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"Knowing syphilis in all
its manifestations and relations, and all other things
clinical will be added into you".
Sir William Osler, 1897
Syphilis is one of the most
interesting diseases of humans. The disease has been
of great historical significance for the practice of
medicine, and for many persons who played important
roles in the history of western world (1). Syphilis
has expanded rapidly during the past two decades. The
increase started gradually in the 1970s, due to the
alteration in sexual behavior. The overall incidence
increased slowly until 1982 and then declined slightly
until 1986 (2). The number of reported cases of syphilis,
including primary, secondary and congenital syphilis,
has been rapidly rising since 1987 (3,4).
Case
Report
This is a report of a patient with syphilis and dementia.
An 88 year old Hispanic female presented with multiple
problems. The daughter noted over the last year that
her mother became less talkative than before. She is
quite most of the time and she is usually not oriented
to time, place and person. She still remembers the immediate
family, but she cannot engage in long conversations.
Her Folstein Mini-Mental score was 17/30, her geriatric
depression scale was 14/30. Other associated problems
include urinary incontinence and gait disturbance. Her
neurological examination revealed: The left pupil is
7 millimeters with minimal reaction to light. The right
pupil was 45 millimeters and reactive to light. Normal
heart sounds S1 and S2, regular rhythm with no gallop
or rail. Unequal pupils with one of them reactive to
light; the other not reactive, pupils react normally
to convergence accommodation. The rest of the cranial
nerves were intact with good gag reflex. Reflexes are
+2 all over; no nystagmus. Babinski was positive on
the left side, muscle power was 3/5, unsteady gait.
Laboratory study revealed a positive VDRL, a positive
FTA. Her CT scan of the brain was normal. Ophthalmology
examination revealed interstitial keratitis. The patient
was hospitalised in 1987. Lumbar puncture was attempted
three times but failed. She received treatment with
IV penicillin for 10 days.
The Stages of Syphilis
Primary Syphilis:
The typical lesions (Chancre) of the untreated illness
typically appears from 10 to 90 days (average 3 weeks)
from exposure. The lesion is normally single but may
be multiple, and while it is normally painless and connected
with regional adenopathy, exceptions occur (5).
Secondary Syphilis:
Classically, secondary Syphilis is featured by macular
or papular lesions on the palms and soles. Nevertheless,
the rash frequently begins on the trunk and spreads
to the extremities ultimately embracing the whole body.
It usually evolves six to eight weeks after the chancre
has healed (2). It is also linked with systemic symptoms,
including low grade fever, malaise, myalgia and generalised
lymphadenopathy (6). Meningitis, iritis, glomulerulonephritis
and hepatitis are infrequent but potential manifestations
of secondary syphilis (Table 1) (5). The differential
diagnosis of secondary Syphilis is broad, which accounts
for the disease's historical name as "the great
imitator" (5). The family of the patient did not
recall any illness that resembles the above.
Latent Syphilis:
The latent stage has no clinical manifestations. It
is divided into an early phase and a late phase. The
Centers for Disease Control currently uses a one year
cutoff to differentiate between early and late latent
infection (2). Latent Syphilis follows the secondary
stage of infection in the untreated patient. Roughly
25% of patients in the early latent stage will have
at least one relapse of mucocutaneous symptoms, which
may be helpful in the clinician's evaluation and management
(7). Up to 35 percent of untreated persons with latent
syphilis acquire the late sequelae of tertiary syphilis
(7).
Tertiary Syphilis
Tertiary Syphilis is an ongoing, inflammatory disease
that can effect any organ system. Among the untreated
patients in the Oslo study who progressed to tertiary
disease, cardiovascular Syphilis developed in 10%, neurosyphilis
in 10% and gummatous Syphilis in 15% (7).
Neurosyphilis
The manifestation of the central nervous system readily
recognised by practicing physicians three or four decades
ago are unfamiliar to many physicians today as the result
of relative rarity of this condition, as happened with
our patient. A helpful schema for classification of
neurosyphilis is shown in (Table 2) . Although this
classification indicates the existence of distinctive
individual forms of neurosyphilis, features of several
of the entities commonly coexist.
Long-term longitudinal studies
performed earlier in this century revealed that out
of 953 persons with primary or secondary syphilis, 6.5
percent subsequently developed CNS involvement (8,9).
