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Show /ounUll of Clinical Neuro-ophthalmology 8(3): 145-155, 1988. © 1988 Raven Press, Ltd., New York Chronic Syphilitic Meningitis Resulting in Superior Orbital Fissure Syndrome and Posterior Fossa Gumma A Report of Two Cases Followed for 20 Years Jon N. Currie, F.R.A.C.P., James R. Coppeto, M.D., and Simmons Lessell, M.D. Two case historie's, each spanning more than 20 years, demonstrate the complexity and persistence of modern neurosyphilis. Both patients present uncommon manifestations of neurosyphilis that may be easily overlooked today: superior orbital fissure syndrome, posterior fossa gumma, and bilateral deafness. Computed tomographic scans were performed in both patients but were diagnostically nonspecific, and syphilis serology testing in both serum and cerebrospinal fluid was repeatedly misleading. Numerous mistaken diagnoses were put forward until tissue was finally available for histologic examination. Perhaps the most disturbing aspects of these two cases are the persistent failure of specific treponemal serologic testing to indicate the diagnosis, and the inability of repeated "adequate" and/ or supramaximal doses of penicillin to prevent continued neurologic deterioration. We believe that chronic neurosyphilis may demand a reevaluation of current diagnostic and therapeutic practice. Key Words: Meningitis, chronic syphilitic-Superior orbital fissure syndrome-Posterior fossa gummaSensorineural deafness- Penicillin. From the Mental Health Research Institute of Victoria, Parkville, Victoria, Australia a.N.c.), the Ophthalmology Department, University of Connecticut Medical Center, Farmington, Connecticut a.R.c.), and the Department of Ophthalmology, Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. Address correspondence and reprint requests to The Mental Health Research Institute, Private Bag No.3, Parkville, Victoria, Australia, 3052. 145 Even with the advent of modern serological tests and computerized tomographic (CT) scanning, the diagnosis of neurosyphilis often proves elusive (1). With the widespread use of antibiotics, early undiagnosed syphilis may be inadvertently and inadequately treated and remain masked. This may be responsible for the development of late syphilis in modified forms (2,3) with tabes dorsalis, general paresis, and other classical presentations being replaced by less familiar entities including meningovascular syphilis (4-11). Although some authors dispute this contention (1), it remains true that the uncommon manifestations of neurosyphilis have always lurked as pitfalls for the diagnostician. We describe two cases, each of which combined several rare manifestations of neurosyphilis, including cerebral gumma, superior orbital fissure syndrome, and bilateral sensorineural deafness. Both patients have been followed for >20 years, with the correct diagnosis eluding numerous clinicians. Diagnostic laboratory tests have been unreliable and repeated antibiotic therapy has proved ineffective. The course of the illness has been complex, protracted and fluctuating, lending credence to Fournier's description: "Syphilis, this tragedy with its acts and intermissions" (12). CASE REPORTS Case 1 In 1931, a previously healthy, 7-year-old boy developed persistent enuresis, complex partial seizures, and deterioration of school performance 146 J. N. CURRIE ET AL. after blunt head trauma. At age 18, an in-hospital evaluation for severe left frontal headaches gave negative results, but a year later when he progressively lost hearing in his left ear, a neurological examination revealed mild mental deficiency, generalized deep tendon hyperreflexia, and right ankle clonus. Cerebrospinal fluid (CSF) examination showed 16 white blood cells (WBC)/mm3, an increased globulin, and a Wassermann test that was negative in 0.1 and 0.2 dilution but positive in 0.4, 0.5, and 1 dilution. Despite the absence of any family history of venereal disease and negative blood syphilis serology, the diagnosis of "congenital tertiary cerebrospinal syphilis" was made and he was treated with arsphenamine and bismuth. At age 21, he developed left frontal headaches and a left lateral rectus palsy. He was now completely deaf in the left ear, had poor pupillary light responses bilaterally, bilaterally "choked" optic disks, gait ataxia, and a left extensor plantar response. Over the next month he developed left ptosis, proptosis, and limitation of movement in all directions in the left eye. Visual acuity remained normal. The CSF contained 8 WBClmm3, protein