- Email: [email protected]
Neurosyphilis
15 Neurosyphilis Virtually every general discussion dealing with neurosyphilis at any length opens with remarks confirming the ability of the disease to imitate other disturbances in the central nervous system in nearly every category. It is a useful literary gambit that has the added advantage of being true. These sentiments can be traced directly back to meticulous work at the bedside carried out by Jonathan Hutchinson, Alfred Fournier, and many other great clinicians of the 19th century, and, while we are cautioned properly by Evan Thomas’ to accept some of their sweeping assertations only with reservations, it is nevertheless a fact that no single disease has been responsible for so many different pathologic reactions in the brain and spinal cord as has syphilis. The purpose of this section is to outline briefly the clinical features of the various types of neurosyphilis and to consider the modifications in these states as they are seen in present-day practice. Current treatment recommendations are also given, and the controversies concerning the use and interpretation of serologic and other laboratory tests on blood and cerebrospinal fluid in the management of the disease are described. Because the course of the disease in the central nervous system does not lend itself readily to staging, and the clinical forms commonly overlap and interdigitate, classifications of neurosyphilis are uniformly unsatisfactory to the more compulsive minds of medicine. Nevertheless, the scheme developed by Merritt, Adams, and Solomon,2y3 and adopted here, is practical and serviceable. It is shown in Table 15-1. Clinical Varieties of Neurosyphilis The clinical varieties of neurosyphilis3-7 time are summarized here.
reviewed
from time to
Asymptomatic Neurosyphilis It has been known since the pioneering efforts of Paul Ravaut,* in 1903, that the CSF is abnormal in a significant number of patients with untreated early syphilis, even in the absence of signs and symptoms referable to the nervous system. Ravaut’s findings were 128
Jan-Mar 1984 Volume 2 Number 1
TABLE
NeurosvDhilis
129
15-1. Classification of Neurosyphilis*
Group
Asymptomatic
lit
Meningeal and Vascular
IIW
Parenchymatous
‘Adopted toverlap
Involvement
Type
I
Abnormalities in the cerebrospinal attributable to syphilis.
fluid (CSF) with no signs or symptoms
Cerebral meningeal 1. Diffuse: Increased intracranial pressure and cranial nerve palsies. 2. Focal (gummatous): Increased intracranial pressure. Focal cerebral symptoms and signs, slow in onset. Cerebral vascular Focal cerebral symptoms and signs, sudden in onset. Spinal meningeal and vascular Paresthesia?,, weakness, atrophy, and sensory loss in the extremities and trunk. Neurons and axons degenerate General paresis (paresis). Tabes dorsalis. Optic atrophy.
from Merritt, Adams, and Solomon.*J of groups II and III is not uncommon.
confirmed and expanded in the 1920s and 1930s in the intensive investigations of J. Earl Moore,gr*” who placed the concept of asymptomatic neurosyphilis on a modern footing and demonstrated spinal fluid changes in untreated primary and secondary cases in more than 28% of cases. Stokes, Beerman, and Ingraham” set the upper and lower limits in literature reviews at 23 and 56%. Asymptomatic neurosyphilis is defined at present as syphilis showing abnormalities in the CSF attributable to infection with T. pallidum, but no clinical symptoms or abnormal signs on detailed neurologic examination. Signs of syphilis in other organ systems may or may not be present. It is assumed that the central nervous system is involved along with all other organ systems in the explosive hematogenous spread of the causative organism following inoculation. Evidence in support of this thesis is to be found in the recent study of Rosenhall and Roupe.1” Using auditory electrical response analysis, these investigatorsdemonstrated subclinical brain stem lesions in 6 of 11 cases of secondary and latent syphilis. That the great majority of CNS infections are self-limiting is evident in the
Gjestland-Bruusgaard study,‘3 proportion of cases of untreated eventually resulted in clinical was shown to be 9.4% for men women.
in which the syphilis that neurosyphilis and 5.0% for
Meningeal and Vascular Syphilis Cerebral meningeal neurosyphilis. In its diffuse form, cerebral meningeal syphilis is an early manifestation of the disease, the great majority of cases occurring within the first year of infection. In 10% of cases, signs of secondary syphilis are also present. Signs and symptoms result from interference with CSF circulation (hydrocephalus), damage to cranial nerves (palsies), and thrombosis of small cortical vessels as a result of specific meningeal inflammation. Headache, stiff neck, and fever are commonly present. Cranial nerve palsies, which are usually multiple, occur in 40% of cases, and the paralysis is transient in most instances. Cranial nerves III, VI, VII, and VIII are favored sites. Papilledema is common. Pupillary changes are also common. The pupils are usually small, unequal, and react sluggishly to light. The true Argyll-Robertson
130
Clinics in
Crissev and Denenholz
pupil (see tabes dorsalis) may occasionally be seen. In a few cases, aphasia and hemiplegia can occur, indicating vessel damage in the cortex, but these signs are usually transient. CSF pressure is usually increased. Slight to moderate increases in cell counts (mostly lymphocytes) are noted; protein levels are increased, and serologic tests are usually positive. Serologic tests on blood are virtually always positive at this stage. It is on the basis of these serologic tests and the accompanying signs of secondary syphilis (when present) that the condition is differentiated from the many other forms of acute and subacute meningitis which it obviously resembles. Focal cerebral meningeal syphilis is manifested by gumma formation, and is extremely rare. The lesion commonly takes its origin in the pia mater and, in growing, steadily compresses and invades the brain substance to produce symptoms identical to those associated with other enlarging tumors. Although CSF and blood serologic tests are positive in a very high proportion of these cases, the diagnosis cannot be made with certainty except by biopsy; neoplasms of the brain can and do occur in the presence of neurosyphilis. In any event, gummata of the brain often respond poorly to antisyphilitic treatment, and surgical intervention is advisable from this standpoint as well. Cerebrovascular syphilis. Included here are those cases of neurosyphilis characterized pathologically by endarteritis and thrombosis of cerebral vessels to produce a variety of focal neurologic signs, particularly hemiplegia and aphasia. The interval between initial infection and onset of the cerebrovascular signs varies considerably, the average being 7 years. The signs and symptoms resemble closely those produced by arteriosclerotic thrombotic disease and vary with the vessels involved. Motor paralysis and speech disturbances are present in a high percentage of cases. Manifestations of meningeal syphilis are sometimes also seen. The disease can be suspected when the patient is unusually young for %troke” and shows serologic evidence of syphilis in the blood and
Dermatoloav
CSF. But even in these instances, concomitant arteriosclerosis is a far more common cause of the problem, and work-up and treatment for arteriosclerosis should be included along with the treatment for syphilis. Spinal meningeal and vascular syphilis, Syphilis of the spinal cord other than tabes dorsalis was rare even when the incidence of syphilis in the general population was high. The signs and symptoms are varied enough to make classification into specific syndromes difficult. When the leptomeninges are the seat of the disease, destructive changes are seen in the nerve roots and marginal areas of the cord. Various combinations of pain, paresthesia, spastic weakness of the legs, muscular atrophy, sensory loss, and sphincter disturbances occur. Erb’s spastic paraplegia is one of the better known entities included in this group. Syphilitic thrombosis of the nutrient vessels to the cord can result in partial or complete transverse myelitis, while gummata of the cord simulate expanding lesions of the neoplastic type. Inflammation and thickening of the dura mater of the cord (syphilitic pachymeningitis) usually affects the cervical area to produce root pain, muscular wasting, sensory loss, diminished tendon reflexes, and eventually spastic paraplegia with sensory loss below the level of the lesion. CSF changes in all these conditions are similar to those found in cerebral meningeal and vascular syphilis. Parenchymatous
Neurosyphilis
Paresis (general paresis, general paralysis of the insane). Paresis is a syphilitic meningoencephalitis manifested by diffuse, nonfocal signs of cerebral disorder, especially psychosis and dementia, attributable to a widespread atrophy of the cerebral cortex which is most severe in the frontal lobes and diminishes in intensity toward the posterior poles. In earlier days it was among the most common conditions responsible for admissions to mental institutions; such is no longer the case, and yet the disease still occurs, and because failure to recognize it promptly results in irreversible damage to the patient,
Jan-Mar 1984 Volume 2 Number 1
Neurosyphilis
it is important to include a searchfor syphilis in the investigation of every patient showing signs of mental disturbance. The incidence of
paresis among untreated cases of syphilis in the Bruusgaard-Gjestland studyI was 3.0% for men, 1.7% for women. Caucasians are more susceptible than blacks, and the disease usually begins 10 to 15 years after the initial infection. The onset may be acute, but more often is insidious and marked by changes in the behavior and personality of the patient. Inability to concentrate, irritability, memory impairment, complaints of headache are features often noted early. As the disease progresses, judgment falters, insight disappears, confusion and disorientation become more marked, and slovenliness in dress and behavior become evident. Melancholia may occur, but euphoria is more characteristic, sometimes accompanied bydelusionsof grandeur. Syphilologists in earlier days often had collections of million dollar checks written for them by these patients. There is, as WillcoxG has pointed out, some truth in the aphorism that everyone in contact with the paretic suffers but the patient himself. Tantrums, paranoia, and violent outbursts can occur, however, along with excesses in sexual activity and in the use of alcohol. Tremors of the lips, tongue, and hands are signs commonly noted in the early stages. Speech becomes impaired; “Methodist Episcopal” remains a useful little test for this, and handwriting deteriorates steadily. Seizures of all types are seen: grand mal, petit mal, and Jacksonian. Tendon reflexes tend to be accentuated, and transient monoplegias and hemiplegias occur. Irregular pupils, often small, unequal, and poorly reactive to light, are observed more often in paresis than the Argyll-Robertson pupil, the latter being more characteristic of tabes dorsalis (see page 132). Untreated, the course is steadily downhill, with progressive mental deterioration. The patient eventually becomes bedridden, totally uncommunicative, incontinent of urine and feces, and prone to decubitus and intercurrent infections of all types. Death occurs in 1
131
to 3 or 4 years, usually after repeated convulsions, or from pneumonia or some other intercurrent infection. A useful mnemonic device for the clinical picture of paresis has been passed along by Holmesl4: Personality, Affect, Reflexes (hyperactive), Eye changes, Sensorium (illusions, delusions, etc.), Intellect (deterioration), Speech (dysarthria). Concomitant signs and symptoms of tabes dorsalis occur in a number of cases (taboparesis), and syphilitic cardiovascular disease is not uncommon in association with paresis. Paresis differs from other forms of neurosyphilis in that the neurons themselves are heavily involved along with the blood vessels and meninges.15 At autopsy, the brain is shrunken and reduced in weight; the leptomeninges are thickened, pale bluish-white, and adherent to the underlying cortex, which is clearly atrophic. These changes, in association with a finely granular appearance of the lining of the fourth ventrical, are characteristic of the disease. The whole ventricular system is dilated, often markedly so. On the microscopic level, there are lymphocytes and plasma cells in the pia-arachnoid. The blood vessels in the cortex are surrounded by cuffs of these cells and exhibit internal and adventitial thickening. The normal laminar disposition of the nerve cells is disrupted, and many of the neurons have disappeared, while those that remain are often jumbled together in an irregular fashion. There is a considerable proliferation of astrocytes and an associated increase in the amount of neuroglial fiber formation, especially in the outer lamina of the cortex. Hortega cells, containing iron pigment and assuming the “rod cell” configuration, are characteristic. Silver stains will show the presence of T. pallidum in most untreated cases. A part of the pathogenesis may be attributable to problems in blood supply arising from the endarteritis, but it is not unreasonable to postulate direct destruction of the neurons themselves as a result of the T. pallidum parasitic cellular attachment phenomenon described in Chapter 3.