The most common forms of nervous system involvement
were asymptomatic neurosyphilis (31%) and tabes 30%.
The incidence of paresis was most likely underrated
since such patients were more probable to have been
treated in psychiatric rather than general hospitals.
General Paresis
General paresis is a meningoencephalitics
associated with true invasion of the cerebrum by T.
Pallidum. The clinical illness is a chronic process
that may present in middle or late adult life. The course
is progressively downhill, in untreated patients. This
form of late Syphilis develops 15 to 20 years after
initial infection. Patients with this disease made up
to 5 to 10 percent of all first admissions of psychotic
patients to psychiatric hospitals prior to World War
II. (9,10).
Symptoms and Signs
The clinical picture is an aggregation of neurologic
findings and psychiatric symptoms. It can imitate nearly
any type of psychiatric or neurological disorder. It
is usually insidious in onset. The early characteristics
are normally of psychiatric kind, and the trend of illness
is that of a dementing process. Initial manifestations
embody progressive memory loss, worsening of intellectual
function and personality changes which was the case
in our patient. Other symptoms include defects in judgement,
emotional lability, delusions, and inappropriate social
or moral behavior, in our case there were no delusional
symptoms. Depression in some studies has been reported
as the predominant presenting feature and the most common
initial diagnosis in patients with paresis (11). The
patient was clinically depressed, with a GDS of 14/30.
In patients with paresis of
apparently sudden clinical onset, the earliest indication
of the disease may be seizures, transient ischemic attacks,
or an apparent stroke with loss of consciousness (apoplectiform
attack), followed by hemiparesis, monoplegia, or aphasia.
Pupillary abnormalities are among the most common neurologic
findings in general paresis ( Table 3). Speech gets
continuously thicker, and the issue may be complicated
by the development of global aphasia. A true Argyll
Robertson pupil is not common in early paresis; at this
stage the pupil may be large (rather than miotic), unequal,
and sluggishly reactive to light and accomodation. Gradually,
normal pupils can turn to Argyll Robertson type that
was present in this patient, characterised by:
(1) The retina is sensitive
(i.e., eye is not blind);
(2) Pupils are small, fixed and do not react to strong
light;
(3) Pupils react normally to convergence-accommodation;
(4) Mydriatics (atropine) fail to dilate pupil fully;
(5) Pupils do not dilate on painful stimuli.
Apathy, hypotonia, unsteadiness,
dementia, and physical deterioration become the major
elements in the clinical picture, as the disease advances.
Recurrent focal or generalized seizures accompany progressive
deterioration resulting in bedridden, paralyzed, incontinent
state. The term Lisauer's dementia paralytica describes
a small group of atypical cases of paresis which showed
focal neurological signs and on autopsy exposed impressive
atrophy of certain cerebral convolution (9), especially
in the frontal and temporal lobes. Such patients formerly
had focal seizures followed by hemiparesis, hemianopia,
or aphasia which thereafter cleared.
The duration of untreated paresis, from the onset of
detectable mental symptoms till death, has ranged from
a few months, in cases of sudden onset, to 4 or 5 years
(9). Spontaneous remissions in mental symptomatology
have happened infrequently, but have not changed the
ultimate course of the disease. In the pre-penicillin
era, treatment of paresis with malaria plus arsenicals
benefited 33 to 50 percent of cases by arresting progression
of the disease and allowing some type of occupational
activity. The shorter the duration, and the milder the
symptoms at the institution of therapy, the better the
prognosis. In this lady treatment started late and no
amelioration of symptoms was noted after treatment.
A few cases of general paresis, despite treatment with
large doses of penicillin, have communicating hydrocephalus
as a complication. This leads to either lack of clinical
amelioration or gradual worsening. These patients develop
gait apraxia, akinetic mutism, incontinence and pyramidal
tract signs along with severe dementia (12). CSF shunting
causes prompt amelioration in several cases. Diminished
CSF absorption by chronic meningitis and meningeal fibrosis
in general paresis seems to be the cause for this process.