of 33 mg/lOO ml and a trace of globulin. Results of serological tests for syphilis on the blood and spinal fluid were negative. A left carotid angiogram and a pneumoencephalogram were normal. The eye findings fluctuated during the next 12 months, until the patient was again hospitalized at age 22 for recurrent pain and swelling in the left orbit, accompanied by bilateral hearing loss. Examination now showed marked left proptosis, mild left ptosis, left ophthalmoparesis, poor pupillary reactions to light and near stimuli, but normal visual acuity. There were also signs of an old left hemiplegia and bilateral nerve deafness with hypoactive labyrinths. Another pneumoencephalogram showed only nonfilling of the ventricles. A ventriculogram was normal, and the spinal fluid was unremarkable. Results of serum and CSF syphilis serologies were negative. Within 4 months his pupils, eye movements, and motor and sensory examination had spontaneously returned to normal. Because skull x-ray films showed chronic sclerotic mastoiditis, his diagnosis at this time was revised to "bilateral deafness due to healed mastoiditis, with mental defiCiency." The patient's left orbital symptoms and signs recurred at age 24. In addition, he had dysarthria, nystagmus on gazing right, and a tendency to veer to the right when walking. EEG showed right occipital slOWing. Spinal fluid examinations performed three times over the next 3 months c;hnwed 36, 0, and 42 lymphocytes/mm3 and pro-tein levels of 54, 78, and 94 mg/IOO ml. All blood and CSF syphilis serologies were negati~e, but a 3-week course of penicillin was given, WIthout effect. Hysteria was now considered "to playa prominent part in his illness." Right frontal headache and progressive lo~s of vision in the right eye began at age 28. VIsual acuity in the right eye fell to the ability to counting fingers at 1 ft, with a large central scotoma. Left visual acuity remained 20/20. The right eye was proptotic, with impaired motility, and the right optic disk margin was blurred with sheathed retinal vessels and venous engorgement. The patient now had complete, bilateral sensorineural deafness with no caloric response in either ear. Gait was wide based, Romberg test was positive, and he had bilateral deep tendon hyperreflexia. The CSF contained 21 lymphocytes/mm3 with protein of 74 mg/IOO ml. Blood and CSF syphilis serologies were normal. Another course of penicillin, 300,000 U b.i.d. for 18 days, was given, again without evident effect. Four months later the right eye was blind, and there was a complete right third nerve palsy with pupil sparing. CSF contained 136 lymphocytes/ mm3, total protein of 87 mg/IOO ml and increased globulin. Results of extensive bacterial, viral, and fungal testing of blood and CSF (again including tests for syphilis) proved negative. Radiographs showed smooth, uniform thickening of the margin of the right optic canal and right anterior clinoid. Bilateral carotid angiography was normal. A biopsy of the right superior rectus muscle showed only fibrosis and atrophy. To explain the intermittent neurologic deficits with fluctuating CSF pleocytosis and protein content, together with local orbital and ocular motor involvement, two diagnoses were proposed at this time: multiple sclerosis and inflammatory pseudotumor of the orbit. The patient did not appear for follow-up until 1973 at age 49 when he developed severe, lancinating right facial pain that responded to carbamazepine therapy. Two years later he had an episode of memory loss, pseudobulbar lability, and slurred speech. On examination the left eye was normal whereas the right eye was blind, with optic atrophy, and had ptosis and restricted adduction, abduction, and elevation. Tendon reflexes were normal but gait was ataxic. A radionucIide brain scan showed an area of minimally increased uptake in the left occipital region, "consistent with an area of acute demyelination. " At age 58 he had 4 months of progressive deterioration of gait and progreSSive dysphagia. On ex- CHRONIC NEUROSYPHILIS AND ORBITAL MANIFESTATIONS 147 amination he had bilateral deafness and mild dysarthria. He was severely ataxic and could not walk without assistance. The tendon reflexes and sensory examination were normal. The right eye was blind, ptotic, and virtually immobile with evidence of aberrant third nerve regeneration. The right corneal reflex was absent and right facial sensation was reduced. Right facial weakness was accompanied by an absent right gag reflex, poor movement of the right pharynx, and difficulty