132
Crissev
and Denenholz
The serum VDRL is usually positive; the FTA-ABS is reactive in 95+% of cases. Both treponemal and non-treponemal CSF tests are also reactive in the great majority of cases. Controversies regarding the significance of these tests are considered on pages 134-136. Cell counts and protein levels in the CSF are regularly elevated. Tabes dorsalis (locomotor ataxia). Tabes dorsalis is an infection of the nervous system by T. pallidurn, characterized pathologically by shrinkage of the posterior roots and posterior columns of the spinal cord, and clinically by incoordination, sensory and trophic disturbances, and involvement of the special senses, particularly the eyes. Once common, the disease is now rare; the incidence of tabes dorsalis in untreated syphilis was set in the Bruusgaard-Gjestlandls figures at 2.5% in men and 1.4% in women. As in all forms of neurosyphilis, Caucasians are affected more often than blacks. The disease usually begins 10 to 20 years after the initial infection, sometimes much later. The principle signs and symptoms of tabes dorsalis are ataxia, areflexia, paresthesias, bladder and eye disturbances, impotency, and pain. The onset is insidious, marked by stumbling and difficulty in walking, especially in the dark, when loss of position sense cannot be adequately compensated for by visual orientation. As the disease progresses, this sensory ataxia becomes more marked. The patient assumes a broad based gait, toes pointed outward, tends to slap the feet on the floor as if for reassurance, and rounds turns with considerable difficulty. Paresthesias appear early, especially in the lower extremities and, in 75% of the cases, are soon joined by “lightning” pains. The latter are sharp jabs of pain, mild to excruciating, and worse in wet weather. They are most common in the feet and legs, but no region is exempt, and they frequently “flit” from one area to another. Girdle sensations are common. Visceral pain, the periodic “gastric”or abdominal “crisis” characteristic of tabes dorsalis, usually begins suddenly with abdominal pain that is often severe enough to be mistaken for
Clinics in Dermatoloav
an acute surgical abdomen, especially when accompanied by nausea and vomiting, as is sometimes the ease. Impotence in men is common, and may be the chief complaint. Visual failure from a concomitant optic atrophy is also common. Urinary retention, delay, or imperfect control occurs in about one-third of the cases, while hearing loss, rectal incontinence, ptosis, and diplopia are less common, but well recognized symptoms. The signs of tabes dorsalis include loss of tendon reflexes in the lower extremities, which occurs in 80 to 90% of cases, and pupillary changes, which are equally common. The classic Argyll-Robertson pupil of tabes dorsalis is bilateral and fixed in its reaction to light, usually at a diameter of approximately 3 mm, and yet continues to react readily in accommodation for near objects. It is not wholly pathognomonic for tabes, however, nor is it even the most common pupillary disturbance seen in the condition. Unequal, irregular pupils that react poorly to light, and sometimes to accommodation as well, are more often encountered. Various ophthalmoplegias may be seen, and cervical sympathetic involvement may result in drooping of the eyelids, with compensatory wrinklingof the brow - the characteristic “tabetic facies” of Hutchinson. Optic atrophy can occur. Objective ataxia with abnormalities in the gait add to the picture. In these cases, Romberg’s sign (unsteadiness or falling when the feet are placed close together and the eyes closed) is usually positive, and the heel-knee test is poorly performed. In advanced cases trophic destructive changes in joints, especially in the lower extremities, lead to a painless arthritis in which the joint becomes enlarged and grossly disorganized and is subject to abnormal movements, hyperextensibility, and the like. Known as Charcot’s joints (Fig. 15-l), these diseased articulations may eventually become incapable of supporting any weight at all. They are not restricted to tabes dorsalis, however, and are sometimes seen in syringomyelia and a number of other neurologic disturbances. Perforating ulcers of the toes and soles (ma1
Jan-Mar 19i3A Volume 2 Number 1
Neurosyphilis
perforans) can also occur in tabes dorsalis (Fig. 15-2). From the classic description of the disease by Romberg at the midpoint of the 19th century onward, investigators have struggled to develop some unifying theory that would explain the peculiarly disparate group of features combined in the full-blown case of tabes dorsalis. The results of many investigations place the seat of the disease in the dorsal root ganglia, where the treponeme probably damages the posterior roots at the point at which they penetrate the pial membrane. It is here that the neurilemmal sheaths cease, and the myelinated fibers are presumed to be more vulnerable. A good many of the signs and symptoms are, of course, easily traced to the loss of pain perception and proprioception that follows destruction of the dorsal roots (Fig. 15-3). The lesion responsible for the Argyll-Robertson pupil has been placed in the mesencephalon.16 Schwarz’T has reviewed the various theories on the pathogenesis of tabes dorsalis and points out that the continued inability of investigators to reproduce the disorder experimentally and the diminishing frequency of the disease have combined to reduce the chances that solutions to the many mysteries connected with it will be found in the near future. The diagnosis is usually made on the basis of symptoms of lightning pains, ataxia, and urinary difficulty associated with pupillary disturbances, areflexia, neurologic signs of proprioception deficit, reactive blood serologic tests, and abnormalities in the spinal fluid. Non-treponemal tests on blood will be negative in many cases, perhaps one-third; treponemal tests should always be done and will be positive some 95% of the time. Early in the disease, cell counts in the cerebrospinal fluid are elevated (as high as 50/pm) and protein levels up to 100 mg/dl are seen. Nontreponemal tests on the cerebrospinal fluid are usually positive in active cases, but are often negative in those that have “burned out”: for practical purposes, false positives do not exist. It is probable that treponemal tests (the CSF-FTA) will be positive in a
133
FIG. 15-l. Tabesdorsalis. Charcotjoint. knee. Disorganization of the joint space with prominent soft tissue calcification.
much higher percentage of cases in all stages of activity but, as will be developed, the value of reactive CSF treponemal tests is dubious. Optic atrophy. Optic atrophy may occur in the absence of any other sign of neurosyphilis, but it is more commonly observed in association with tabes dorsalis or even general
134
Crissev and Denenholz
Clinics in Dermatoloav
FIG. 15-2. Tabes dorsalis. Trophic ulcers, toes (ma1 perforans).
paresis. In any event, it is rare. In the typical case the disease begins with constriction of the visual field in one eye, which progresses steadily until the central field is fully involved, and total blindness results. Involvement of the second eye begins months to years later and follows the same course. Total blindness supervenes within 10 years in most instances. Fundoscopic examination shows increasing pallor of the discs, which, in advanced cases, may be paper white. Margins are unaffected, but in late cases the center of the disc may exhibit a bluish, funnel-shaped, central depression. These clinical signs arise from typical syphilitic lymphocytic and plasma cell infiltrates in the pia around the optic nerve and an endarteritis of the nutrient blood vessels that penetrate the nerve in the intraneural septa. The VDRL-CSF test may or may not be positive, but in the absence of concomitant signs of tabes dorsalis, it is not possible to make a certain diagnosis of syphilitic optic atrophy without serologic confirmation.
Cerebrospinal Fluid in Neurosmhilis As noted earlier, the discovery ination of the CSF was a valuable
that examtool for the
FIG. 15-3. Tabes dorsalis. Spinal cord cross section at T5. Luxol-Fast blue stain for myelin. FascicuIus gracilis (arrows) shows absence of myelin staining where there has been axonal loss with secondary myelin loss. In more extensive cases, posterior columns can be entirely destroyed.
investigation and monitoring of neurosyphilis was made early in the century by Ravaut.8 Fordyce, Wile, Stokes, and J. E. Moore were instrumental in expanding on the theme and in transferring the European technology to North American centers.18 Moore, in particular, codified and popularized the division of CSF alterations into three groups on the basis of the intensity of the changes: Type I - pleocytosis, slight elevation in protein, negative non-treponemal and Lange colloidal gold tests. Test II - more marked pleocytosis, more elevated protein, negative or weakly reactive non-treponemal tests, and variable zone positive colloidal gold tests. Type III - (known for many years as the “red flag CSF”) - high cell counts, high protein levels, positive non-treponemal tests, and first zone or “paretic” colloidal gold patterns. This once-popular scheme has lost much of its usefulness in recent years, although it still appears in some texts in modified form. The
Jan-Mar 1984 Volume 2 Number 1
Neurosyphilis
Lange colloidal gold test, in particular, is an obsolete procedure, dependent on albumin/ globulin ratios better determined in other ways; it is without value, either as a diagnostic aid or as a guide to disease activity, and has been abandoned entirely in North America. Drawing on the Ravaut-Moore material, his own extensive experience at the WagnerJauregg clinic, and the work of many others, Bernhard DattneP of Vienna, was able, in the 193Os, to show convincingly that the CSF cell counts and protein levels were the most sensitive and reliable indicators of activity in neurosyphilis. In 1937 he joined the clinic of Evan Thomas at the Bellevue Hospital in New York City and, in 1942, in collaboration with Thomas, published an extremely influential report in which a set of guidelines was offered for the diagnosis and management of neurosyphilis in accordance with these principles.20 Known as the “DattnerThomas spinal fluid concept,” this set of guidelines was accepted by most of the profession for a generation, although even at its highest point of popularity, exceptions to parts of the general concept were noted and the oversimplification inherent in any such scheme was recognized. The essence of the Dattner-Thomas approach was this: Signs and symptoms of neurosyphilis are not reliable criteria of activity in a syphilitic process in the central nervous system, nor is a reactive CSF nontreponemal test necessarily proof of active disease. Elevated cell counts and total protein determinations are the hallmarks of activity; with the exception of an occasional case of “burned out” tabes dorsalis, neither is ever normal in untreated neurosyphilis. Successful treatment is followed by a return of cells to normal in two or three months; protein declines slowly to normal in 6 months or so, while non-treponemal CSF tests decline in titer, although they may never become negative. If relapse, as indicated by reversal in levels of cells and protein, has not occurred within 15 months after therapy, the patient can be presumed to be cured.2l There was, in addition to the acceptance of
135
these criteria, a great reluctance on the part of clinicians to make a diagnosis of neurosyphilis of the meningovascular or paretic varieties in the absence of a reactive nontreponemal CSF test, although exceptions were made again in clear-cut cases of “burned out’ tabes dorsalis. The result was that the approach to the diagnosis, treatment, and follow-up of neurosyphilis was understandable to everyone and reasonably well standardized. This consensus, this pax neurosyphilitica, lasted until the 1960s and 1970s when challenges to all elements of the doctrine on which it was based began to appear. They arose to a great extent from a willingness, particularly on the part of neurologists, to accept “modified” or “atypical” clinical presentations (considered below) as evidence of neurosyphilis, even in the absence of reactive CSF non-treponemal tests, elevated protein levels, or pleocytosis. The challenges also seemed to receive support from newer developments in serologic research. As in the blood, CSF tests for syphilis can be classified as treponemal and non-treponemal. The modification of the VDRL for measurement of reagin levels in the CSF (abbreviated here as the VDRLCSF) has now supplanted all other nontreponemal CSF tests. One of the few facts agreed upon by nearly all participants in the controversies currently evident in the world of neurosyphilis is that false positive VDRLCSF results are rare. The two apparently valid examples recently reported2”*“” are the exceptions that prove the rule. Estimates on the number of false negatives vary from 30% to more than 50%,24 although in the absence of absolute reference standards for a diagnosis of neurosyphilis, these numbers are essentially without meaning. Nevertheless, the fact that the non-treponemal CSF tests seemed to be negative, not only in burned out tabes dorsalis cases, but also in certain meningovascular presentations that mimicked syphilis and appeared to respond to penicillin treatment stimulated the search for CSF tests able to detect antibody directed against T. pallidurn itself. A beginning was made in 1960 with the development of the unabsorbed
136
Crissev and Denenholz
CSF treponemal antibody test (CSF-FTA) by Harris, Bossak, Deacon, and Bunch.25 A series of reports has since appeared26-33 in which absorbed and unabsorbed variants of the CSF-FTA were compared with the VDRL-CSF and with one another. In all of these studies the FTA tests on CSF were reactive in all stages of syphilis more often than the non-treponemal tests, and were also often reactive in the “atypical” forms of neurosyphilis being seen by neurologists. But the question of significance remains. Comparison of CSF serologic tests with one another without reference to clinical findings is an exercise in circular reasoning, and in those studies in which clinical correlation was attempted,26y33 the investigators were forced by the nature of the problem to assign arbitrary weights to those clinical findings sometimes attributable to neurosyphilis. On the latter, there can never be any universal agreement, and each investigator, therefore, has the power to alter the sensitivity and specificity estimates for treponemal CSF tests by expanding or restricting the clinical criteria utilized as reference standards. That, to say the least, is an uncertain road to truth. It is probable that many of the positive results in the studies cited are attributable to transfer of antibody from serum across the blood-brain barrier. This explanation is supported by the investigations of Jaffe and co-workers32 in which it was shown that CSF-FTA test reactivity appeared most likely when the titer of the serum FTA test was high. In the light of these uncertainties, the conclusions of Jaffe and co-workers seem justified: Without other supporting clinical or laboratory data, the diagnostic value of a reactive CSF-FTA test is unknown, and without such supporting data, tests of this type should not be used to diagnose neurosyphilis. The newly developed CSF treponemal tests based on microhemagglutination procedures23y34 35 appear to suffer from similar difficulties and will need further study before their usefulness can be evaluated.
