Pure Motor Hemiplegia due to Meningovascular Neurosyphilis Donald R. Johns, MD; Maureen Tierney, MD; Stephen W. Parker, MD \s=b\ Two young male homosexuals devel- oped prodromal syndrome followed by penicillin-responsive meningitis and the acute onset of pure motor hemiplegia. The clinical and laboratory features are consistent with meningovascular neurosyphilis. Basis pontis infarctions were subsequently demonstrated on magnetic resonance imaging scans. To our knowledge, this is the first description of syphilitic arteritis as a pathophysiologic basis for pure motor hemiplegia. (Arch Neurol 1987;44:1062-1065) Uure motor hemiplegia (PMH) was defined by Fisher and Curry1 as unilateral complete or incomplete paralysis of the face, arm, and leg unaccompanied by sensory signs, visual field defect, dysphasia, apractognosia, or brain-stem signs. The original pathologic lesions were lacu¬ nar infarctions of the internal capsule and basis pontis, but a wide variety of causes have subsequently been de¬ scribed along the full extent of the pyramidal motor pathway.27 To our knowledge, PMH has not been described in the setting of meningo¬ vascular neurosyphilis (MVNS). This report documents the occurrence of PMH due to ischemie infarctions of the basis pontis caused by MVNS in two homosexual men who subsequent¬ ly developed the acquired immunode¬ ficiency syndrome (AIDS). REPORT OF CASES Case 1.—A 35-year-old right-handed hospital with man was admitted to another Accepted for publication May 20, 1987. From the Departments of Neurology (Drs Johns and Parker) and Medicine (Infectious Disease Unit) (Dr Tierney), Massachusetts General Hospital, Boston. Dr Johns is now with the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore. Reprint requests to ACC 735, Massachusetts General Hospital, 15 Parkman St, Boston, MA 02114 (Dr Parker). flaccid right hemiplegia of one day's dura¬ tion. He had a two-month history of mild fatigue, malaise, and a 5-lb weight loss. He had daily severe throbbing periorbital headaches that were present on awakening for two weeks, and that were accompanied by nausea and anorexia for three days. On the day prior to admission his right side "gave out" and he collapsed on the floor. Over the next three hours the weakness progressed in a stepwise fashion to a com¬ plete paralysis of the right arm and leg. On admission, he was noted to have a flaccid right hemiplegia that remained unchanged prior to transfer to Massachu¬ setts General Hospital, Boston, four days later. He denied sensory symptoms, visual symptoms, hearing deficit, dysphagia, dysarthria, dysphasia, fever, lymphade¬ nopathy, rash, drug abuse, and tick bite. He was bisexual and had been promiscu¬ ously sexually active in the past, but had been abstinent for six months. He had been treated for two episodes of gonorrhea but denied a history of chancre or previous cases of syphilis. There was neither a per¬ sonal history of migraine nor a family history of neurologic disease. On physical examination the patient was thin, chronically ill-appearing, afebrile, and normotensive, with shotty cervical and axillary adenopathy. The heart sounds were normal without murmur or click, and the carotid pulses were full and without bruit. Neurologic examination revealed a depressed affect, minimal neck pain and stiffness at extreme flexion, mild right central facial palsy, a complete flaccid hemiplegia of the right arm and leg, hyper¬ active deep tendon reflexes, extensor plan¬ tar response, Hoffman's sign, and triple flexion response on the right. Results of detailed examination of sensation, pupil¬ lary responses, and extraocular move¬ ments were normal. Significant laboratory findings included mild transient elevation of serum transaminase levels, antinuclear antibody titer of +1:8, cutaneous anergy to mumps and purified protein derivative, negative serum antibody to human immunodeficiency virus (HIV), a T-cell helper to suppressor ratio of 0.07:1, IgG antibody to Borrellia burgdorferi, acute 1:160 and convalescent 1:80, and minimal prolapse of the anterior Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/15/2015 mitral valve