swallowing. The right side of the tongue was atrophied (Fig. 1). CT scan showed an enhancing mass in the right cerebellopontine angle with widening of the right internal auditory canal and sharply defined erosion of the posterior face of the right petrous bone (Fig. 2). The fourth ventricle was displaced to the left, without hydrocephalus. The mass contained areas of calcification. A large, supratentorial, early filling vein was also present (Fig. 3). Two round, densely enhancing lesions were also seen above the region of the right pterion (Fig. 3). These were partially calcified and appeared to arise from the dura. The diagnosis was thought to be multiple meningiomatosis or neurofibromatosis. Four-vessel angiography outlined a right posterior fossa mass, with little evidence of tumor blush. The serum VORL and FTA-Abs tests were negative. Surgical removal of the posterior fossa tumor was attempted. Via a right suboccipital craniectomy a firm, encapsulated mass adherent to the dura was partially removed. Histologically, the tissue was highly cellular, containing many small lymphocytes, plasma cells, and multinucleated giant cells, with a central zone of caseation and necrosis (Fig. 4). Blood vessels showed severe vasculitic changes (Fig. 5) and there was considerable connective tissue in the outer portions of the tumor. The lesion was diagnosed as a cerebral FIG. 1. Case 1. Atrophy and weakness of the right sioe of the tongue. FIG. 2. Case 1. Computed tomography scan with contrast showing a large right cerebellopontine angle mass. gumma. Postoperatively, the patient was given 24 million U of intravenous penicillin daily for 21 days. After surgery and antibiotic therapy his headaches, gait, speech, swallowing, and facial anesthesia improved markedly, but there was no change in the ophthalmic findings. FIG. 3. Case 1. Computed tomography scan with contrast showing a large supratentorial early filling vein (V). and a densely enhancing mass arising from the dura (G). I Clill NClIro-Ol'hthallllol, Vol. 8, No, 3. 1988 148 FIG. 4. Case 1. Section from the gummatous posterior fossa mass, showing a highly cellular tissue mass with central caseation and necrosis (hematoxylin and eosin stain). ]. N. CURRIE ET AL. Follow-up CT scan 6 months later showed residual tumor in the right posterior fossa and a decrease in size and density of the right frontal masses. Case 2 A 33-year-old man first presented in 1963 with fever and a left paratonsillar abscess. Biopsy of the paratonsillar lesion showed only "nonspecific acute and chronic inflammation." Eighteen months later he developed intermittent diplopia on left gaze, which became continuous after 4 weeks, accompanied by pain and numbness over the left side of the forehead. Examination showed mild left proptosis, a left Horner's syndrome, a left lateral rectus palsy, and hypalgesia over the oph-thalmic division of the trigeminal nerve with intact corneal sensation. There was an area of increased uptake in the left subfrontal region on radionuclide brain scan, but plain skull and orbital radiographs and left carotid angiogram were normal. CSF contained 66 mg/100 ml protein and no cells. The serum VORL was nonreactive, as was the CSF. In the next 3 months he also developed a partial left third nerve palsy and right-ear hearing loss. However, the diplopia and ophthalmoplegia then improved spontaneously and no clear diagnosis was reached. The patient remained asymptomatic until 1970 (age 41), when over three days he developed occipital headache, nausea, vomiting, diplopia on left gaze, and a right hemiparesis. Examination showed a left lateral rectus palsy, horizontal nys- FIG. 5. Case 1. Section from the gummatous posterior fossa mass, showing intense vasculitic changes (hematoxylin and eosin stain). CHRONIC NEUROSYPHILIS AND ORBITAL MANIFESTATIONS 149 tagmus on gaze to either side, decreased left facial and corneal sensation, and a right hemiparesis with a right extensor plantar response. Cerebellar function was normal, but there was bilateral loss of vibration sense in the lower limbs to the knees. There was also severe bilateral sensorineural hearing loss. Plain skull radiographs and an EEG were normal. Radionuclide brain scan showed increased uptake of tracer in the left posterior fossa. Left vertebral angiogram showed a mass in the left cerebellopontine angle, with slight tumor blush, and this was confirmed by ventriculogram. The CSF contained no cells but the protein was 176 mg/lOO ml. VDRL was nonreactive in serum and CSF. The FTA-Abs was positive in his serum but