Clinics in Dermatoloav
Attempts to circumvent the problems posed by the relative insensitivity of the VDRL-CSF and the false positive reactions in CSF treponemal tests in evaluating suspected cases of neurosyphilis are also to be found in recent studies describing... -the use of monospecific conjugates, antiIgG, IgM, and IgA in the performance of the CSF-FTA test.36 - the precise calculation of the concentrations of IgG, IgM, and IgA in CSF.37 - the identification of oligoclonal IgG in the CSF.38 - the correction of CSF treponemal test titers in accordance with the albumin quotient to exclude errors arising from disturbed function of the brain barrier.24 -the identification of active neurosyphilis by the presence of plasma cells in the CSF cytogram in combination with elevations and electrophoretic abnormalities in CSF IgG and associated increases in serum levels of IgM.39 All these developments are promising and may be called upon for diagnostic support in the future when tests based on them become routinely available. Clearly, what is needed is a simple reliable method for demonstrating the presence in the CSF of T. pallidurn itself, either by culture or animal inoculation.
Is Neurosyphilis Changing? Although Luxon and associates,40 in a 1979 study of neurosyphilis were unable to find any clinical presentations unknown in the pre-antibiotic era, a number of other observers41-46 are convinced that widespread use of antibiotics for other conditions in subcurative doses has resulted in the occurrence of “modified” or “atypical” forms of the disease. These formes frustes manifest themselves as bits or parts of the classical syndromes described above, most commonly as changes that fit best in the meningovascular or tabetic categories. Often the patient presents with a single sign or symptom,
Jan-Mar 1904 Volume 2 Number 1
TABLE
Neurosyphilis
137
15-2. Symptoms and signs of 241 patients with neurosyphilis’ Percent of patients
Symptoms Seizures Focal General Not specific Ophthalmic symptoms Stroke; confusion Dizziness Personality changes
*Source: Hooshmand
(poor vision, etc.)
24.2 4.2 10.0 10.0 11.6 11.1 7.9 2.0
Signs Reflex changes Absent ankle jerk Pupil changes Sensory abnormalities Chorioretinitis, retinitis pigmentosa Organic brain syndrome Babinski’s sign Depression Ptosis Optic atrophy Mania Personality changes
H, Escobar MR. Kopf SW. Neurosyphilis.
absent ankle jerks, or pupillary changes, or seizures, for example. Presenting signs and symptoms as noted in the 1972 study of 241 cases by Hooshmand, Escobar, and Kopf43 are shown in Table 15-2. Broadly similar results were reported by Joyce-Clarke and Molteno.44 In the 148 cases of neurosyphilis observed by the latter investigators, 85 were judged to represent modified formes frustes of the disease. That the incidence of the classical forms of neurosyphilis is falling everywhere there can be no doubt,47 and insofar as the modified or atypical cases fit the well accepted criteria for the diagnosis of symptomatic neurosyphilis-suspicious neurologic signs, a positive treponemal test in blood, and a positive VDRL-CSF test accompanied by elevated cells and protein levels-few would dispute their validity. But many cases do not; the diagnosis in a significant number has been made by inference, based on nothing more than a positive serum FTA-ABS test and perhaps a positive CSF-FTA test, along with new neurologic signs. The objections to this position have been reviewed by Jordan.481t is generally accepted that, with very few exceptions, a patient with a positive serum FTAABS test has or has had syphilis. Neurologic dysfunction appearing in such a patient may
Percent of patients 75.8 66.6 44.8 33.7 12.0 a.7 5.3 5.0 4.6 46 3.3 2.0
a study of 241 patients. JAMA 1972;219:726-9.
or may not have anything to do with T. pallidum, and in the absence of a reactive VDRLCSF test, there is no good way to distinguish between “modified” neurosyphilis and nonsyphilitic neurologic disease occurring in a patient with cured or latent syphilis. The CSF-FTA test cited as confirmatory evidence in some atypical case presentations, is not a reliable test for the disease (see page 136). while pleocytosis and elevated protein levels in the CSF are features common to many nonsyphilitic neurologic disturbances. Favorable response to penicillin treatment has also been offered as evidence that certain atypical presentations were, in fact, syphilitic, but in view of the spontaneous improvement or stabilization that often takes place in other neurologic diseases, postpenicillin improvement may in reality be an example of the post hoc propter hoc fallacy in action. And finally, poorest of all of the evidence cited on behalf of a syphilitic cause for some of the atypical presentations is the failure to find anything else to account for the clinical picture, as though all other derangements of the nervous system are known and readily reveal themselves ante-mortem. Disputes and difficulties in these matters will no doubt continue until, as noted earlier, some more specific and sensitive test for neu-
Crissey
138
Clinics in Dermatology
and Denenholz
rosyphilis appears, a routinely applicable culture or animal inoculation procedure, for example. Moreover, the consequences to the patient of failure to treat active syphilis of the central nervous system can be so severe that many physicians are likely to brush aside more rigid diagnostic criteria and treat the condition at hand in the spirit of the “therapeutic trial.” The matter is controversial, but many, including the authors of this monograph, consider the approach acceptable, providing the risks entailed are fully explained and the patient is also made aware that the decision has been based on hope for a favorable outcome rather than diagnostic certainty. When a therapeutic trial is undertaken, however, it is well to avoid drawing erroneous conclusions concerning the results. To regard (much less publish) atypical clinical neurologic presentations with negative VDRL-CSF tests as bona fide syphilitic treatment failures when they do not respond to antibiotics is not a defensible position.
Indications for Treatment as Neurosyphilis Absolute A reactive VDRL-CSF test in combination with elevation of the cell count above 5 cells/pm and total protein levels above 40 mg/dl, with or without neurologic signs or symptoms, constitutes an absolute indication to treat the case as neurosyphilis. Treponemal tests on serum are positive in 95+% of these cases, but Dewhurst has reported a 3.5% incidence of negative non-treponemal tests in serum in the presence of reactive non-treponemal tests in the CSF.4g Discretionary Neurologic signs or symptoms known to be associated sometimes with neurosyphilis, occurring in a patient with serum serologic evidence of syphilis, a reactive CSF treponemal test, but a negative VDRL-CSF test, constitutes a less than absolute indication for treatment as neurosyphilis. If CSF cell counts
and total protein levels are elevated or if the signs or symptoms appear to be progressive, it is better to treat in accordance with neurosyphilis regimens, but with the clear understanding that the neurologic disturbance may have nothing to do with syphilis. The CSF-FTA test or its hemagglutination counterpart, the CSF-TPHA test, should be reactive, however; a negative treponemal CSF test effect%vel,yexludes acti’ve neurosyphilis.24 In burned-out tabes dorsalis, CSF may be entirely normal, and serum non-treponemal tests may be negative. In these cases the serum treponemal tests are almost always positive. It is advisable, as a matter of public policy, to treat cases of this type, although response is usually nil. N.B.: All of the patients in the above categories are presumed to have or to have had syphilis, and unless documented evidence for adequate treatment is available, all should be treated for the disease. It is the choice of antibiotics, the method of administration, the dosage schedules, and the follow-up procedures that differ in treating the case as neurosyphilis rather than latent syphilis.
Neurosyphilis Treatment and Follow-up Schedules As in the case of the clinical criteria for the diagnosis of neurosyphilis and the interpretation of CSF laboratory findings, the treatment of syphilis of the central nervous system is a matter of some dispute. Potentially effective drug regimens recommended by the Centers for Disease Controls0 in 1982 are as follows: 1. Aqueous crystalline penicillin G: 12-24 million units, intravenously per day (2-4 million units every 4 hours) for 10 days, followed by benzathine penicillin G: 2.4 million units, intramuscularly (IM), weekly for 3 doses. OT
2. Aqueous procaine penicillin G: 2.4 million units, IM daily plus probenecid 500 mg, by mouth, 4 times a day, both for 10 days,
Jan-Mar 1984 Volume 2 Number 1
Neurosyphilis
followed by benzathine penicillin G: 2.4 million units, IM weekly for 3 doses. OY
Benzathine penicillin G: 2.4 million units, IM, weekly for 3 doses. These regimens are accompanied by a caveat that none has been adequately studied, and the following statement: 3.
