Keywords
idiopathic intracranial hypertension - pseudotumor cerebri - history
Introduction
The disease now most frequently referred to as pseudotumor cerebri syndrome (PTCS),
according to the most recent diagnostic criteria,[1] has been known by various names since its first clinical descriptions: pseudotumor
cerebri, benign intracranial hypertension (BIH), and idiopathic intracranial hypertension
(IIH).[2] These terms were introduced, respectively, by Nonne,[3] Foley,[4] and Buchheit et al.[5] The variation in nomenclature reflects the unclear etiology of this syndrome. From
a historical point of view, the initial recognition of the disease depended on the
following two critical steps: (1) invention of the ophthalmoscope by von Helmholtz
in 1851[6] and its application in medical practice and (2) introduction by Quincke[7] of lumbar puncture, a technique that finally lead to rigorous measurement of the
cerebrospinal fluid (CSF) pressure.
Earliest Descriptions of Pseudotumor Cerebri Syndrome
Authors had previously summarized the first description of this syndrome.[8]
[9] One historic key manuscript is a monograph that focused on diseases of the optic
nerve, published by The Transactions of the Ophthalmological Society, United Kingdom,
in 1880.[10] At that time lumbar puncture was not yet utilized to assess the CSF opening pressure,
which later became a fundamental criterion in the diagnosis of PTCS. The earliest
descriptions of the PTCS syndrome, lacking the evaluation of CSF pressure, might be
regarded as presumptive. However, some of the early reports were highly suggestive
of PTCS, because of the description of the typical symptoms (e.g., headache, diplopia)
in the context of specific funduscopic findings (i.e., papilledema) on the background
of known PTCS-related risk factors (e.g., female gender, obesity, endocrine derangements).[10] Notably, in the 19th century, papilledema was usually referred to as optic neuritis.[8]
[11]
From a long chapter published in 1880,[10] we know that Dr. Hughlings Jackson[10] mentioned reports regarding “…a recoverable optic neuritis in young women suffering
from uterine derangement….” In 1881, Gowers[12] described “optic neuritis,” likely associated with iron deficiency anemia, a disorder
now identified as an important risk factor for PTCS. In an article published in 1900,[13] Williamson and Roberts[13] reported 100 cases of “double optic neuritis” associated with headache; in this
group of patients they assessed a higher prevalence of female gender, obesity, and
menstrual irregularities. However, the earliest clinical descriptions pointing to
PTCS seem to have been authored by Sir William Broadbent,[14] a neurologist born in 1835 in West Yorkshire. Indeed, Dr. Broadbent[14] described in 1872, a 12-year-old girl admitted to St. Mary hospital in London because
of a 2-year history of headache and papilledema (referred by him as “chocked disc”
[[Fig. 1]]), on a background of menstrual irregularities. Her symptoms resolved after menstrual
regularity was restored, although she remained blind from the sequel of the papilledema.
Fig. 1 Extract from a paper on the cause and significance of the chocked disc in intracranial
diseases published by Sir William Henry Broadbent in the British Medical Journal in
1872.
Sir William Broadbent ([Fig. 2]) studied Medicine in the Royal School of Medicine in Manchester and worked for most
of his career at St Mary's Hospital in London (1859–1896). Broadbent was a leading
British authority at that time in the field of cardiology and neurology. In 1881,
he was elected President of the London Medical Society and in 1887, the President
of the Clinical Society of London. In 1891, Broadbent[15] helped to save the life of Prince George (the future King George V) from typhoid
fever. In 1893, he was created a Baronet by Queen Victoria and, later, was appointed
a Knight Commander of the Royal Victorian Order in March 1901.[15]
Fig. 2 Sir William Henry Broadbent (January 23, 1835, Huddersfield, West Yorkshire–July
10, 1907, London).
The History of a Syndrome among Courses and Recourses
The articles by Quincke[16]
[17] and Nonne,[3] spanning the years 1893 to 1904, initiated the concept of PTCS as a specific disease
entity. Despite the earliest description of a non–tumor-related increase of intracranial
pressure (ICP) (see section Earliest Descriptions of PTCS), the first report of PTCS, documented by elevated CSF opening pressure during lumbar
puncture, was ascribed to Quincke[16]; he described it in 1893 under the name “meningitis serosa.” Quincke ([Fig. 3]) was born in Frankfurt-an-der-Oder. He studied Medicine in Berlin, Wurzburg and
Heidelberg, and became a doctor in 1863. Virchow was his most important mentor. Quincke
was the first to characterize anaphylaxis-related angioedema, a condition that was
later defined as “Quincke edema.”
Fig. 3 Dr. Heinrich Irenaeus Quincke (August 26, 1842, Frankfurt an der Oder–May 19, 1922,
Frankfurt am Main).
Quincke was also the pioneer of lumbar puncture: he described this procedure at the
10th Congress of Internal Medicine in Wiesbaden during April 1891.[7] Through lumbar puncture, he was also the first clinician able at that time to measure
intracranial pressure.[18] He deeply studied the CSF circulation and, by injecting the red sulfide of mercury
into the subarachnoid space of rabbits, was also the first to demonstrate the CSF
flow.[9]
[18] Quincke attributed the clinical features of headache and visual disturbance, of
what is today known as PTCS, to an elevation of ICP. He also thought that increased
CSF production was the cause of the observed rise of ICP. Finally, he also understood
some of the first PTCS-related comorbidities/risk factors, including head injury,
pregnancy, infections, and otitis media.[10] Patients followed up by Quincke[16] complained of headache and visual disturbances, coupled with papilledema and increased
ICP pressure, as documented by lumbar puncture. Overall, Quincke[17] reported 10 cases suggestive of PTCS (seven females, three males) and remarked on
the female preponderance.