negative in the CSF. Left posterior fossa craniectomy showed thickened dura adherent to a firm, well encapsulated tumor mass that extended laterally and posteriorly into the cerebellopontine angle and had a slight yellowish discoloration. Piecemeal dissection accomplished almost complete removal of the tumor mass, except for fragments adherent to the dura in the region of the transverse sinus. On microscopic section many areas of tissue were very cellular, containing mainly small lymphocytes with some plasma cells and larger multinucleated giant cells (Fig. 6). Blood vessels showed an intense endarteritis and perivasculitis (Fig. 7) and silver and reticulin stains showed an abundance of collagen fibers and fibrosis. The histopathological diagnosis was syphilitic gumma. The patient was then treated for 15 days with 600,000 U/day of intramuscular procaine penicillin and his diplopia and hemiparesis resolved. Six months later his left lateral rectus paresis re-curred. The CSF now contained 14 WBClmm3 and a protein of 94 mg/lOO ml. Following another 15day course of 600,000 U/day of intramuscular procaine penicillin the ophthalmoplegia and CSF pleocytosis resolved, but the CSF protein remained elevated. Results of serum and CSF VDRL and FTA-Abs tests were negative at all examinations. Left lateral rectus palsy and CSF pleocytosis recurred again after a further 6 months. Again serum and CSF VDRL and FTA-Abs tests were negative. He was treated with a lO-day course of twice-daily intramuscular injections of 600,000 U of benzathine penicillin followed by 1.4 million U four times per day of oral penicillin V for another 10 days. Again the ophthalmoplegia and CSF pleocytosis resolved, only to return 2 months later, now accompanied by bilateral ankle clonus. CSF protein was now 120 mg/lOO ml. Results of serum and CSF VDRL and FTA-Abs tests again were all negative, as was a Treponema pallidum immobilization test. A radionuclide brain scan showed persistent uptake of tracer in the ventricles and over the brain convexities at 72 h. After 25 million U of procaine penicillin during 20 days the ophthalmoplegia and CSF pleocytosis again resolved. Left horizontal diplopia next recurred 4 months later, this time accompanied by nausea and rightlimb hyperreflexia. Despite treatment with 30 million U of procaine penicillin the neurological signs now persisted. Again, results of serum and CSF syphilis serologies were negative. Angiography showed a small area of residual tumor in the left cerebellopontine angle. Within a few months the left horizontal diplopia worsened, followed by the FIG. 6. Case 2. Section from the posterior fossa gumma, showing a highly cellular tissue mass with many small lymphocytes, some plasma cells and Occasional multinucleated giant cells (hematoxylin and eosin stain). 1C/i" Neuro-ophthalmol. Vol. 8. No.3. 1988 150 FIG. 7. Case 2. Section from the posterior fossa gumma, showing intense endarteritis and perivasculitis. f. N. CURRIE ET AL. acute onset of left third and fourth cranial nerve palsies with pupillary involvement and reduced left corneal sensation. Vision in the left eye declined rapidly to 20/200, but the fundus appeared normal. Severe bilateral hearing loss persisted. CSF now contained 26 WBClmm3 and a protein of 176 mg/lOO ml. Results of serum and CSF VORL and FTA-Abs tests were negative. Four-vessel angiography and pneumoencephalogram showed the residual posterior fossa tumor to be unchanged. He was treated with high doses of oral prednisone for a diagnosis of recurrent inflammation of the cavernous sinus and superior orbital fissure. When a repeat lumbar puncture 1 week later showed that the CSF pleocytosis was increasing, a 20-day course of 1.2 million U/day of intramuscular procaine penicillin was initiated. In 8 weeks the ophthalmoplegia and visual loss had resolved and the CSF was free of cells, although the CSF protein remained elevated. This episode was attributed to a gumma or syphilitic inflammation in the supraorbital region, accompanied by a mild meningitic reaction, and a low maintainence dose of prednisone was continued. Two similar recurrences of left ophthalmoplegia and CSF pleocytosis occurred during the next 2 years. Both resolved after a brief period of increased prednisone dosage. Venography showed poor filling of the left cavernous sinus. Results of serum and CSF VDRL and FTA-Abs remained negative. In April 1976, at age 46, the patient developed progressive diplopia in all fields of gaze. There was now a right sixth nerve palsy in addition to recurrent left third