Published studies show that a total dose of 6.0 to 9.0 million units of penicillin G over a 3- to 4-week period results in a satisfactory clinical response in approximately 90% of patients with neurosyphilis. This information must be considered along with the observation that regimens employing benzathine penicillin or procaine penicillin in doses under 2.4 million units daily do not consistently provide treponemicidal levels of penicillin in CSF, and with the knowledge that several case reports show the failure of such regimens to cure neurosyphilis. The literature on neurosyphilis treatment problems and the adequacy of CSF penicillin levels has been summarized to 1979 by Sparling.“’ He concluded from his survey that high dose. in hospital, intravenous penicillin for at least 10 days is the most conservative therapy acceptable for symptomatic neurosyphilis, while procaine penicillin given on an outpatient basis in daily intramuscular injections of 600,000 units for 15 days was acceptable for asymptomatic neurosyphilis. Since Sparling’s report, a number of studies52m5” have appeared casting further doubt on the ability of pencillin G benzathine injections to produce treponemicidal levels in the CNS. Ducas and Robsons go so far as to recommend abandonment of this form of penicillin as a first-line agent in the treatment of neurosyphilis. On the other hand, combinations of aqueous procaine penicillin G injections and oral probenecid appear to achieve adequate levels in the CNS.57 It therefore appears that regimens no. 1 and no. 2 recommended by the Centers for Disease Control are adequate and much to be preferred to regimen no. 3. Despite the doubts on the efficacy of penicillin G benzathine in the
139
treatment of neurosyphilis, its use in syphilis present less than one year seems to be accepted by nearly everyone, although clearly some of these patients already have asymptomatic neurosyphilis. It is to guard against CNS relapse in these cases that CSF examination at the end of one or two years is recommended after treatment for early syphilis. The question of what to do with patients with neurosyphilis who are allergic to penicillin is troublesome indeed, and wholly undecided. No antibiotic other than penicillin has been evaluated properly. Penicillinsensitive patients with neurosyphilis should have their allergy confirmed by skin test by personnel expert in the performance of that sometimes dangerous procedure. The successes reported by Onoda in the treatment of all stages of syphilis with doxycycline,5b and the demonstrated ability of that antibiotic to achieve concentrations in the brain far higher than its parent drug, tetracycline,j9 have encouraged Hotson to recommend it in the treatment of neurosyphilis in patients with confirmed penicillin allergies. He suggests 300 mg of doxycycline a day, given orally in divided doses for 30 days. The Jarisch-Herxheimer reaction, as it occurs in neurosyphilis, is described in Chapter 12. The lightning pains of tabes dorsalis sometimes respond to diphenylhydantoin or carbamazepine. Intractable cases may require cordotomy. Gastric crises can usually be controlled by intravenous fluids, barbiturates, or phenothiazines. However roughly the diagnostic aspects of the “Dattner-Thomas spinal fluid concept” have been treated in recent years, there is no doubt it provides the most reliable approach to monitoring treatment response in ordinary cases of neurosyphilis. Lumbar puncture should be performed 6 weeks after completion of treatment and again 3 months later. Cell counts should fall steadily to normal in three months. Elevated protein levels respond a little more slowly , reaching normal in 3 to 6 months. VDRL titers usually fall, but may never become negative. Failure of cells or protein to return to normal, or
Clinics in 140
Crissey and Denenholz
reversal in their downward trend, constitutes an indication for retreatment. Persistent abnormalities require repeat CSF examination at intervals of a year or two. Treatment failure of course means that sufficient numbers of virulent treponemes were not killed or inactivated to permit the immune system to tip the balance in favor of the host; failure in this respect no doubt also accounts for the observations that viable organisms have been observed in the CNS and eyes of patients with syphilis long after completion of intensive antibiotic treatment. A large literature dealing with this phenomenon appeared in the late 1960s and early 197Os, reviewed to 1972 by Dunlop.60 Tramont reported two more examples in 1976,6l but the subject has not generated much interest recently, partly because of doubts raised concerning some of the observations,@ and partly perhaps because no one knows quite what to make of it.
Prognosis Treatment cannot replace structure already destroyed, and results can be discouraging, especially in general paresis, which seems to progress in a good many cases even when therapy has been intensive.63 Nevertheless, a surprising amount of recovery of function can take place in most forms of neurosyphilis, and lack of prospects for significant improvement should not be a contraindication to treat. Drug Names carbamazepine: Tegretol diphenylhydantoin: Dilantin doxycycline: Vibramycin References 1. Thomas EW. Some aspects of neurosyphilis. Med Clin North Am. 1965;48:699-705. 2. Merritt HH. Adams RD. Solomon HC. Neuro-
Dermatology
syphilis. 1946.
New York: Oxford University
Press,
3. Merritt HH. Textbook of neurology. 6th ed. Philadelphia: Lea & Febiger, 1979:135. 4. King A, Nicol C. Rodin P. Venereal diseases. 4th ed. London: Baillikre Tindall, 1980: 81-103. 5. Gilroy J. Meyer JS. Medical neurology. New York: Macmillan, 1979:4X-77.
3rd ed.
6. Willcox RR. Textbook of venereal diseases and treponematoses. 2nd ed. Springfield, IL: Charles C Thomas, 1964:213-29. 7. Catterall RD. Neurosyphilis. 1977;17:585-604.
Br J Hosp Med.
8. Ravaut P. Le liquide kephalo-rachidien des syphilitiques en pkriode secondaire. Ann Dermatol Syphilig. 1903;4:537-54. 9. Moore JE. Studies in asymptomatic neurosyphilis. II. the classification, treatment, and prognosis of early asymptomatic neurosyphilis. Bull Johns Hopkins Hosp. 1922;33:231-46. 10. Moore JE, Hopkins HH. Asymptomatic neurosyphilis. VI. the prognosis of early and late neurosyphilis. JAMA. 1930;95:1637-41. 11. Stokes JH, Beerman H. Ingraham NR. Modern clinical syphilology. 3rd ed. Philadelphia: W.B. Saunders, 1945:608-9. 12. Rosenhall responses 57:241-5.
U, Roupe G. Auditory brain-stem in syphilis. Br J Vener Dis. 1981;
13. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis. Med Clin North Am. 1964:48:613-23. 14. Holmes KK. Syphilis. In: Isselbacher KJ, et al., eds. Harrison’s principles of internal medicine. 9th ed. New York: McGraw-Hill, 1980: 716-26. 15. McMenemey WH, Smith WT. Syphilis of the nervous system. In: Symmers W. Systemic pathology Vol. 5.2nd ed. Edinburgh: Churchill Livingstone. 1979:2118-25. 4th 16. DeJong RN. The neurologic examination. ed. Hagerstown, MD: Harner and Row. 1979: 133-4. 17. Schwarz GA. Neurosyphilis. In: Goldensohn ES, Appel SH. eds. Scientific approaches to clinical neurology. Vol. 1. Philadelphia: Lea & Febiger. 1977:482-97. 18. Moore JE. The genesis of neurosyphilis. Dermatol Syphilol. 1921:4:55-61.
Arch
19. Dattner B. Die moderne Therapie der Neurosyphilis. Vienna: Wilhelm Maudrich, 1933.
Jan-Mar 1984 Volume 2 Number 1
20. Dattner
Neurosyphilis
B, Thomas EW. The management
neurosyphilis. 1942;26:21-31. 21. Thomas
agement.
Am J Syph Gonor Vener
of Dis.
EW. Syphilis, its course and manNew York: MacMillan, 1949:237-41.
141
35. Luger A, Schmidt B, Spendlingwimmer I. Horn F. Recent observations on the serology of syphilis. Br J Vener Dis. 1980:56:12-6. 36. Le Clerc
G, Giroux M, Birry A, Kasatiya S. Study of fluorescent treponemal antibody test on cerebrospinal fluid using monospecific anti-immunoglobulin conjugates IgG. IgM, and IgA. Br J Vener Dis. 1978:54:303-8.
22. Delaney
P. False positive serology in spinal fluid associated with a spinal cord tumor. Neurology 1976;26:591-3.
23. Madiedo
37. Gibowski M, Machonko T. Immunoglobulins in the cerebrospinal fluid of patients with late syphilis. Br J Vener Dis. 1981;57:20-4.
24. Luger
intrathecal 38. Vartdal F, et al. Neurosyphilis: synthesis of oligoclonal antibodies to Treponema pallidurn. Ann Neurol. 1982;11:35-40.
G, Ho KC, Walsh P. False-positive VDRLand FTA in cerebrospinal fluid. JAMA. 1980;244:688-9.
A, Schmidt BL, Steyrer K, Schonwald E. Diagnosis of neurosyphilis by examination of the cerebrospinal fluid. Br J Vener Dis. 1981;57:232-7.
39. Kolar
OJ, Burkhart JE. Neurosyphilis. Vener Dis. 1977;53:221-5.
25. Harris
A, Bossak HM, Deacon WE, Bunch WL Jr. Comparison of the fluorescent treponemal antibody test with other tests for syphilis on cerebrospinal fluids. Br J Vener Dis. 1960;36:178-80.
26. Escobar
MR. Dalton HP, Allison MJ. Fluorescent antibody tests for syphilis using cerebrospinal fluid: clinical correlation in 150 cases. Am J Clin Pathol. 1970;53:886-90.
27. Garner
MF, Backhouse JL. Fluorescent onemal antibody tests on cerebrospinal Br J Vener Dis. 1971;47:356-8.
trepfluid.
28. Duncan
WP, Jenkins TW, Parham CE. Fluorescent treponemal antibody-cerebrospinal fluid (FTA-CSF) test. Br J Vener Dis. 1972;48:97-101.
40. Luxon L. Lees AJ, Greenwood
ilis today. Lancet
30. Mahony
JOH, Harris JRW, Sydney-McCann J. et al. Evaluation of the CSF-FTA-ABS test in latent and tertiary treated syphilis. Acta Derm Venereol (Stockh). 1972:52:71-4.
31. Wilkinson
AE. Fluorescent body tests on cerebrospinal Dis. 1973:49:346-g.
treponemal antifluid. Br J Vener
RJ. Neurosyph-
1979;1:90-3.
41. Kofman 0. The changing
pattern of neurosyphilis. Can Med Assoc J. 1956:74:807-12.
42. Joffe R, Black MM, Floyd M. Changing
clinical picture of neurosyphilis: report of seven unusual cases. Br Med J. 1968:1:211-2.
43. Hooshmand
F, Escobar MR. Kopf SW. Neurosyphilis, a study of 241 patients. JAMA. 1972; 219:726-g.
44. Joyce-Clarke
N, Molten0 ACB. Modified neurosyphilis in the Cape Peninsula. S Afr Med J. 1978;53:10-4.
45. Editorial.
Modified 1978;2:647-8.
29. Kasatiya
SS. Caloenescu M, Birry A. Automated fluorescent treponemal antibody (AFTA) test for cerebrosninal fluids in the diagnosis of neurosyphilis.ACan J Pub Health. 1972;63:447-52.
Br J
neurosyphilis.
Br Med J.
46. Hotson JR. Modern
treated chronic 1981;135:191-200. 47. Heathfield
Practitioner.
neurosyphilis: a partially meningitis. West J Med.
KWG. The decline 1976;217:753-62.
48. Jordan
K. More on neurosyphilis. 1982;136: 106-67.
49.
of neurolues. West J Med.
Dewhurst K. The composition of the cerebrospinal fluid in the neurosyphilitic psychases. Acta Neural Stand. 1969;45:119-23.
32. Jaffe HW, Larsen
50. Sexually transmitted diseases treatmentguidelines,1982. MMWR 1982;31:51s.
33. McGeeney
51. Sparling PF. Current problems in sexually transmitted diseases. In: Stollerman GH. ed. Advances in internal medicine. Chicago: Year Book Medical Publishers, 1979;24:203-28.
34. Kasatiya
52. Greene BM. Miller NR. Bvnum TE. Failure of penicillin G benzathine in the treatment of neurosyphilis. Arch Intern Med. 1980:140: 1117-8.
SA, Peters M, et al. Tests for treponemal antibody in CSF. Arch Intern Med. 1978;138:252-5. T, Yount F, Hinthorn DR, Liu C. Utility of the FTA-ABS test of cerebrospinal fluid in the diagnosis of neurosyphilis. Sex Transm Dis. 1979:6:195-8. S, Birry A. Further evaluation of the microhaemagglutination test to determine treponemal antibodies in CSF. Br J Vener Dis. 1980;56:77-80.
53. Polnikorn
N, et al. Penicillin
concentrations
in
Crissev and Denenholz
142
cerebrospinal fluid after different treatment regimens for syphilis. Br J Vener Dis. 1980; 56:363-7. 54. Ducas J, Robson HG. Cerebrospinal
cillin levels during therapy JAMA. 1981;246:2583-4. 55.
Clinics in Dermatolwv
Rein MF. Treatment JAMA. 1981;246:2613.
fluid penifor latent syphilis.
of neurosyphilis.
56. Polnikorn
N, et al. Penicillin concentrations in the cerebrospinal fluid after benzathine penicillin and probenecid in the treatment of syphilis. Br J Vener Dis. 1982;58:342.
57. Dunlop EMC, Al-egaily
SS, Houang ET. Production of treponemicidal concentration of penicillin in cerebrospinal fluid. Br Med J. 1981;283:646.
58. Onoda
Y. Therapeutic
effect of oral doxycy-
cline on syphilis. 55:110-5.