Laboratory
Findings
The blood nontreponemal serology has been reported positive
in 95 to 100 percent of cases of paresis (9,12). In
another study, only 48.5 percent of patients with a
diagnosis of neurosyphilis had a positive nontreponemal
serology (13). However, 56.3 percent of patients had
a history of earlier treatment of syphilis. Thus, this
series may not be as conflicting with other studies
as it seems, since earlier treatment may have been adequate
to cause seroconversion (without preventing the subsequent
development of neurosyphilis). The serum FTA-ABS test
is uniformly positive in patients with paresis. In our
case both VDRL and FTA were positive.
CSF abnormalities are present in practically all cases
of untreated paresis (9). The characteristic CSF findings,
include the following:
(1) Normal or, occasionally,
slightly increased pressure;
(2) Lymphocytic pleocytosis (usually 8 to 100 lymphocytes
per cubic millimeter);
(3) Increased protein concentration usually 50 to 100
mg/dl)
(4) Increased globulin concentration;
(5) Positive colloidal gold reaction, when performed
(6) Normal or occasionally, mildly reduced glucose;
and
(7) Reactive nontreponemal test.
The CSF nontreponemal tests
show a very high specificity, and false positive VDRL
test is remarkably exceptional. Thus, a positive CSF
VDRL test is a powerful indication for a diagnosis of
neurosyphilis. However, CSF nontreponemal tests may
have a sensitivity of less than 100 percent. In some
patients with clinically diagnosed neurosyphilis (14),
CSF Wassermann reactions have been reported negative.
This can happen in a patient whose neurosyphilis process
has been confined by treatment leaving steady mental
changes.
In a few clinically characteristic
cases of neurosyphilis (15) CSF VDRL may be negative,
and the entire CSF analysis may be normal. Although
abnormalities occur in the CSF of 25 to 40 percent of
patients with untreated secondary syphilis (16), designating
early association of nervous system, treatment with
penicillin usually prevents any progression to symptomatic
neurosyphilis. CSF FTA-ABS may be reactive as a product
of diffusion of serum syphilis, therefore there are
problems with the specificity of this test (17). False
positive reactions occur in 0.5 to 4.5 percent. In addition,
a reactive CSF FTA-ABS result may not indicate active
neurosyphilis, since the reactivity may be produced
by diffusion of serum immunoglobulins into the CSF (18).
Also contamination of a CSF specimen with very small
amounts of FTA-positive blood can produce a false positive
CSF FTA test (19). For these reasons the interpretation
of a positive CSF FTA test is unclear (20). At present,
a positive CSF FTA test alone in a patient with neurologic
findings of uncertain nature does not establish a diagnosis
of neurosyphilis.
In patients with paresis EEG
is abnormal in 80 percent of cases. Recently CT scan
has been utilized to assess cerebral syphilis (21).
Findings on CT scan range from extensive regions of
decreased attenuation of the cerebral white matter,
particularly in the frontal lobes and paraventricular
areas of parietal lobes to enlargement of cortical sulci
and associated ventricular dilation (21). These findings
resemble the CT scan pattern observed in demyelinating
disorders. Other CT findings include cortical atrophy
and multiple areas of hypodensity in both cerebellar
hemispheres and in the brain stem (these findings are
consistent with infarctions) (21). Godt et al (22) found
both enhancing lesions (gummas) and generalized cortical
and subcortical atrophy in several patients with neurosyphilis.
Chest roentgenograms may show widening of the aorta,
consistent with syphilitic aortitis, which occasionally
coexists with parenchymatous neurosyphilis.
Diagnosis and Differential Diagnosis
The clinical picture, is easily distinguishable
in its full-blown form, however is more hard to ascertain
when atypical or incomplete. Spinal fluid alterations
usually help in the diagnosis. The CSF is abnormal in
all untreated cases of general paresis, but the same
alterations can happen in the middle of other neurosyphilis.
Hence, the association of preexisting CSF alterations
of asymptomatic syphilitic meningitis with a diversity
of organic brain syndromes can be misdiagnosed as general
paresis. These include cerebral tumor, subdural hematoma,
cerebral arteriosclerosis, Alzheimer's disease, multiple
sclerosis, senile dementia, and chronic alcoholism.
CT scan findings, the presence of pupillary changes,
and a history of drug or alcohol abuse are useful in
accurate diagnosis. Hallucinations are important in
delirium tremens but are unusual in general paresis.
However alcoholic worsening and Korsakoff's psychosis
can present a picture of memory loss, unsuitable conduct,
mood swings, and faulty opinion that is hard to differentiate
from paresis.