and sixth nerve palsies and residual left Horner's syndrome, left facial weakness, and right hyperreflexia. Visual acuity was J Gin Neuro-ophthalmol. Vol. 8, No.3, 1988 20/70 bilaterally, with normal fundi. CSF contained 28 lymphocytes/mm3 and protein was 139 mg/100 ml. Skull tomograms showed Widespread destruction of the clivus and floor and walls of the sella, and there was a mass in the sphenoid sinus that extended into the posterior wall of the nasopharynx and was visible on examination, Venogram showed bilateral involvement of the cavernous sinuses, more marked on the left. A CT scan was performed for the first time, and showed a residual left posterior fossa mass and a nasopharyngeal mass with its base on the left petrous bone. Biopsy of the nasopharyngeal mass showed a "nonspecific acute and chronic inflammatory process." High-dose prednisone therapy had little effect and over the next 2 years arteriograms demonstrated progressive enlargement of the mass with encasement of the intracavernous portion of the left internal carotid artery. In 1978, 1 week after experiencing several transient episodes of right arm and leg weakness, he developed a right hemiplegia with brief loss of consciousness. Examination showed left third and sixth nerve palsies, right sixth nerve palsy, bilateral sensorineural hearing loss, and a moderate right hemiplegia. On CT scan there was a large, irregular, calcified contrast- enhancing mass in the left parasellar region, associated with bone destruction. It involved the sella, medial aspect of the left middle cranial fossa, left clivus, and left cerebellopontine angle. There was also a recent ischemia in the watershed territory of the left internal carotid artery. Carotid angiography outlined the large paraseUar and cerebellopontine angle tumor and showed encasement of the left carotid siphon. The CSF contained 19 lymphocytes/mm3 and protein of 115 mg/lOO ml, CHRONIC NEUROSYPHILIS AND ORBITAL MANIFESTATIONS 151 but results of the serum and CSF VORL and FTAAbs were negative. He was given a lO-day course of 2 million U of intravenous penicillin every 4 h, in addition to aspirin antiplatelet therapy. Further weakening of the right arm occurred, and CT scan showed an additional area of ischemia in the left frontal region. However, the right hemiparesis then improved remarkably, and after 2 months there was only minor residual right arm weakness, but persistent left eye ophthalmoparesis. The patient's condition remained stable for 12 months, until he suddenly had a massive left hemisphere infarction with complete aphasia, right hemiparesis, and right hemianopia. CT scan confirmed the area of infarction, and although he remained alert, his neurological deficits showed little subsequent improvement. DISCUSSION There are many striking similarities in the picture of neurosyphilis presented by each of these two patients. Both experienced a prolonged and fluctuating illness that eluded diagnosis, with many diverse signs and symptoms that, in retrospect, could be attributed to neurosyphilis. Chief among these were the development of a superior orbital fissurelcavernous sinus syndrome, bilateral hearing loss, and a posterior fossa gumma. In both patients serological testing for syphilis was of little or no use for diagnosis, and in both patients the disease progressed despite repeated treatments considered "adequate" at the time they were given. It remains uncertain whether the first patient had congenital or acquired neurosyphilis. Both cerebral gumma and superior orbital fisSure syndrome are considered such rare complications of neurosyphilis that they have virtually disappeared from modern reviews (1,8,9,11). Although gummas were cited as comprising 6.3-19% of intracranial tumors before the turn of the century (13,14), by 1912 they occupied only 2.6% of Cushing's neurosurgical tumors and by 1927 only 0.2% (15). Similar percentages (0.1-0.5%) continue to be reported (16-20). In both of our patients the diagnosis of cerebral gumma was only made from classical histological findings after neurosurgical intervention for a posterior fossa mass lesion (19,21,22). In neither patient was the diagnosis suspected before, or even at the time of operation, and in both cases the posterior fossa gumma acted solely as a slowly growing mass. Preoperative diagnosis of cerebral gummas has always proved difficult, because they usually act as expanding mass lesions without causing any specific syndromes (23), and have no pathognomonic neuroradiological features (24). Angiographically, they appear