++
The inflammatory process in the subarachnoid space produces the
classic spectrum of presentation, which comprises acute syphilitic
meningitis, arteritis (meningovascular syphilis), meningoencephalitis
(syphilitic dementia, general paresis), and dorsal root ganglionopathy
(tabes dorsalis). These entities may overlap; however, relatively
pure forms predominate, demonstrating a characteristic time course
and presentation following the initial primary infection (see Figure 20–1).
++
Acute syphilitic meningitis is the earliest symptomatic subtype
and often accompanies the rash of the secondary stage of syphilis.
When the meningeal inflammation involves blood vessels in the subarachnoid
space, vascular syphilis occurs, usually within the first 5 years.
The parenchymal forms follow over a more protracted interval of
several decades. The syndromes of neurosyphilis most commonly seen
in recent years are syphilitic meningitis and cerebrovascular syphilis
(see Table 20–1), because these are the earliest forms
seen following a new infection.
++
++
CSF abnormalities
are the hallmark of each stage of neurosyphilis. Lymphocytic pleocytosis
with cell counts ranging from 10–500 WBCs/μL
is found in the most acute form, syphilitic meningitis. Decreasing
numbers of cells are reported in syphilitic vascular disease, paresis,
and tabes dorsalis. The glucose concentration may be mildly reduced
in syphilitic meningitis. The protein concentration, the least specific
of CNS parameters in neurosyphilis, is rarely greater than 200 mg/dL
in syphilitic meningitis, syphilitic vascular disease, and paresis.
Isolated protein elevations should be interpreted with caution.
Protein concentrations of less than 100 mg/dL
are the rule in tabes. The gamma globulin portion of the CSF protein
is commonly elevated, and oligoclonal bands may be present, as is
characteristic of any chronic meningitis. In late, “burned
out” tabes dorsalis, after the period of inflammation,
CSF findings may be normal, although positive CSF VDRL serologic
test results may be retained.
++
Abnormal cellularity of the CSF defines disease activity, the
potential amelioration of symptoms with therapy, and the adequacy
of response to treatment (see Table 20–2). Therefore, repeat
CSF examination should be performed after treatment (see later discussion).
Persistence of CSF VDRL titer elevation following antibiotic treatment
and cell count normalization is of uncertain significance.
++
++
A negative
treponemal serologic test result in blood (fluorescent treponemal
antibody absorbed [FTA-ABS] or T
pallidum particle agglutination [TP-PA])
excludes the diagnosis of neurosyphilis. A positive nontreponemal
CSF serologic test result (CSF VDRL) establishes the diagnosis of
neurosyphilis (and an increased cell count in response to the spirochete
documents the presence of active disease).
++
Whether true negative CSF VDRL serologic test results occur in
the presence of presumed active neurosyphilis is an unresolved question.
The classic literature relied on the relatively insensitive Wassermann
reaction, and the clinical case series in patients with early neurosyphilis
(meningeal and meningovascular) were contaminated by nonsyphilitic
syndromes of viral meningitis and cerebral vascular disease that
were unrecognized at that time. Thus, data from these clinical groups
are of uncertain value. Where clinical diagnoses were clear in the
older literature (eg, paresis and tabes dorsalis), the large numbers
of reported cases suggest that seronegativity (even with the Wassermann
reaction) was very rare. CSF serologic diagnosis in early syphilis
remains a problem. For this reason, patients with a compatible clinical
diagnosis and a mild elevation of cell count but nonreactive CSF
VDRL are referred to as having “probable” neurosyphilis.
++
The occurrence of seronegative, active neurosyphilis in HIV co-infected
patients has been suggested. However, spirochete penetration into
the nervous system is not different in HIV-infected or-uninfected
patients. Late serologic conversions in patients with secondary
syphilis are well known, and the fact that the cellular response
of the CSF may precede serologic positivity in early syphilis may
explain many of these cases.
++
The role of the more sensitive treponemal test (FTA) in the CSF
analysis remains uncertain, because the unabsorbed FTA test produces
an unacceptably high false-positive response (4.5% of normal)
and the addition of sorbent (FTA-ABS) decreases sensitivity to 75%.
However, some laboratories now perform FTA-ABS and FTA tests of
CSF to exclude neurosyphilis in at-risk patients in whom the CSF
is abnormal but the CSF VDRL test is nonreactive.
