation of secretions and/or their inadequate
removal, favoring secondary pneumonic processes (which can be severe, especially in
the first six months of life).[34]
[37]
Such inflammation leads to massive migration of lymphocytes, which are the first line
of defense. Although the pathogenicity model is toxin-mediated, some bacteria can
also be found in local macrophages, denoting tissue penetration.[34]
Pertussis has an incubation period of 7 to 10 days, starting with a nonspecific cough
and fever, similar to other infectious diseases of the airways. However, after about
a week, the period of paroxysmal attacks of a characteristic (whooping) cough begins,
which can last up to six weeks, causing great suffering to the patients and their
families.[1]
[37]
In uncomplicated cases, full recovery occurs within two to three months. Although
pneumonic conditions are the most common complications, in 5.2% of all cases and in
11.8% of infants younger than 6 months, neurological complications such as encephalopathies
can occur. These are severe conditions, worsened by hypoxia caused by airway obstruction,
and a neuroimmune-mediated mechanism must be considered.[2]
[35]
[37]
There are no animal reservoirs or vectors related to the transmission of pertussis,
with humans playing an essential role in its life cycle. It is a highly contagious
disease that can affect 80% of susceptible household contacts.[37]
The mass immunization of communities played a crucial role in the reduction of the
cases of pertussis. The first “whole-cell” (cellular) pertussis vaccine was administered
in the United States in 1914. Later, in 1948, it became associated with diphtheria
and tetanus components, receiving the name DTP.[38]
The DTP vaccine provides protective levels in 70% to 90% of the population immunized
with four doses, but, due to the drop in levels of protective antibodies, it would
need to be repeated every 10 years.[4]
[35]
Due to the local reactions and adverse effects, an acellular DTP vaccine was developed,
which purports to cause a lower incidence of adverse effects. However, the traditional
DTP vaccine is still being used in several countries, including Brazil, where it is
conjugated with two more components (constituting the PV), immunizing against H. influenzae and hepatitis B.[1]
After immunization, the antigens present in VP, in particular those of the cell formulation,
activate CD4 + 1 (Th1) T Helper lymphocytes that secrete cytokines such as Interleukin
2 (Il-2), Interferon γ and Tumor Necrosis Factor α (TNF-α).
These cytokines in turn promote the activation of CD4+ T Helper Lymphocytes 17 (Th-17)
producing Interleukin 17 (Il-17), which seems to play a crucial role in the long-term
post-immunization immune response and which is also related to the production experimental
encephalomyelitis.[34]
There are several proposed mechanisms for postimmunization CNS inflammation, with
the granulocyte-macrophage colony-stimulating factor (GM-CSF) and the activation of
T lymphocytes playing a crucial role in this process.[6]
[39]
In experimental animal models, decreased GM-CSF activity was associated with reduced
development of encephalomyelitis. The use of exogenous administration demonstrated
an increase in the severity/onset of the condition. The GM-CSF is secreted by T Helper
lymphocytes and induces microglial proliferation and activation.[6]
[39]
Microglial activation increases the local production of oxygen free radicals, nitrogenous
species, glutamate, TNF-α, neurotoxic phenotypic differentiation of microglia and
an increase in pro-inflammatory mediators such as Interleukin-1B (Il-1B) and Interleukin-16
(Il-16).[39]
The GM-CSF also contributes to the “break” of the BCSFB and to the recruitment of
inflammatory cells from the peripheral blood. It also induces the proliferation of
macrophages involved in the positive feedback of Th-1 and Th-17 cells.[6]
[7]
[34]
The systemic inflammatory process postimmunization with the PV could decompensate
hydrocephalus through a multifactorial mechanism related to the BCSFB.
The “break” of the BCSFB, which causes a higher concentration of proteins in the CSF,
could increase the intracystic oncotic pressure. This would cause a slight increase
in volume and secondary mechanical obstruction of the CSF drainage pathways.
The greater inflow of water through the BCSFB by diffusion would cause an unbalance
in the cystic water inflow/outflow (valvular mechanism) which could also explain the
deterioration of the patient's clinical condition.[14]
The BCSFB differs from the blood-brain barrier (BBB) in several respects, but it is
no less important. It has distinct regulatory and secretion mechanisms that give it
great importance in the physiology and mechanical protection of the brain parenchyma.
It is formed by the arachnoid and choroid plexuses and their interface with the cerebral
cortex (convexity) and ependymal surfaces of the ventricular cavities.[40]
[41]
The choroid plexuses are structures composed of highly-permeable capillaries and lined
with a specialized epithelium that do not ultrafilter plasma CSF, but rather secrete
it. They have microvilli that increase their surface and still receive differentiated
irrigation, about ten times that received by the cerebral cortex.[42]
In adults, the choroid plexuses produce about 600 mL of CSF daily, which shows the
high “turnover” of the CSF. They not only help from a biomechanical point of view,
protecting CNS structures by reducing their weight (floating effect), but they also
have an essential metabolic role, as they carry micronutrients, peptides and hormones.[43]
Their simple cubic epithelium has a basement membrane rich in type-IV collagen (α
3, α 4, and α 5 monoclonal chains), and are similar to renal glomeruli in terms of
selective permeability. They are rich in utrophin A, a transmembrane protein that
provides structural stability and plays important roles related to cell signaling
and homeostasis.[44]
Choroid plexus cells capture HCO3−, Cl− and Na+ ions by active transport, and are
rich in the number of mitochondria, endoplasmic reticulum and Golgi complex, mainly
related to the secretion of products by transcellular transport.[42]
[45]
[46]
The cells of the choroid plexuses have a modified apical surface, which is responsible
for ion secretion via active transport (via apical Na+, K+, 2Cl− cotransporters).
This structure enables the passage of water through an osmotic gradient, regulated
by mediated cellular transport channels such as aquaporin-1 (AQP1).[42]
[45]
[46]
The passage of small proteins and other solutes by pinocytosis and/or exocytosis (transcellular
transport) occurs on this surface.[42]
[45]
[46]
Claudins 1, 2 and 11 proteins, especially Claudin 2 (CLDN-2), promote firm cell junction
of this epithelium in the so-called occluding zone of the choroidal apical surface.
Its genomic expression provides resistance to the cell surface, modulating inappropriate
ionic exchanges and preventing larger molecules such as peptides, ferritin, and immunoglobulins
from crossing the BCSFB.[42]
[47]
The inflammatory response through TNF-α and interferon γ could negatively modulate
CLDN2, enabling the disruption of the BCSFB, favoring paracellular transport, decreasing
the selective permeability of the cell surface and increasing the protein content
of the CSF.
The occurrence of an inflammatory reaction in the apical region and consequent dysfunction
would promote inadequate modulation of ionic transport, enabling a greater ionic inflow
into the CSF and the consequent increase in the passage of water through AQP1, resulting
in an increase in CSF volume.[42]
Thus, the immune and inflammatory effects caused by postPV immunization may have been
the determining factors for the alteration of homeostasis, causing decompensation
of the infant's hydrocephalus.