as space-occupying lesions, possibly with evidence of local vasculitis. The lesions may be avascular or show a hyperperfusion blush and early draining veins, as in case 1 (23,25,26). CT scan cannot differentiate them diagnostically from other mass lesions, but if sequential CT scans show regression of the lesion after penicillin therapy, the diagnosis of cerebral gumma is greatly strengthened (24). In both of our patients all the gummas showed areas of calcification on CT scan, a feature not previously mentioned in the few reports available in the literature documenting the CT scan appearances of cerebral gummas (24,26). Gummas usually occur as solitary lesions over the cerebral convexities, adhering to both dura and brain (16,18-20). They have also been reported as occasionally arising in the hypophysis, hypothalamus, thalamus, occipital lobe, interpeduncular fossa, and third ventricle (19,27,28). However, the posterior fossa is a rare location for gumma (19,29,30) and gummas are a particularly rare posterior fossa tumor. Brackmann and Bartels (31), in reviewing 1,354 cerebellopontine angle tumors, found 25 rare tumors that were not neurinomas of cranial nerves, meningiomas, or cholesteatomas. None of these was a gumma. It is therefore interesting that in addition to our two cases, two of the few recently reported cases of intracranial gumma identified by CT scanning were also located in the posterior fossa, one in the cerebellopontine angle and the other in the pons and midbrain (24,25). Syphilis of the orbit was first described by Boerhaave (32) in 1749, and although well-recognized in the literature of the early part of this century, it has always been a rare manifestation of the disease (33-41). Of 130,000 patients with eye disease seen at the Leipzig clinic before 1909, only 0.013% were diagnosed as luetic periostitis or orbital gumma (34). Kemp, writing in 1923, noted that only five of 6,000 cases of syphilis at the Johns Hopkins Hospital clinic had involved the orbit (37), and Fine could discover only two orbital gummas in 40,000 eye patients evaluated at the Stanford clinic from 1913-1939 (41). In recent years orbital syphilis has become almost unknown, so that Spoor et aI., in reporting a case in 1983, stated that it represented to their knowledge "the first report of active syphilis mimicking idiopathic orbital inflammation" (42). Orbital involvement can occur with congenital or acquired syphilis (38), and the clinical features J Clill Nellro-or'hthalmo/, Vol. 8, No.3, 1988 152 f. N. CURRIE ET AL. are remarkably uniform from case to case (37,41). They are well-exemplified in the presentation of bilateral orbital disease in case 1 (at 21 and 28 years) and unilateral disease with extension into the cavernous sinus in case 2 (at 34 and 42 years). Of 24 recorded cases to 1939, Fine noted that five were bilateral but not of simultaneous onset in the two orbits (41). The onset is usually some years after the initial infection, and symptoms may last for weeks to months (37). Common manifestations include orbital pain, proptosis, ophthalmoplegias, ptosis, pupil involvement, and hypalgesia in the distribution of the first two divisions of the trigeminal nerve (37,38,41,43). The orbital pain, an early symptom that may precede other symptoms by weeks or months (44), is often worse at night and resembles the pain of optic neuritis in that it is often exacerbated by touching or moving the eye (37,41). Visual loss is a late complication, but can be expected in untreated cases of prolonged duration in which the lesion is situated near the apex of the orbit (37). In our first patient, complete and irreversible visual loss was at first attributed to "multiple sclerosis" but was clearly associated with a progressive orbital apex syndrome that had been present for at least 7 years. Multiple sclerosis is a common misdiagnosis in neurosyphilis, which can mimic every clinical and laboratory manifestation of multiple sclerosis (10). Visual loss in our second patient occurred with reactivation of inflammation in the region of the orbital apex and cavernous sinus. Disk edema ("choked disks") with secondary optic atrophy is common; however, primary optic atrophy may occur alone (41). The pathology of orbital syphilis involves either gumma formation, periostitis, or both. Rarely, there may also be a true syphilitic osteitis (36,44). Direct involvement of the ocular muscles is rare, and compression of ocular motor, sensory, or optic nerves at the orbital apex gives rise to most of the clinical features (37). As