An adult-onset seizure disorder
can be a presentation of paresis or of an exceptional
form of neurosyphilis. Paresis may be ruled out when
CSF irregularities are lacking. When CSF alterations
of neurosyphilis are present, the inquest change to
whether the seizures symbolize epilepsy in a patient
with asymptomatic neurosyphilis or whether they are
the presentations of syphilitic brain injury. The presence
of focal neurologic findings in patients with neurosyphilis-produced
seizures aids in answering the question.
Management
ANTIBIOTIC THERAPY
The management of neurosyphilis and outcome has markedly
improved since the introduction of penicillin. In a
multicenter study including treatment of over 1000 patients
with paresis, a total penicillin dosage of six million
units was judged to be satisfactory (23). Patients who
required re-treatment to arrest the infection had received
less than six million units of penicillin initially.
In the past decade it has been recognized that the treatment
with 7.2 million units of benzathine penicillin G (2.4
million units intramuscularly weekly for 3 doses) is
sufficient treatment for all kinds of neurosyphilis.
The most recent recommendations of the Centers of Disease
Control (24) involve the use of either intraveneous
aqueous penicillin G for 10 days, intramuscular procaine
penicillin G for 10 days, or weekly injections of benzathine
penicillin G for 3 doses (Table 4) (24). Intravenous
penicillin G for 10 to 15 days is the most reasonable
therapy to employ for symptomatic or asymptomatic neurosyphilis.
This assures penicillin concentrations in CSF which
are continuously at least several fold above the minimally
treponimicidal concentration of 0.018 microgram per
milliliter during therapy (25, 26). Alternatively, daily
aqueous procaine penicillin G (plus probenecid) for
10 to 14 days would be preferable to benzathine penicillin
G, that is no longer recommended by the World Health
Organization.
FOLLOW-UP AND RE-TREATMENT
The CSF data are normally a reliable index of the activity
of neurosyphilis and furnish a gauge of the efficacy
of the antibiotic therapy. When initial penicillin therapy
has stopped the infection, repeat CSF examination at
3 to 6 months reveals normal cell count and, if initially
elevated, a decline in concentration of protein (27).
One year after treatment CSF
examination reveals a persistent fall in the protein
level and a decrease in the titer of the nontreponemal
serologic test. However, the latter may not become completely
negative for several years or longer and is not an indication
of active neurosyphilis under these circumstances. In
three to six months if the CSF cell count does not return
to normal or if, having returned to normal, the count
rises again in relapse, then re-treatment is indicated.
If relapse has not occurred during a period of 2 years
after adequate penicillin therapy, it is unlikely to
occur. Subsequently, reexamination should be done annually
for several years. Blood serologic testing should be
performed at 6 and 12 months and afterwards at yearly
intervals for at least 3 years (28).
PROGNOSIS
The natural history of the disease is progressive, and
the result is ultimately deadly. The span of life from
the beginning of tangible mental symptoms to death normally
extends from a few months to 4 or 5 years, but an infrequent
treated patient with so-called stationary paresis has
survived for 10 years (9). Recent studies involving
longer term follow-up indicate the development of new
neurosyphilis signs in 39 percent of patients treated
with penicillin (29). Advancement of the disease can
happen indeed in the absence of reactive CSF tests.
It is equivocal whether the evolution of new signs in
patients with paresis treated with what has been determined
adequate penicillin dosage is due to persistence of
treponemes in the CSF, to the need for spirochetocidal
concentrations of penicillin in the CSF (30, 31), or
to an increased susceptibility to other neurologic processes.
More study of these treatment failures is required.
Conclusion
Syphilis is still prevalent,
especially in particular sectors of the population.
Late complications can be somewhat less of an issue
than the preantibiotic era, however vigilance to the
probability of late Syphilis and appreciation of clinical
manifestations of late Syphilis are crucial if these
forms of disease are to be diagnosed and treated adequately.
The main consideration must be vigilance in finding,
treating, and preventing early Syphilis. Since all forms
of Syphilis, especially certain types of late Syphilis,
are less common than the glory days of Syphilis as a
clinical specialty, it is important to educate others
and to remind ourselves of the multiple faces of the
great actor, lues venerea.
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