leaflet shown on echocardio¬ gram. Results of the following tests were normal or negative: serum immunoelectrophoresis, coagulation parameters, blood cultures, bacterial, fungal, mycobacterial, and viral (including HIV) cultures of the cerebrospinal fluid (CSF), and cryptococcal antigen in the CSF. Initially, the rapid plasma reagin (RPR) titer was +1:256 with a fluorescent treponemal antibody absorption (FTA-ABS) of 4+, and five months later the RPR was negative. The Table shows the results of serial lumbar punctures, all of which had normal opening and closing pressures. Results of contrast cranial computed tomographic (CT) scans performed one and 11 days after the initial event were normal. A magnetic resonance imaging (MRI) scan three weeks after the initial event revealed a lesion in the basis pontis region of the left upper pons with prolonged Tl and T2 (Figure, left), consistent with an infarc¬ tion. There was a marked rise in the CSF pleocytosis, with a leukocyte count of 63 to 234 X10VL (63 to 234/mm3), prior to the initiation of antibiotic therapy. The patient was started on intravenous penicil¬ lin G therapy (20 million U/d) on admis¬ sion to Massachusetts General Hospital and completed a three-week course with¬ out the occurrence of a Jarisch-Herxheimer reaction. Results of serial CSF examina¬ tions showed improvement and eventual normalization of the CSF (Table). The flac¬ cid right hemiplegia gradually became spastic and the patient regained a signifi¬ cant degree of strength. On discharge to a rehabilitation facility two months after admission he could ambulate with a walker but had impairment of fine movements of the right hand. Results of neurologic examination five months after the event revealed minimal right spastic hemiparesis, hyperreflexia, extensor plantar response, and mild impairment of fine finger movements of the right hand. The follow-up CSF exami¬ nation result was normal (Table). A con¬ trast CT scan result clearly demonstrated the left basis pontis infarction (Figure, right) without atrophy or other lesions. Serum HIV antibody was now reactive, he developed Pneumocystis carinii pneumo- Results of Serial Cerebrospinal Fluid Examinations* Case 2 Case 1 Day 3 Day 5 Day 10 Day 24 Day 42 Day 1 Day 6 Day 26 Leukocytes, No. X106/L 154 (154)_2 (2)_6 (6)_111 (111) 18 (18)_0 (No./mm3)_63 (63)_234 (234) 89 (0.89) 92 (0.92)_60 (0.60)_83(0.83) Lymphocytes, %_84 (0.84) 100(1.0) 100(1.0)_ 0.69 (69) 0.51 (51)t 034 (34)_0.24(24) Protein, g/L (mg/dL)_0.94 (94) 0.80(80) 0.58(58) 1.30(130) 2.7 (48) Glucose, mmol/L (mg/dL) 1.8(33)_1.8 (33)_2.3 (41)_2.7 (49)_12.6(227) 1.6(28)_2.1 (38) RPR___-_+_„_._-_U8_1_^4_ FTA-ABS_.___„_._2+_„_._._^_._^_._^_^__ Oligoclonal bands, No. 1 ... ... * ... ... ... ... ... Day designations indicate number of days following onset of pure motor hemiplegia; RPR, rapid plasma reagin; FTA-ABS, fluorescent treponemal antibody absorption; minus sign, absence of substance; plus sign, presence of substance. tlgG. 0.136 g/L (13.6 mg/dL); albumin. 0.38 g/L (38 mg/dL); ratio of IgG to albumin, 0.36:1. Left, Inversion recovery sequence transverse magnetic resonance images showing lesion in left basis pontis region of upper pons with prolonged T1, consistent with infarction. Right, Contrast computed tomographic scan, performed four months after magnetic resonance imaging shown at left, now clearly reveals left basis pontis infarction. No atrophy or other pathologic lesions were evident. nia, and was treated with two courses of intravenous sulfamethoxazole and tri- methoprim therapy. Case 2.