with other manifestations of neurosyphilis (45,46), orbital involvement may develop after relatively minor local trauma (38,43), and this may have occurred in our first case. Diagnosis proves difficult with orbital syphilis, as it does with cerebral gumma, because radiologic studies at best show only nonspecific features of inflammation (37,41,43), as in our first case. After the institution of treatment, recovery usually begins within 3-6 weeks, but its success depends in part on the degree of preceding nerve damage (41). Spontaneous remissions may also occur, as happened in both our patients. Direct extension of an orbital apex lesion may result in involvement of adjacent intracranial regions or nasal sinuses (37,47). The right frontal gumma in case 1 and the cavernous sinus and sella involvement in case 2 could well represent such direct extension. Hearing loss was an early feature in both our patients and asymmetric progression to complete deafness occurred despite antisyphilitic therapy. Although hearing loss has been recognized for centuries in both early and late congenital syphilis (48-50), late acquired syphilis is still often overlooked as a cause of deafness (51-54). Hearing loss appears to be more frequent in neurosyphilis than in other forms of syphilis (53). Estimates range from 3-38% in congenital syphilis (49,50), 17% in early latent, 25% in late latent, 29% in asymptomatic neurosyphilis, and 80% in symptomatic (tabes, paresis) neurosyphilis (55). Most patients present with cochleovestibular symptoms that are often similar to Meniere's disease, and the hearing loss is usually bilateral and sequential, progressing asymmetrically in the two ears as in both our cases. The clinical course of both auditory and vestibular loss is often relentlessly progressive, frequently proceeding to total deafness in a relatively short time (53). Occasionally the loss of hearing is acute (52,56). Again, diagnosis may be difficult because the nonspecific serological tests for syphilis are frequently negative (53), and there are no characteristic features on audiometry or temporal bone radiography (53,57). However, the FTA-Abs is often reactive, although not in our two patients. Penicillin therapy is often effective in restoring hearing in early syphilis, but is much less effective in late syphilis, and long-term prednisone therapy may be required in addition to antibiotics to maintain any hearing improvement that is obtained. The duration and severity of hearing loss in late syphilis are not necessarily indicative of response to treatment, so intensive therapy is almost always warranted (52-54,58,59). Despite the presence of cerebral gumma and advancing neurosyphilis, serologic testing for syphilis was of little diagnostic use in either of our patients. Results of the nonspecific serum tests in our first patient were never positive, and only one CSF Wasserman test was positive, early in the course of his disease. Results of specific treponemal serology of blood and CSF were always negative except for one positive CSF FTA-Abs after surgery. In the second patient, results of serum FTA-Abs were positive on only two occasions, and CSF serology results were never positive. Nevertheless, by clinical, CSF, and histologic CHRONIC NEUROSYPHILIS AND ORBITAL MANIFESTATIONS 153 findings, the diagnosis of neurosyphilis seems irrefutable. It is now widely recognized that the sensitivity of nontreponemal tests decreases considerably in late syphilis (60). Results of the serum VDRL may be negative in up to 39% of patients with late syphilis (61), and up to 51% of patients with neurosyphilis (8). The CSF VDRL is positive in only 57% of cases of neurosyphilis (8). Although no large-scale study of the serological findings with intracranial gumma has been reported, Bagdasar in 1929 found the serum Wasserman reaction (WR) was negative in 40% and the CSF WR negative in 50% of his cases (16). In more recent reports of cerebral gumma, Pilleri et al. (20) found that results of specific syphilitic testing in serum and CSF were negative, but most other authors have reported positive serum serologies, with mixed CSF results (24,26). In old series of syphilitic orbital disease, results of nonspecific serologic tests were negative in up to 22% of cases (37,41). The FTA-Abs test is now recommended as the most effective indicator of syphilic infection (10,62-65), with 95-97% positivity in the serum of patients with neurosyphilis. However, caution is needed in the application of these rates of reactivity, because most of these