Br J Vener
Dis.
1979;
59. Barza M, et al. Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs. Antimicrob Agents Chemother. 1975;8:713-20. 60. Dunlop EMC. Persistence of treponemes treatment. Br Med J. 1972;2:577-80. 61. Tramont EC. Persistence dum following penicillin 1976;236:2206-7.
after
of Treponema palliG therapy. JAMA.
62. Wither K, Wither V. Immunopathology of syphilis. In: Schell RF, Musher DM, eds. Pathogenesis and immunology of treponemal infection. New York: Marcel Dekker, 1983:139-59. 63. Wilner E, Brody JA. Prognosis of general paresisafter treatment. Lancet. 1968$:1370-l.
reviewed
from time to
Asymptomatic Neurosyphilis It has been known since the pioneering efforts of Paul Ravaut,* in 1903, that the CSF is abnormal in a significant number of patients with untreated early syphilis, even in the absence of signs and symptoms referable to the nervous system. Ravaut’s findings were 128
Jan-Mar 1984 Volume 2 Number 1
TABLE
NeurosvDhilis
129
15-1. Classification of Neurosyphilis*
Group
Asymptomatic
lit
Meningeal and Vascular
IIW
Parenchymatous
‘Adopted toverlap
Involvement
Type
I
Abnormalities in the cerebrospinal attributable to syphilis.
fluid (CSF) with no signs or symptoms
Cerebral meningeal 1. Diffuse: Increased intracranial pressure and cranial nerve palsies. 2. Focal (gummatous): Increased intracranial pressure. Focal cerebral symptoms and signs, slow in onset. Cerebral vascular Focal cerebral symptoms and signs, sudden in onset. Spinal meningeal and vascular Paresthesia?,, weakness, atrophy, and sensory loss in the extremities and trunk. Neurons and axons degenerate General paresis (paresis). Tabes dorsalis. Optic atrophy.
from Merritt, Adams, and Solomon.*J of groups II and III is not uncommon.
confirmed and expanded in the 1920s and 1930s in the intensive investigations of J. Earl Moore,gr*” who placed the concept of asymptomatic neurosyphilis on a modern footing and demonstrated spinal fluid changes in untreated primary and secondary cases in more than 28% of cases. Stokes, Beerman, and Ingraham” set the upper and lower limits in literature reviews at 23 and 56%. Asymptomatic neurosyphilis is defined at present as syphilis showing abnormalities in the CSF attributable to infection with T. pallidum, but no clinical symptoms or abnormal signs on detailed neurologic examination. Signs of syphilis in other organ systems may or may not be present. It is assumed that the central nervous system is involved along with all other organ systems in the explosive hematogenous spread of the causative organism following inoculation. Evidence in support of this thesis is to be found in the recent study of Rosenhall and Roupe.1” Using auditory electrical response analysis, these investigatorsdemonstrated subclinical brain stem lesions in 6 of 11 cases of secondary and latent syphilis. That the great majority of CNS infections are self-limiting is evident in the
Gjestland-Bruusgaard study,‘3 proportion of cases of untreated eventually resulted in clinical was shown to be 9.4% for men women.
in which the syphilis that neurosyphilis and 5.0% for
Meningeal and Vascular Syphilis Cerebral meningeal neurosyphilis. In its diffuse form, cerebral meningeal syphilis is an early manifestation of the disease, the great majority of cases occurring within the first year of infection. In 10% of cases, signs of secondary syphilis are also present. Signs and symptoms result from interference with CSF circulation (hydrocephalus), damage to cranial nerves (palsies), and thrombosis of small cortical vessels as a result of specific meningeal inflammation. Headache, stiff neck, and fever are commonly present. Cranial nerve palsies, which are usually multiple, occur in 40% of cases, and the paralysis is transient in most instances. Cranial nerves III, VI, VII, and VIII are favored sites. Papilledema is common. Pupillary changes are also common. The pupils are usually small, unequal, and react sluggishly to light. The true Argyll-Robertson
130
Clinics in
Crissev and Denenholz
pupil (see tabes dorsalis) may occasionally be seen. In a few cases, aphasia and hemiplegia can occur, indicating vessel damage in the cortex, but these signs are usually transient. CSF pressure is usually increased. Slight to moderate increases in cell counts (mostly lymphocytes) are noted; protein levels are increased, and serologic tests are usually positive. Serologic tests on blood are virtually always positive at this stage. It is on the basis of these serologic tests and the accompanying signs of secondary syphilis (when present) that the condition is differentiated from the many other forms of acute and subacute meningitis which it obviously resembles. Focal cerebral meningeal syphilis is manifested by gumma formation, and is extremely rare. The lesion commonly takes its origin in the pia mater and, in growing, steadily compresses and invades the brain substance to produce symptoms identical to those associated with other enlarging tumors. Although CSF and blood serologic tests are positive in a very high proportion of these cases, the diagnosis cannot be made with certainty except by biopsy; neoplasms of the brain can and do occur in the presence of neurosyphilis. In any event, gummata of the brain often respond poorly to antisyphilitic treatment, and surgical intervention is advisable from this standpoint as well. Cerebrovascular syphilis. Included here are those cases of neurosyphilis characterized pathologically by endarteritis and thrombosis of cerebral vessels to produce a variety of focal neurologic signs, particularly hemiplegia and aphasia. The interval between initial infection and onset of the cerebrovascular signs varies considerably, the average being 7 years. The signs and symptoms resemble closely those produced by arteriosclerotic thrombotic disease and vary with the vessels involved. Motor paralysis and speech disturbances are present in a high percentage of cases. Manifestations of meningeal syphilis are sometimes also seen. The disease can be suspected when the patient is unusually young for %troke” and shows serologic evidence of syphilis in the blood and
Dermatoloav
CSF. But even in these instances, concomitant arteriosclerosis is a far more common cause of the problem, and work-up and treatment for arteriosclerosis should be included along with the treatment for syphilis. Spinal meningeal and vascular syphilis, Syphilis of the spinal cord other than tabes dorsalis was rare even when the incidence of syphilis in the general population was high. The signs and symptoms are varied enough to make classification into specific syndromes difficult. When the leptomeninges are the seat of the disease, destructive changes are seen in the nerve roots and marginal areas of the cord. Various combinations of pain, paresthesia, spastic weakness of the legs, muscular atrophy, sensory loss, and sphincter disturbances occur. Erb’s spastic paraplegia is one of the better known entities included in this group. Syphilitic thrombosis of the nutrient vessels to the cord can result in partial or complete transverse myelitis, while gummata of the cord simulate expanding lesions of the neoplastic type. Inflammation and thickening of the dura mater of the cord (syphilitic pachymeningitis) usually affects the cervical area to produce root pain, muscular wasting, sensory loss, diminished tendon reflexes, and eventually spastic paraplegia with sensory loss below the level of the lesion. CSF changes in all these conditions are similar to those found in cerebral meningeal and vascular syphilis. Parenchymatous
Neurosyphilis
Paresis (general paresis, general paralysis of the insane). Paresis is a syphilitic meningoencephalitis manifested by diffuse, nonfocal signs of cerebral disorder, especially psychosis and dementia, attributable to a widespread atrophy of the cerebral cortex which is most severe in the frontal lobes and diminishes in intensity toward the posterior poles. In earlier days it was among the most common conditions responsible for admissions to mental institutions; such is no longer the case, and yet the disease still occurs, and because failure to recognize it promptly results in irreversible damage to the patient,
Jan-Mar 1984 Volume 2 Number 1
Neurosyphilis
it is important to include a searchfor syphilis in the investigation of every patient showing signs of mental disturbance. The incidence of
paresis among untreated cases of syphilis in the Bruusgaard-Gjestland studyI was 3.0% for men, 1.7% for women. Caucasians are more susceptible than blacks, and the disease usually begins 10 to 15 years after the initial infection. The onset may be acute, but more often is insidious and marked by changes in the behavior and personality of the patient. Inability to concentrate, irritability, memory impairment, complaints of headache are features often noted early. As the disease progresses, judgment falters, insight disappears, confusion and disorientation become more marked, and slovenliness in dress and behavior become evident. Melancholia may occur, but euphoria is more characteristic, sometimes accompanied bydelusionsof grandeur. Syphilologists in earlier days often had collections of million dollar checks written for them by these patients. There is, as WillcoxG has pointed out, some truth in the aphorism that everyone in contact with the paretic suffers but the patient himself. Tantrums, paranoia, and violent outbursts can occur, however, along with excesses in sexual activity and in the use of alcohol. Tremors of the lips, tongue, and hands are signs commonly noted in the early stages. Speech becomes impaired; “Methodist Episcopal” remains a useful little test for this, and handwriting deteriorates steadily. Seizures of all types are seen: grand mal, petit mal, and Jacksonian. Tendon reflexes tend to be accentuated, and transient monoplegias and hemiplegias occur. Irregular pupils, often small, unequal, and poorly reactive to light, are observed more often in paresis than the Argyll-Robertson pupil, the latter being more characteristic of tabes dorsalis (see page 132). Untreated, the course is steadily downhill, with progressive mental deterioration. The patient eventually becomes bedridden, totally uncommunicative, incontinent of urine and feces, and prone to decubitus and intercurrent infections of all types. Death occurs in 1
131
to 3 or 4 years, usually after repeated convulsions, or from pneumonia or some other intercurrent infection. A useful mnemonic device for the clinical picture of paresis has been passed along by Holmesl4: Personality, Affect, Reflexes (hyperactive), Eye changes, Sensorium (illusions, delusions, etc.), Intellect (deterioration), Speech (dysarthria). Concomitant signs and symptoms of tabes dorsalis occur in a number of cases (taboparesis), and syphilitic cardiovascular disease is not uncommon in association with paresis. Paresis differs from other forms of neurosyphilis in that the neurons themselves are heavily involved along with the blood vessels and meninges.15 At autopsy, the brain is shrunken and reduced in weight; the leptomeninges are thickened, pale bluish-white, and adherent to the underlying cortex, which is clearly atrophic. These changes, in association with a finely granular appearance of the lining of the fourth ventrical, are characteristic of the disease. The whole ventricular system is dilated, often markedly so. On the microscopic level, there are lymphocytes and plasma cells in the pia-arachnoid. The blood vessels in the cortex are surrounded by cuffs of these cells and exhibit internal and adventitial thickening. The normal laminar disposition of the nerve cells is disrupted, and many of the neurons have disappeared, while those that remain are often jumbled together in an irregular fashion. There is a considerable proliferation of astrocytes and an associated increase in the amount of neuroglial fiber formation, especially in the outer lamina of the cortex. Hortega cells, containing iron pigment and assuming the “rod cell” configuration, are characteristic. Silver stains will show the presence of T. pallidum in most untreated cases. A part of the pathogenesis may be attributable to problems in blood supply arising from the endarteritis, but it is not unreasonable to postulate direct destruction of the neurons themselves as a result of the T. pallidum parasitic cellular attachment phenomenon described in Chapter 3.