Max Nonne ([Fig. 4]) was a German neurologist in Hamburg. His most important mentor was Wilhelm Heinrich
Erb, the neurologist who first described brachial plexus palsy, also known as “Erb-Duchenne”
palsy. In the history of PTCS, Nonne had the distinction of introducing his original
work by the still-remaining term “pseudotumor cerebri” ([Fig. 5]); this term described the constellation of signs and symptoms related to raised
ICP but without any intracranial tumor.[3] He reported in 1904 on 18 patients with signs suggesting PTCS,[19] although their clinical characteristics did not fulfill the actual diagnostic criteria.
Fig. 4 Dr. Max Nonne (January 13, 1861, Hamburg–August 12, 1959, Hamburg).
Fig. 5 Title page of the original article published by Dr. Max Nonne in 1904, where he introduced
for the first time the term “pseudotumor cerebri.”
In the 1930s, Symonds[20] reported on children who developed signs of elevated ICP in association with middle
ear infection. He was strongly impressed by the large amount of CSF drained by lumbar
puncture. Symonds[20] hypothesized that an “increased ICP due to the presence of an excess of normal CSF”
might follow a middle ear disease which impairs sinus venous drainage. He, therefore,
defined this condition as “otitic hydrocephalus,” reflecting the increase in CSF volume
in the ventricular system.[8] He also recommended diversion of CSF by lumbar puncture as the best treatment choice
in these patients.[20]
In subsequent years, the introduction of radiological techniques, such as ventriculography
and angiography, allowed the exclusion of any significant expansion in the ventricular
system of these patients.[8] In fact, Dyke and Davidoff[21] were the first to describe a series of adult and pediatric patients, with signs
and symptoms suggestive of PTCS, in whom the lack of any ventricular dilatation on
ventriculography was demonstrated. They used the term “hypertensive meningeal hydrops”[21] to define the condition of intracranial hypertension characterized by normal findings
on ventriculography, in place of the term “otitic hydrocephalus” coined by Symonds.
Dandy[22] also reported a large series of patients with signs and symptoms of intracranial
hypertension in whom ventriculography showed the absence of ventricular dilatation.
He, therefore, confirmed the conclusion of Dyke and Davidoff. Dandy used the term
“intracranial pressure without brain tumor” to describe the disease and was the first
to propose diagnostic criteria for this condition.[23] He also hypothesized on the underlying pathophysiology and proposed that changes
in cerebral circulation were responsible for the raised ICP, rather than an increase
of CSF volume.
The first author who recognized a possible metabolic-endocrine pathophysiological
basis for the condition was Thomas[24] in 1933; he understood that obese young women were particularly prone to develop
this raised ICP syndrome, likely, due to some endocrine disturbances affecting CSF
and cerebral circulation dynamics. Joynt and Sahs[ 25] in 1957 demonstrated intracellular and extracellular edema on brain biopsy samples
obtained from patients with raised ICP syndrome. Following their study, there was
a growing perception of cerebral edema as the cause of intracranial hypertension.
Accordingly, diuretics (acetazolamide) and corticosteroids were started in the treatment
of these patients.
Foley[4] in 1955 introduced the term “BIH,” which became the most commonly term used to define
this condition in the next several decades. In the subsequent years, with progress
in neuro-ophthalmological examinations, the natural history of this condition proved
to be not always benign, as some patients with “BIH” developed permanent blindness;
consequently, the conventional designation at that time was changed to “IIH.”[5] Ironically, in recent years, the nomenclature of this syndrome has been changed
from “IIH” to “PTCS,”[1] the original term used by Nonne more than a century ago.
Notably, in 1955, Foley outlined some of the peculiar findings of PTCS: “The most
important symptoms being headache of moderate degree, obscurations of vision, diplopia,
and sometimes tinnitus; marked papilledema and abducens palsies are the only signs,
the CSF is normal in composition and the prognosis is almost invariably good, the
condition subsiding within a few weeks or months.” Interestingly, Foley was also interested
in explaining the underlying pathophysiology of the syndrome and in 1955 suggested
that: “…an underlying endocrine imbalance, with presumably a disturbance of electrolytes,
is in some way connected with the alteration of intracranial pressure.”[4] These concepts became meaningful again in contemporary times. In fact, recently
great attention has been directed toward the role of CSF electrolyte imbalances due
to endocrine derangements in PTCS. Indeed, some authors suggest that an impaired endocrine-metabolic
homeostasis plays an universal etiological role in explaining most cases of primary
PTCS related to well known risk factors (e.g., female gender, obesity, adrenal disorders,
recombinant growth hormone therapy, and vitamin A imbalance).[26]
[27]
[28] However, further studies are needed to explain the elevation of ICP in this historically
mysterious but yet fascinating and challenging disease.