+++
Clinical Diagnosis of Neurosyphilitic Subtypes
+++
Acute Syphilitic Meningitis
++
Symptomatic syphilitic meningitis occurs during the first months
to 2 years following the primary infection, and 10% of
cases occur coincident with the secondary rash. The typical patient
is afebrile, with headache, and may have some degree of confusion.
Unilateral or bilateral swelling of the optic disk is common. Meningeal
signs may be positive. The course is subacute. CSF examination demonstrates
a lymphocytic pleocytosis (see Table 20–1). Currently,
the most useful serologic test for the diagnosis of syphilitic CNS
involvement is the CSF VDRL; rapid plasma reagin (RPR) or other
nontreponemal testing of CSF has no role in CNS evaluation.
++
The meningeal inflammatory process may be concentrated at the
vertex or base of the brain. Vertex involvement produces a communicating
hydrocephalus, whereas basilar inflammation produces cranial nerve
(CN) abnormalities, particularly CNs II and III and those of the cerebellopontine
angle (VI, VII, and VIII); asymmetry is the rule. Meningeal enhancement
may be seen on magnetic resonance imaging of the brain.
++
The diagnosis is made in patients with meningeal symptoms, cranial
nerve abnormalities, and lymphocytic pleocytosis with a positive
serologic test result. A negative CSF VDRL serologic result may
occur in a patient with very early CSF sampling, because CSF inflammation
precedes seropositivity. The meningeal symptoms may resolve without
treatment but leave the patient at risk for later forms of neurosyphilis.
+++
Meningovascular Syphilis
++
When the CSF inflammatory process compromises arteries within the
subarachnoid space, a syndrome of vasculitis involving mid-sized
vessels is produced. The middle cerebral artery is most often affected,
but any cerebral or spinal cord blood vessel may be involved, producing
cortical syndromes or myelopathy in isolation or in combination.
The clinical syndrome produced is distinct from that of thromboembolic
stroke both in presentation and time course. Patients often have prodromal
symptoms of headache, personality change, or emotional lability.
The vascular occlusive syndrome is superimposed and, as is typical
for a vasculitis, progresses over hours or days rather than occurring
suddenly (see Table 20–1).
++
Increased white blood cell count in the CSF is uniformly seen.
A positive CSF VDRL serologic result establishes the diagnosis.
Neuroradiologic imaging most often shows involvement of the deep
penetrating branches of the middle cerebral artery supplying the
central white matter, particularly the white matter in the lenticulostriate
distribution (see Figure 20–2A). Angiography shows concentric
constriction of medium-caliber vessels (see Figure 20–2B).
The angiographic features can be seen in a vascular bed prior to
clinical symptoms (eg, cerebral arteritis in a patient being evaluated
for a spinal presentation).
++
++
Parenchymal involvement of the brain by the spirochete produces
a dementing syndrome (general paresis or dementia paralytica). This
evolution occurs within 3–30 years after the primary infection,
with a peak incidence between 10 and 20 years (see Figure 20–1).
There is a male predominance. The clinical symptoms are notoriously
nonspecific, being those of any organic brain syndrome (see Table
20–3). The classic features of psychosis with grandiose
delusional states were uncommon even in the prepenicillin era.
++
++
Features useful in differentiating syphilitic dementia from other
causes of progressive dementia (in a patient with a reactive treponemal
serologic test) are the relatively early age of onset in syphilitic
dementia (most commonly between 30 and 50 years) and the fact that
untreated cases of syphilitic dementia are fatal within a few months
to a few years. Furthermore, the CSF is always abnormal in syphilitic
dementia, showing lymphocytic pleocytosis. The blood and CSF VDRL serologic
results are positive. Several instances of unilateral or bilateral
medial temporal lobe high-intensity magnetic resonance imaging T2
or fluid-attenuated inversion recovery imaging abnormalities, with
or without associated atrophy, have been reported in patients with
the mistaken diagnosis of herpes simplex encephalitis (see Figure
20–3). The high-intensity signals resolve with treatment,
but the presence of atrophy may predict a fixed cognitive deficit.
Seizures, including status epilepticus, may be the presenting manifestation
of parenchymal syphilis, again offering a presentation similar to
that of encephalitis.