132
Crissev
and Denenholz
The serum VDRL is usually positive; the FTA-ABS is reactive in 95+% of cases. Both treponemal and non-treponemal CSF tests are also reactive in the great majority of cases. Controversies regarding the significance of these tests are considered on pages 134-136. Cell counts and protein levels in the CSF are regularly elevated. Tabes dorsalis (locomotor ataxia). Tabes dorsalis is an infection of the nervous system by T. pallidurn, characterized pathologically by shrinkage of the posterior roots and posterior columns of the spinal cord, and clinically by incoordination, sensory and trophic disturbances, and involvement of the special senses, particularly the eyes. Once common, the disease is now rare; the incidence of tabes dorsalis in untreated syphilis was set in the Bruusgaard-Gjestlandls figures at 2.5% in men and 1.4% in women. As in all forms of neurosyphilis, Caucasians are affected more often than blacks. The disease usually begins 10 to 20 years after the initial infection, sometimes much later. The principle signs and symptoms of tabes dorsalis are ataxia, areflexia, paresthesias, bladder and eye disturbances, impotency, and pain. The onset is insidious, marked by stumbling and difficulty in walking, especially in the dark, when loss of position sense cannot be adequately compensated for by visual orientation. As the disease progresses, this sensory ataxia becomes more marked. The patient assumes a broad based gait, toes pointed outward, tends to slap the feet on the floor as if for reassurance, and rounds turns with considerable difficulty. Paresthesias appear early, especially in the lower extremities and, in 75% of the cases, are soon joined by “lightning” pains. The latter are sharp jabs of pain, mild to excruciating, and worse in wet weather. They are most common in the feet and legs, but no region is exempt, and they frequently “flit” from one area to another. Girdle sensations are common. Visceral pain, the periodic “gastric”or abdominal “crisis” characteristic of tabes dorsalis, usually begins suddenly with abdominal pain that is often severe enough to be mistaken for
Clinics in Dermatoloav
an acute surgical abdomen, especially when accompanied by nausea and vomiting, as is sometimes the ease. Impotence in men is common, and may be the chief complaint. Visual failure from a concomitant optic atrophy is also common. Urinary retention, delay, or imperfect control occurs in about one-third of the cases, while hearing loss, rectal incontinence, ptosis, and diplopia are less common, but well recognized symptoms. The signs of tabes dorsalis include loss of tendon reflexes in the lower extremities, which occurs in 80 to 90% of cases, and pupillary changes, which are equally common. The classic Argyll-Robertson pupil of tabes dorsalis is bilateral and fixed in its reaction to light, usually at a diameter of approximately 3 mm, and yet continues to react readily in accommodation for near objects. It is not wholly pathognomonic for tabes, however, nor is it even the most common pupillary disturbance seen in the condition. Unequal, irregular pupils that react poorly to light, and sometimes to accommodation as well, are more often encountered. Various ophthalmoplegias may be seen, and cervical sympathetic involvement may result in drooping of the eyelids, with compensatory wrinklingof the brow - the characteristic “tabetic facies” of Hutchinson. Optic atrophy can occur. Objective ataxia with abnormalities in the gait add to the picture. In these cases, Romberg’s sign (unsteadiness or falling when the feet are placed close together and the eyes closed) is usually positive, and the heel-knee test is poorly performed. In advanced cases trophic destructive changes in joints, especially in the lower extremities, lead to a painless arthritis in which the joint becomes enlarged and grossly disorganized and is subject to abnormal movements, hyperextensibility, and the like. Known as Charcot’s joints (Fig. 15-l), these diseased articulations may eventually become incapable of supporting any weight at all. They are not restricted to tabes dorsalis, however, and are sometimes seen in syringomyelia and a number of other neurologic disturbances. Perforating ulcers of the toes and soles (ma1
Jan-Mar 19i3A Volume 2 Number 1
Neurosyphilis
perforans) can also occur in tabes dorsalis (Fig. 15-2). From the classic description of the disease by Romberg at the midpoint of the 19th century onward, investigators have struggled to develop some unifying theory that would explain the peculiarly disparate group of features combined in the full-blown case of tabes dorsalis. The results of many investigations place the seat of the disease in the dorsal root ganglia, where the treponeme probably damages the posterior roots at the point at which they penetrate the pial membrane. It is here that the neurilemmal sheaths cease, and the myelinated fibers are presumed to be more vulnerable. A good many of the signs and symptoms are, of course, easily traced to the loss of pain perception and proprioception that follows destruction of the dorsal roots (Fig. 15-3). The lesion responsible for the Argyll-Robertson pupil has been placed in the mesencephalon.16 Schwarz’T has reviewed the various theories on the pathogenesis of tabes dorsalis and points out that the continued inability of investigators to reproduce the disorder experimentally and the diminishing frequency of the disease have combined to reduce the chances that solutions to the many mysteries connected with it will be found in the near future. The diagnosis is usually made on the basis of symptoms of lightning pains, ataxia, and urinary difficulty associated with pupillary disturbances, areflexia, neurologic signs of proprioception deficit, reactive blood serologic tests, and abnormalities in the spinal fluid. Non-treponemal tests on blood will be negative in many cases, perhaps one-third; treponemal tests should always be done and will be positive some 95% of the time. Early in the disease, cell counts in the cerebrospinal fluid are elevated (as high as 50/pm) and protein levels up to 100 mg/dl are seen. Nontreponemal tests on the cerebrospinal fluid are usually positive in active cases, but are often negative in those that have “burned out”: for practical purposes, false positives do not exist. It is probable that treponemal tests (the CSF-FTA) will be positive in a
133
FIG. 15-l. Tabesdorsalis. Charcotjoint. knee. Disorganization of the joint space with prominent soft tissue calcification.
much higher percentage of cases in all stages of activity but, as will be developed, the value of reactive CSF treponemal tests is dubious. Optic atrophy. Optic atrophy may occur in the absence of any other sign of neurosyphilis, but it is more commonly observed in association with tabes dorsalis or even general
134
Crissev and Denenholz
Clinics in Dermatoloav
FIG. 15-2. Tabes dorsalis. Trophic ulcers, toes (ma1 perforans).
paresis. In any event, it is rare. In the typical case the disease begins with constriction of the visual field in one eye, which progresses steadily until the central field is fully involved, and total blindness results. Involvement of the second eye begins months to years later and follows the same course. Total blindness supervenes within 10 years in most instances. Fundoscopic examination shows increasing pallor of the discs, which, in advanced cases, may be paper white. Margins are unaffected, but in late cases the center of the disc may exhibit a bluish, funnel-shaped, central depression. These clinical signs arise from typical syphilitic lymphocytic and plasma cell infiltrates in the pia around the optic nerve and an endarteritis of the nutrient blood vessels that penetrate the nerve in the intraneural septa. The VDRL-CSF test may or may not be positive, but in the absence of concomitant signs of tabes dorsalis, it is not possible to make a certain diagnosis of syphilitic optic atrophy without serologic confirmation.
Cerebrospinal Fluid in Neurosmhilis As noted earlier, the discovery ination of the CSF was a valuable
that examtool for the
FIG. 15-3. Tabes dorsalis. Spinal cord cross section at T5. Luxol-Fast blue stain for myelin. FascicuIus gracilis (arrows) shows absence of myelin staining where there has been axonal loss with secondary myelin loss. In more extensive cases, posterior columns can be entirely destroyed.
investigation and monitoring of neurosyphilis was made early in the century by Ravaut.8 Fordyce, Wile, Stokes, and J. E. Moore were instrumental in expanding on the theme and in transferring the European technology to North American centers.18 Moore, in particular, codified and popularized the division of CSF alterations into three groups on the basis of the intensity of the changes: Type I - pleocytosis, slight elevation in protein, negative non-treponemal and Lange colloidal gold tests. Test II - more marked pleocytosis, more elevated protein, negative or weakly reactive non-treponemal tests, and variable zone positive colloidal gold tests. Type III - (known for many years as the “red flag CSF”) - high cell counts, high protein levels, positive non-treponemal tests, and first zone or “paretic” colloidal gold patterns. This once-popular scheme has lost much of its usefulness in recent years, although it still appears in some texts in modified form. The
Jan-Mar 1984 Volume 2 Number 1
Neurosyphilis
Lange colloidal gold test, in particular, is an obsolete procedure, dependent on albumin/ globulin ratios better determined in other ways; it is without value, either as a diagnostic aid or as a guide to disease activity, and has been abandoned entirely in North America. Drawing on the Ravaut-Moore material, his own extensive experience at the WagnerJauregg clinic, and the work of many others, Bernhard DattneP of Vienna, was able, in the 193Os, to show convincingly that the CSF cell counts and protein levels were the most sensitive and reliable indicators of activity in neurosyphilis. In 1937 he joined the clinic of Evan Thomas at the Bellevue Hospital in New York City and, in 1942, in collaboration with Thomas, published an extremely influential report in which a set of guidelines was offered for the diagnosis and management of neurosyphilis in accordance with these principles.20 Known as the “DattnerThomas spinal fluid concept,” this set of guidelines was accepted by most of the profession for a generation, although even at its highest point of popularity, exceptions to parts of the general concept were noted and the oversimplification inherent in any such scheme was recognized. The essence of the Dattner-Thomas approach was this: Signs and symptoms of neurosyphilis are not reliable criteria of activity in a syphilitic process in the central nervous system, nor is a reactive CSF nontreponemal test necessarily proof of active disease. Elevated cell counts and total protein determinations are the hallmarks of activity; with the exception of an occasional case of “burned out” tabes dorsalis, neither is ever normal in untreated neurosyphilis. Successful treatment is followed by a return of cells to normal in two or three months; protein declines slowly to normal in 6 months or so, while non-treponemal CSF tests decline in titer, although they may never become negative. If relapse, as indicated by reversal in levels of cells and protein, has not occurred within 15 months after therapy, the patient can be presumed to be cured.2l There was, in addition to the acceptance of
135
these criteria, a great reluctance on the part of clinicians to make a diagnosis of neurosyphilis of the meningovascular or paretic varieties in the absence of a reactive nontreponemal CSF test, although exceptions were made again in clear-cut cases of “burned out’ tabes dorsalis. The result was that the approach to the diagnosis, treatment, and follow-up of neurosyphilis was understandable to everyone and reasonably well standardized. This consensus, this pax neurosyphilitica, lasted until the 1960s and 1970s when challenges to all elements of the doctrine on which it was based began to appear. They arose to a great extent from a willingness, particularly on the part of neurologists, to accept “modified” or “atypical” clinical presentations (considered below) as evidence of neurosyphilis, even in the absence of reactive CSF non-treponemal tests, elevated protein levels, or pleocytosis. The challenges also seemed to receive support from newer developments in serologic research. As in the blood, CSF tests for syphilis can be classified as treponemal and non-treponemal. The modification of the VDRL for measurement of reagin levels in the CSF (abbreviated here as the VDRLCSF) has now supplanted all other nontreponemal CSF tests. One of the few facts agreed upon by nearly all participants in the controversies currently evident in the world of neurosyphilis is that false positive VDRLCSF results are rare. The two apparently valid examples recently reported2”*“” are the exceptions that prove the rule. Estimates on the number of false negatives vary from 30% to more than 50%,24 although in the absence of absolute reference standards for a diagnosis of neurosyphilis, these numbers are essentially without meaning. Nevertheless, the fact that the non-treponemal CSF tests seemed to be negative, not only in burned out tabes dorsalis cases, but also in certain meningovascular presentations that mimicked syphilis and appeared to respond to penicillin treatment stimulated the search for CSF tests able to detect antibody directed against T. pallidurn itself. A beginning was made in 1960 with the development of the unabsorbed
136
Crissev and Denenholz
CSF treponemal antibody test (CSF-FTA) by Harris, Bossak, Deacon, and Bunch.25 A series of reports has since appeared26-33 in which absorbed and unabsorbed variants of the CSF-FTA were compared with the VDRL-CSF and with one another. In all of these studies the FTA tests on CSF were reactive in all stages of syphilis more often than the non-treponemal tests, and were also often reactive in the “atypical” forms of neurosyphilis being seen by neurologists. But the question of significance remains. Comparison of CSF serologic tests with one another without reference to clinical findings is an exercise in circular reasoning, and in those studies in which clinical correlation was attempted,26y33 the investigators were forced by the nature of the problem to assign arbitrary weights to those clinical findings sometimes attributable to neurosyphilis. On the latter, there can never be any universal agreement, and each investigator, therefore, has the power to alter the sensitivity and specificity estimates for treponemal CSF tests by expanding or restricting the clinical criteria utilized as reference standards. That, to say the least, is an uncertain road to truth. It is probable that many of the positive results in the studies cited are attributable to transfer of antibody from serum across the blood-brain barrier. This explanation is supported by the investigations of Jaffe and co-workers32 in which it was shown that CSF-FTA test reactivity appeared most likely when the titer of the serum FTA test was high. In the light of these uncertainties, the conclusions of Jaffe and co-workers seem justified: Without other supporting clinical or laboratory data, the diagnostic value of a reactive CSF-FTA test is unknown, and without such supporting data, tests of this type should not be used to diagnose neurosyphilis. The newly developed CSF treponemal tests based on microhemagglutination procedures23y34 35 appear to suffer from similar difficulties and will need further study before their usefulness can be evaluated.