studies required a positive FTA-Abs to make the diagnosis of neurosyphilis and placed their emphasis on interpretation of false-positive results or the effects of treatment (8,61,62,66). There are no large studies that look at rates of FTA-Abs negativity in cases of clinically or histologically proven neurosyphilis. The value of the CSF FTA-Abs remains uncertain because of its variability and lower sensitivity, and a nonreactive CSF FTA-Abs does not exclude neurosyphilis (64,66). Although Wilkinson (67) has stated that the CSF FTA-Abs test is virtually always positive when the CSF cell count and protein concentration are abnormal, this was not true in either of our cases and has also been disputed by others (64,66). Some authors propose that an unreactive serum FTA-Abs excludes neurosyphilis and obviates an examination of the CSF (65,68). We believe that this assumption is unwise and that in chronic neurosyphilis, particularly with some of the less common presentations, the 3-5% false-negative "window of vulnerability" associated with the serum FTA-Abs test may in fact open wider. Our two cases reemphasize that the diagnosis of neurosyphilis should be based on clinical judgment and the results of all CSF and serum tests, rather than on serologic tests alone (64). Neurosyphilis activity is also judged by CSF pleocytosis and protein levels, rather than by serologic titers (64). After "effective" treatment of active neurosyphilis, the increased cell count usually disappears within 6 months, whereas elevated protein levels decline slowly, and may persist for several years (64). However, normal CSF cell counts and protein concentrations can occur in patients with active, progressive neurosyphilis (2,8,64). In general, the CSF pleocytosis in both our patients correlated well with exacerbations and remissions of disease activity, but the CSF protein content was less useful. The question of "adequate" treatment remains one of the most controversial aspects of neurosyphilis (10,62,69,70). Clinical progression of symptomatic neurosyphilis commonly occurs despite antibiotic therapy (4,8,71-74), as it did in both our patients. A commonly used penicillin regimen has been 6-9 million U total dose, administered as either 3 million U of intramuscular benzathine penicillin weekly for 3 weeks or 600,000 U of intramuscular procaine penicillin daily for 10-15 days (62,75). Our first patient received such a regimen twice, in addition to arsphenamine and bismuth early in his disease, and our second patient received three such courses in 1 year, followed by doses of 25, 30, and 24 million U of intramuscular procaine penicillin and one dose of 120 million U intravenously, all over a period of 7 years. In both patients the disease still relentlessly progressed. Mohr et al. have demonstrated that low serum and CSF penicillin levels are achieved using these recommended doses, and they found no detectable penicillin in the CSF of 12 of 13 patients with neurosyphilis treated with 3-6 million U of intramuscular benzathine penicillin at weekly intervals (76). CSF penetration of penicillin after administration of procaine penicillin is similarly poor or nonexistent (65,77). Hooshmand et al. (8) found that although CSF cell counts remained normal in 112 patients with neurosyphilis after treatment with 20-24 U of intramuscular penicillin over 3 weeks, five of the 89 patients followed up for more than 2 years showed relentless clinical deterioration. Twelve tabetic and meningovascular syphilitic patients treated with 2.4-9 million U of penicillin continued to show clinical and CSF activity. Collart and Poitevin demonstrated virulent pathogenic T. pallidul1l in a tabetic patient 4 months after receiving 50 million U of intramuscular penicillin (78). In at least a small number of cases documented by positive animal transfer, isolation of T. I Gill Nellro-ophthalmol. Vol. 8. No.3, 1988 154 J. N. CURRIE ET AL. pallidum has been achieved from treated patients with ocular or late neurosyphilis and congenital syphilis (78-82), and Tramont demonstrated CSF T. pallidum in two patients with neurosyphilis, recently treated with 2.4 million U of intramuscular benzathine penicillin weekly for 3 weeks (83). Studies such as these, and cases such as we report here, raise serious doubts about the adequacy of current treatment for neurosyphilis. It is believed that for satisfactory therapy a continuous therapeutic level of penicillin is required in the serum and CSF for at least 10-20 days (69,84). 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