++
++
Tabes dorsalis occurs within 5–50 years after a primary
syphilitic infection, with a peak incidence 10–20 years
after infection. This form of neurosyphilis in now uncommon. In
the prepenicillin era, a marked male predominance occurred. The
classic triad of symptoms—tabetic “lightning” pains,
sensory ataxia, and bladder disturbances—are combined with
a triad of signs—pupillary abnormalities, areflexia, and
the Romberg sign. Lightning pains (localized, transient, agonizing, shooting
pain, most often in the legs but affecting any body region) eventually
occur in 75–90% of patients.
++
Either vibration or position sense may be affected out of proportion
to the other. This proprioceptive sensory loss produces a wide-based
gait with impaired balance that is exacerbated by eye closure (the
Romberg sign). Whether the primary pathologic site is in the proximal
dorsal root segments within the root entry zone or in the dorsal
root ganglion remains an unresolved question.
++
Argyll-Robertson pupils are a characteristic finding but occur
in only half of patients with tabes dorsalis. These pupils constrict
to accommodation but not to light (the so-called light-near disassociation
phenomenon). The typical pupils are small and irregular, bilaterally,
but a host of other abnormalities can be seen. A lesion location
involving the midbrain tectum has been proposed to explain this
phenomenon. The differential diagnosis of these pupils includes
diabetic autonomic neuropathy (pseudo tabes) and pineal region tumors
or other lesions of the midbrain tectum.
++
The sensory impairment also results in the phenomenon of Charcot
joints and distal ulcers. These phenomena and lightning pains may
persist despite treatment.
+++
Altered or Atypical Neurosyphilis
++
Modified or atypical presentations of the classic clinical syndromes
of neurosyphilis have been suggested to be common in the antibiotic
era, particularly in HIV-coinfected patients. Several series of
patients confirm the classic spectrum of clinical presentations
of neurosyphilis, in the setting of HIV although tabes dorsalis
is now rare. In one series, no marked differences in clinical patterns
were noted in 518 syphilis patients seen at the same hospital in
1930–1940 compared with 121 syphilis patients seen during
1970–1984. An increase in the number of cases of asymptomatic
syphilis in the latter time period was attributed to the availability
of more refined treponemal-specific tests. Another series, which
compared neurosyphilis patients with and without HIV coinfection,
found no clinical or serologic differences among patients, and a
postmortem study concurred.
++
The serologic response to treatment does not markedly differ
in early syphilis patients with or without HIV coinfection. In CSF,
normalization of pleocytosis (the marker of disease activity) does
not differ in patients with or without HIV coinfection, although
normalization of CSF VDRL results and protein concentration may
be impeded in HIV patients. The significance of such serofast states
in immunocompromised HIV-coinfected patients is uncertain.
Flood JM, Weinstock HS, Guroy ME, et al. Neurosyphilis
during the AIDS epidemic, San Francisco, 1985–1992.
J Infect Dis 1998;177;931–940.
[PubMed: 9534965]
(Large and most recent retrospective report of
117 neurosyphilis patients from San Francisco hospitals during 1985–1992;
meningitis was the most common presentation, followed by vascular
syphilis.)
Marra CM. Neurosyphilis.
Curr Neurol
Neurosci Rep 2004; 4:435–440.
[PubMed: 15509443]
(A
recent review focusing on the problems of diagnosis and treatment
in patients with HIV coinfection.)
O’Donnell JA, Emery CL. Neurosyphilis: A current review.
Curr Infect Dis Rep 2005;7:277–284.
[PubMed: 15963329]
(A recent, comprehensive review of diagnosis
and treatment of patients with and without HIV coinfection.)
Timmermans M, Carr J. Neurosyphilis in the modern era.
J Neuro Neurosurg Psychiatry 2004;75:1727–1730.
[PubMed: 15548491]
(Discusses the spectrum of neurosyphilis in the
postantibiotic era, including use of positive CSF FTA-ABS results
in the setting of nonreactive VDRL to make the diagnosis.)
Wolters
EC. Neurosyphilis: A changing diagnostic problem? Eur
Neurol 1987;26:23–28.
[PubMed: 3545845]
(Classic
article comparing neurosyphilis presentation in the preantibiotic
era [518 patients] with presentation during the
antibiotic era [121 patients] at the same hospital.)