Clinics in Dermatoloav
Attempts to circumvent the problems posed by the relative insensitivity of the VDRL-CSF and the false positive reactions in CSF treponemal tests in evaluating suspected cases of neurosyphilis are also to be found in recent studies describing... -the use of monospecific conjugates, antiIgG, IgM, and IgA in the performance of the CSF-FTA test.36 - the precise calculation of the concentrations of IgG, IgM, and IgA in CSF.37 - the identification of oligoclonal IgG in the CSF.38 - the correction of CSF treponemal test titers in accordance with the albumin quotient to exclude errors arising from disturbed function of the brain barrier.24 -the identification of active neurosyphilis by the presence of plasma cells in the CSF cytogram in combination with elevations and electrophoretic abnormalities in CSF IgG and associated increases in serum levels of IgM.39 All these developments are promising and may be called upon for diagnostic support in the future when tests based on them become routinely available. Clearly, what is needed is a simple reliable method for demonstrating the presence in the CSF of T. pallidurn itself, either by culture or animal inoculation.
Is Neurosyphilis Changing? Although Luxon and associates,40 in a 1979 study of neurosyphilis were unable to find any clinical presentations unknown in the pre-antibiotic era, a number of other observers41-46 are convinced that widespread use of antibiotics for other conditions in subcurative doses has resulted in the occurrence of “modified” or “atypical” forms of the disease. These formes frustes manifest themselves as bits or parts of the classical syndromes described above, most commonly as changes that fit best in the meningovascular or tabetic categories. Often the patient presents with a single sign or symptom,
Jan-Mar 1904 Volume 2 Number 1
TABLE
Neurosyphilis
137
15-2. Symptoms and signs of 241 patients with neurosyphilis’ Percent of patients
Symptoms Seizures Focal General Not specific Ophthalmic symptoms Stroke; confusion Dizziness Personality changes
*Source: Hooshmand
(poor vision, etc.)
24.2 4.2 10.0 10.0 11.6 11.1 7.9 2.0
Signs Reflex changes Absent ankle jerk Pupil changes Sensory abnormalities Chorioretinitis, retinitis pigmentosa Organic brain syndrome Babinski’s sign Depression Ptosis Optic atrophy Mania Personality changes
H, Escobar MR. Kopf SW. Neurosyphilis.
absent ankle jerks, or pupillary changes, or seizures, for example. Presenting signs and symptoms as noted in the 1972 study of 241 cases by Hooshmand, Escobar, and Kopf43 are shown in Table 15-2. Broadly similar results were reported by Joyce-Clarke and Molteno.44 In the 148 cases of neurosyphilis observed by the latter investigators, 85 were judged to represent modified formes frustes of the disease. That the incidence of the classical forms of neurosyphilis is falling everywhere there can be no doubt,47 and insofar as the modified or atypical cases fit the well accepted criteria for the diagnosis of symptomatic neurosyphilis-suspicious neurologic signs, a positive treponemal test in blood, and a positive VDRL-CSF test accompanied by elevated cells and protein levels-few would dispute their validity. But many cases do not; the diagnosis in a significant number has been made by inference, based on nothing more than a positive serum FTA-ABS test and perhaps a positive CSF-FTA test, along with new neurologic signs. The objections to this position have been reviewed by Jordan.481t is generally accepted that, with very few exceptions, a patient with a positive serum FTAABS test has or has had syphilis. Neurologic dysfunction appearing in such a patient may
Percent of patients 75.8 66.6 44.8 33.7 12.0 a.7 5.3 5.0 4.6 46 3.3 2.0
a study of 241 patients. JAMA 1972;219:726-9.
or may not have anything to do with T. pallidum, and in the absence of a reactive VDRLCSF test, there is no good way to distinguish between “modified” neurosyphilis and nonsyphilitic neurologic disease occurring in a patient with cured or latent syphilis. The CSF-FTA test cited as confirmatory evidence in some atypical case presentations, is not a reliable test for the disease (see page 136). while pleocytosis and elevated protein levels in the CSF are features common to many nonsyphilitic neurologic disturbances. Favorable response to penicillin treatment has also been offered as evidence that certain atypical presentations were, in fact, syphilitic, but in view of the spontaneous improvement or stabilization that often takes place in other neurologic diseases, postpenicillin improvement may in reality be an example of the post hoc propter hoc fallacy in action. And finally, poorest of all of the evidence cited on behalf of a syphilitic cause for some of the atypical presentations is the failure to find anything else to account for the clinical picture, as though all other derangements of the nervous system are known and readily reveal themselves ante-mortem. Disputes and difficulties in these matters will no doubt continue until, as noted earlier, some more specific and sensitive test for neu-
Crissey
138
Clinics in Dermatology
and Denenholz
rosyphilis appears, a routinely applicable culture or animal inoculation procedure, for example. Moreover, the consequences to the patient of failure to treat active syphilis of the central nervous system can be so severe that many physicians are likely to brush aside more rigid diagnostic criteria and treat the condition at hand in the spirit of the “therapeutic trial.” The matter is controversial, but many, including the authors of this monograph, consider the approach acceptable, providing the risks entailed are fully explained and the patient is also made aware that the decision has been based on hope for a favorable outcome rather than diagnostic certainty. When a therapeutic trial is undertaken, however, it is well to avoid drawing erroneous conclusions concerning the results. To regard (much less publish) atypical clinical neurologic presentations with negative VDRL-CSF tests as bona fide syphilitic treatment failures when they do not respond to antibiotics is not a defensible position.
Indications for Treatment as Neurosyphilis Absolute A reactive VDRL-CSF test in combination with elevation of the cell count above 5 cells/pm and total protein levels above 40 mg/dl, with or without neurologic signs or symptoms, constitutes an absolute indication to treat the case as neurosyphilis. Treponemal tests on serum are positive in 95+% of these cases, but Dewhurst has reported a 3.5% incidence of negative non-treponemal tests in serum in the presence of reactive non-treponemal tests in the CSF.4g Discretionary Neurologic signs or symptoms known to be associated sometimes with neurosyphilis, occurring in a patient with serum serologic evidence of syphilis, a reactive CSF treponemal test, but a negative VDRL-CSF test, constitutes a less than absolute indication for treatment as neurosyphilis. If CSF cell counts
and total protein levels are elevated or if the signs or symptoms appear to be progressive, it is better to treat in accordance with neurosyphilis regimens, but with the clear understanding that the neurologic disturbance may have nothing to do with syphilis. The CSF-FTA test or its hemagglutination counterpart, the CSF-TPHA test, should be reactive, however; a negative treponemal CSF test effect%vel,yexludes acti’ve neurosyphilis.24 In burned-out tabes dorsalis, CSF may be entirely normal, and serum non-treponemal tests may be negative. In these cases the serum treponemal tests are almost always positive. It is advisable, as a matter of public policy, to treat cases of this type, although response is usually nil. N.B.: All of the patients in the above categories are presumed to have or to have had syphilis, and unless documented evidence for adequate treatment is available, all should be treated for the disease. It is the choice of antibiotics, the method of administration, the dosage schedules, and the follow-up procedures that differ in treating the case as neurosyphilis rather than latent syphilis.
Neurosyphilis Treatment and Follow-up Schedules As in the case of the clinical criteria for the diagnosis of neurosyphilis and the interpretation of CSF laboratory findings, the treatment of syphilis of the central nervous system is a matter of some dispute. Potentially effective drug regimens recommended by the Centers for Disease Controls0 in 1982 are as follows: 1. Aqueous crystalline penicillin G: 12-24 million units, intravenously per day (2-4 million units every 4 hours) for 10 days, followed by benzathine penicillin G: 2.4 million units, intramuscularly (IM), weekly for 3 doses. OT
2. Aqueous procaine penicillin G: 2.4 million units, IM daily plus probenecid 500 mg, by mouth, 4 times a day, both for 10 days,
Jan-Mar 1984 Volume 2 Number 1
Neurosyphilis
followed by benzathine penicillin G: 2.4 million units, IM weekly for 3 doses. OY
Benzathine penicillin G: 2.4 million units, IM, weekly for 3 doses. These regimens are accompanied by a caveat that none has been adequately studied, and the following statement: 3.
Published studies show that a total dose of 6.0 to 9.0 million units of penicillin G over a 3- to 4-week period results in a satisfactory clinical response in approximately 90% of patients with neurosyphilis. This information must be considered along with the observation that regimens employing benzathine penicillin or procaine penicillin in doses under 2.4 million units daily do not consistently provide treponemicidal levels of penicillin in CSF, and with the knowledge that several case reports show the failure of such regimens to cure neurosyphilis. The literature on neurosyphilis treatment problems and the adequacy of CSF penicillin levels has been summarized to 1979 by Sparling.“’ He concluded from his survey that high dose. in hospital, intravenous penicillin for at least 10 days is the most conservative therapy acceptable for symptomatic neurosyphilis, while procaine penicillin given on an outpatient basis in daily intramuscular injections of 600,000 units for 15 days was acceptable for asymptomatic neurosyphilis. Since Sparling’s report, a number of studies52m5” have appeared casting further doubt on the ability of pencillin G benzathine injections to produce treponemicidal levels in the CNS. Ducas and Robsons go so far as to recommend abandonment of this form of penicillin as a first-line agent in the treatment of neurosyphilis. On the other hand, combinations of aqueous procaine penicillin G injections and oral probenecid appear to achieve adequate levels in the CNS.57 It therefore appears that regimens no. 1 and no. 2 recommended by the Centers for Disease Control are adequate and much to be preferred to regimen no. 3. Despite the doubts on the efficacy of penicillin G benzathine in the
139
treatment of neurosyphilis, its use in syphilis present less than one year seems to be accepted by nearly everyone, although clearly some of these patients already have asymptomatic neurosyphilis. It is to guard against CNS relapse in these cases that CSF examination at the end of one or two years is recommended after treatment for early syphilis. The question of what to do with patients with neurosyphilis who are allergic to penicillin is troublesome indeed, and wholly undecided. No antibiotic other than penicillin has been evaluated properly. Penicillinsensitive patients with neurosyphilis should have their allergy confirmed by skin test by personnel expert in the performance of that sometimes dangerous procedure. The successes reported by Onoda in the treatment of all stages of syphilis with doxycycline,5b and the demonstrated ability of that antibiotic to achieve concentrations in the brain far higher than its parent drug, tetracycline,j9 have encouraged Hotson to recommend it in the treatment of neurosyphilis in patients with confirmed penicillin allergies. He suggests 300 mg of doxycycline a day, given orally in divided doses for 30 days. The Jarisch-Herxheimer reaction, as it occurs in neurosyphilis, is described in Chapter 12. The lightning pains of tabes dorsalis sometimes respond to diphenylhydantoin or carbamazepine. Intractable cases may require cordotomy. Gastric crises can usually be controlled by intravenous fluids, barbiturates, or phenothiazines. However roughly the diagnostic aspects of the “Dattner-Thomas spinal fluid concept” have been treated in recent years, there is no doubt it provides the most reliable approach to monitoring treatment response in ordinary cases of neurosyphilis. Lumbar puncture should be performed 6 weeks after completion of treatment and again 3 months later. Cell counts should fall steadily to normal in three months. Elevated protein levels respond a little more slowly , reaching normal in 3 to 6 months. VDRL titers usually fall, but may never become negative. Failure of cells or protein to return to normal, or
Clinics in 140
Crissey and Denenholz
reversal in their downward trend, constitutes an indication for retreatment. Persistent abnormalities require repeat CSF examination at intervals of a year or two. Treatment failure of course means that sufficient numbers of virulent treponemes were not killed or inactivated to permit the immune system to tip the balance in favor of the host; failure in this respect no doubt also accounts for the observations that viable organisms have been observed in the CNS and eyes of patients with syphilis long after completion of intensive antibiotic treatment. A large literature dealing with this phenomenon appeared in the late 1960s and early 197Os, reviewed to 1972 by Dunlop.60 Tramont reported two more examples in 1976,6l but the subject has not generated much interest recently, partly because of doubts raised concerning some of the observations,@ and partly perhaps because no one knows quite what to make of it.
Prognosis Treatment cannot replace structure already destroyed, and results can be discouraging, especially in general paresis, which seems to progress in a good many cases even when therapy has been intensive.63 Nevertheless, a surprising amount of recovery of function can take place in most forms of neurosyphilis, and lack of prospects for significant improvement should not be a contraindication to treat. Drug Names carbamazepine: Tegretol diphenylhydantoin: Dilantin doxycycline: Vibramycin References 1. Thomas EW. Some aspects of neurosyphilis. Med Clin North Am. 1965;48:699-705. 2. Merritt HH. Adams RD. Solomon HC. Neuro-
Dermatology
syphilis. 1946.
New York: Oxford University
Press,
3. Merritt HH. Textbook of neurology. 6th ed. Philadelphia: Lea & Febiger, 1979:135. 4. King A, Nicol C. Rodin P. Venereal diseases. 4th ed. London: Baillikre Tindall, 1980: 81-103. 5. Gilroy J. Meyer JS. Medical neurology. New York: Macmillan, 1979:4X-77.
3rd ed.
6. Willcox RR. Textbook of venereal diseases and treponematoses. 2nd ed. Springfield, IL: Charles C Thomas, 1964:213-29. 7. Catterall RD. Neurosyphilis. 1977;17:585-604.
Br J Hosp Med.
8. Ravaut P. Le liquide kephalo-rachidien des syphilitiques en pkriode secondaire. Ann Dermatol Syphilig. 1903;4:537-54. 9. Moore JE. Studies in asymptomatic neurosyphilis. II. the classification, treatment, and prognosis of early asymptomatic neurosyphilis. Bull Johns Hopkins Hosp. 1922;33:231-46. 10. Moore JE, Hopkins HH. Asymptomatic neurosyphilis. VI. the prognosis of early and late neurosyphilis. JAMA. 1930;95:1637-41. 11. Stokes JH, Beerman H. Ingraham NR. Modern clinical syphilology. 3rd ed. Philadelphia: W.B. Saunders, 1945:608-9. 12. Rosenhall responses 57:241-5.
U, Roupe G. Auditory brain-stem in syphilis. Br J Vener Dis. 1981;
13. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis. Med Clin North Am. 1964:48:613-23. 14. Holmes KK. Syphilis. In: Isselbacher KJ, et al., eds. Harrison’s principles of internal medicine. 9th ed. New York: McGraw-Hill, 1980: 716-26. 15. McMenemey WH, Smith WT. Syphilis of the nervous system. In: Symmers W. Systemic pathology Vol. 5.2nd ed. Edinburgh: Churchill Livingstone. 1979:2118-25. 4th 16. DeJong RN. The neurologic examination. ed. Hagerstown, MD: Harner and Row. 1979: 133-4. 17. Schwarz GA. Neurosyphilis. In: Goldensohn ES, Appel SH. eds. Scientific approaches to clinical neurology. Vol. 1. Philadelphia: Lea & Febiger. 1977:482-97. 18. Moore JE. The genesis of neurosyphilis. Dermatol Syphilol. 1921:4:55-61.
Arch
19. Dattner B. Die moderne Therapie der Neurosyphilis. Vienna: Wilhelm Maudrich, 1933.
Jan-Mar 1984 Volume 2 Number 1
20. Dattner
Neurosyphilis
B, Thomas EW. The management
neurosyphilis. 1942;26:21-31. 21. Thomas
agement.
Am J Syph Gonor Vener
of Dis.
EW. Syphilis, its course and manNew York: MacMillan, 1949:237-41.
141
35. Luger A, Schmidt B, Spendlingwimmer I. Horn F. Recent observations on the serology of syphilis. Br J Vener Dis. 1980:56:12-6. 36. Le Clerc
G, Giroux M, Birry A, Kasatiya S. Study of fluorescent treponemal antibody test on cerebrospinal fluid using monospecific anti-immunoglobulin conjugates IgG. IgM, and IgA. Br J Vener Dis. 1978:54:303-8.
22. Delaney
P. False positive serology in spinal fluid associated with a spinal cord tumor. Neurology 1976;26:591-3.
23. Madiedo
37. Gibowski M, Machonko T. Immunoglobulins in the cerebrospinal fluid of patients with late syphilis. Br J Vener Dis. 1981;57:20-4.
24. Luger
intrathecal 38. Vartdal F, et al. Neurosyphilis: synthesis of oligoclonal antibodies to Treponema pallidurn. Ann Neurol. 1982;11:35-40.
G, Ho KC, Walsh P. False-positive VDRLand FTA in cerebrospinal fluid. JAMA. 1980;244:688-9.
A, Schmidt BL, Steyrer K, Schonwald E. Diagnosis of neurosyphilis by examination of the cerebrospinal fluid. Br J Vener Dis. 1981;57:232-7.
39. Kolar
OJ, Burkhart JE. Neurosyphilis. Vener Dis. 1977;53:221-5.
25. Harris
A, Bossak HM, Deacon WE, Bunch WL Jr. Comparison of the fluorescent treponemal antibody test with other tests for syphilis on cerebrospinal fluids. Br J Vener Dis. 1960;36:178-80.
26. Escobar
MR. Dalton HP, Allison MJ. Fluorescent antibody tests for syphilis using cerebrospinal fluid: clinical correlation in 150 cases. Am J Clin Pathol. 1970;53:886-90.
27. Garner
MF, Backhouse JL. Fluorescent onemal antibody tests on cerebrospinal Br J Vener Dis. 1971;47:356-8.
trepfluid.
28. Duncan
WP, Jenkins TW, Parham CE. Fluorescent treponemal antibody-cerebrospinal fluid (FTA-CSF) test. Br J Vener Dis. 1972;48:97-101.
40. Luxon L. Lees AJ, Greenwood
ilis today. Lancet
30. Mahony
JOH, Harris JRW, Sydney-McCann J. et al. Evaluation of the CSF-FTA-ABS test in latent and tertiary treated syphilis. Acta Derm Venereol (Stockh). 1972:52:71-4.
31. Wilkinson
AE. Fluorescent body tests on cerebrospinal Dis. 1973:49:346-g.
treponemal antifluid. Br J Vener
RJ. Neurosyph-
1979;1:90-3.
41. Kofman 0. The changing
pattern of neurosyphilis. Can Med Assoc J. 1956:74:807-12.
42. Joffe R, Black MM, Floyd M. Changing
clinical picture of neurosyphilis: report of seven unusual cases. Br Med J. 1968:1:211-2.
43. Hooshmand
F, Escobar MR. Kopf SW. Neurosyphilis, a study of 241 patients. JAMA. 1972; 219:726-g.
44. Joyce-Clarke
N, Molten0 ACB. Modified neurosyphilis in the Cape Peninsula. S Afr Med J. 1978;53:10-4.
45. Editorial.
Modified 1978;2:647-8.
29. Kasatiya
SS. Caloenescu M, Birry A. Automated fluorescent treponemal antibody (AFTA) test for cerebrosninal fluids in the diagnosis of neurosyphilis.ACan J Pub Health. 1972;63:447-52.
Br J
neurosyphilis.
Br Med J.
46. Hotson JR. Modern
treated chronic 1981;135:191-200. 47. Heathfield
Practitioner.
neurosyphilis: a partially meningitis. West J Med.
KWG. The decline 1976;217:753-62.
48. Jordan
K. More on neurosyphilis. 1982;136: 106-67.
49.
of neurolues. West J Med.
Dewhurst K. The composition of the cerebrospinal fluid in the neurosyphilitic psychases. Acta Neural Stand. 1969;45:119-23.
32. Jaffe HW, Larsen
50. Sexually transmitted diseases treatmentguidelines,1982. MMWR 1982;31:51s.
33. McGeeney
51. Sparling PF. Current problems in sexually transmitted diseases. In: Stollerman GH. ed. Advances in internal medicine. Chicago: Year Book Medical Publishers, 1979;24:203-28.
34. Kasatiya
52. Greene BM. Miller NR. Bvnum TE. Failure of penicillin G benzathine in the treatment of neurosyphilis. Arch Intern Med. 1980:140: 1117-8.
SA, Peters M, et al. Tests for treponemal antibody in CSF. Arch Intern Med. 1978;138:252-5. T, Yount F, Hinthorn DR, Liu C. Utility of the FTA-ABS test of cerebrospinal fluid in the diagnosis of neurosyphilis. Sex Transm Dis. 1979:6:195-8. S, Birry A. Further evaluation of the microhaemagglutination test to determine treponemal antibodies in CSF. Br J Vener Dis. 1980;56:77-80.
53. Polnikorn
N, et al. Penicillin
concentrations
in
Crissev and Denenholz
142
cerebrospinal fluid after different treatment regimens for syphilis. Br J Vener Dis. 1980; 56:363-7. 54. Ducas J, Robson HG. Cerebrospinal
cillin levels during therapy JAMA. 1981;246:2583-4. 55.
Clinics in Dermatolwv
Rein MF. Treatment JAMA. 1981;246:2613.
fluid penifor latent syphilis.
of neurosyphilis.
56. Polnikorn
N, et al. Penicillin concentrations in the cerebrospinal fluid after benzathine penicillin and probenecid in the treatment of syphilis. Br J Vener Dis. 1982;58:342.
57. Dunlop EMC, Al-egaily
SS, Houang ET. Production of treponemicidal concentration of penicillin in cerebrospinal fluid. Br Med J. 1981;283:646.
58. Onoda
Y. Therapeutic
effect of oral doxycy-
cline on syphilis. 55:110-5.
Br J Vener
Dis.
1979;
59. Barza M, et al. Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs. Antimicrob Agents Chemother. 1975;8:713-20. 60. Dunlop EMC. Persistence of treponemes treatment. Br Med J. 1972;2:577-80. 61. Tramont EC. Persistence dum following penicillin 1976;236:2206-7.
after
of Treponema palliG therapy. JAMA.
62. Wither K, Wither V. Immunopathology of syphilis. In: Schell RF, Musher DM, eds. Pathogenesis and immunology of treponemal infection. New York: Marcel Dekker, 1983:139-59. 63. Wilner E, Brody JA. Prognosis of general paresisafter treatment. Lancet. 1968$:1370-l.