—A 38-year-old right-handed homosexual man presented four months prior to admission because of penile chan¬ cres. He was treated with a single dose of intramuscular penicillin. At that time he also noted a "red" right eye, mild photo¬ phobia, and blurry vision in the right eye. Over the ensuing months his visual com¬ plaints gradually worsened after an initial period of improvement, he lost approxi¬ mately 9 kg and he noticed decreased hear¬ ing in his left ear. For three weeks prior to admission he noted occipital headache, mild stiff neck, and mental dullness, with¬ out fever or rash. He denied recent travel, exposure to pets, and intravenous drug use. He denied a history of previous syphilis but had been treated for several episodes of gonorrhea. On the day of admission he noted acute deterioration of the vision in his right eye. The right eye showed evidence of posterior uveitis with nearly complete retinal de¬ tachment. There was no evidence of optic neuritis and the left eye was normal. There was moderately severe sensorineural hear¬ ing loss in the left ear with a mild loss in Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/15/2015 the right ear. Results of physical examina¬ tion were otherwise notable for lack of fever, a 3 X 3-cm pigmented plaque in the right axilla, and five 1 X 0.5-cm reddishpurple macules on both ankles. The neck was supple, and there was cervical, axil¬ lary, and inguinal lymphadenopathy. There were no heart murmurs or carotid bruits. Results of neurologic examination revealed intact cortical function, and no focal motor or sensory deficits. A scierai buckle procedure was per¬ formed on the night of admission. A lum¬ bar puncture revealed a mononuclear pleo¬ cytosis, hypoglycorrhachia, and an ele- vated CSF protein level (Table). Gram's stain, acid-fast bacillus smear, and cryptococcal antigen and toxoplasmosis antibody stains were all negative. Serum HIV anti¬ body test result was reactive, and the HIV culture from the CSF was positive. Intravenous penicillin G therapy (20 million U/d) was started for presumptive syphilitic meningitis. Serum RPR titer was +1:256 with an FTA-ABS of 4+, and CSF RPR titer was +1:8. Just prior to receiving the first dose of penicillin, the patient noted weakness of his left arm and leg, dysarthria, and "twitching" of his left upper extremity. The involuntary move¬ ment of the left upper extremity recurred two additional times on day 1 and once on day 2 of therapy. The weakness progressed in a stepwise fashion over 36 hours. At its most severe, the neurologic deficit was 3/5 strength in the left arm and leg, with a left Babinski's sign, mild left central facial palsy, and minimal dysarthria. Sensation, extraocular movements, and pupillary reactions were normal. An electroencepha¬ logram was normal and a cranial CT scan revealed only mild cortical atrophy. An MRI scan revealed a small infarction in the right basis pontis. An audiogram showed bilateral moder¬ ately severe high-frequency sensorineural hearing loss, more severe in the right ear, and brain-stem auditory evoked responses were consistent with a cochlear defect. A skin biopsy specimen of the right axillary lesion revealed a plasma cell infiltrate with a negative Dieterlhe stain for treponemes. A biopsy specimen of the ankle lesions showed early vascular prolifera¬ tion, which was suspicious but not diagnos¬ tic of Kaposi's sarcoma. The patient became febrile to 38.9°C (102°F) approximately six hours after pen¬ icillin therapy was started. The fever per¬ sisted for 24 hours and prednisone therapy (50 mg/d) was administered for two days for a presumed Jarisch-Herxheimer reac¬ tion. Results of repeated CSF examination six days after the initiation of penicillin therapy showed an improvement in the CSF formula, with a leukocyte count of 18 X 10VL (18/mm3); glucose, 1.9 mmol/L (34 mg/dL); and protein, 0.8 g/L (80 mg/ dL). On discharge after 14 days of penicil¬ lin treatment, the motor deficit had resolved but the left Babinski's sign per¬ sisted. Results of follow-up CSF examina¬ tion four weeks after the initial event were normal (Table). COMMENT The pathologic basis of PMH was originally described as a lacunar infarction of the internal capsule or basis pontis.1 Subsequently, a wide variety of pathologic processes have been shown to cause PMH, including ischemie infarction,25 intracerebral hemorrhage,3·56 occluded internal ca¬ rotid artery,5 subdural hematoma,5 metastatic tumor,5 nocardial abscess,7 and multiple sclerosis.5 These varied pathologic causes have occurred throughout the extent of the pyrami- dal motor pathway: the motor cor¬ tex,5·7 corona radiata and internal cap¬ sule,3·5·6 mesencephalic cerebral pe¬ duncle,2 basis pontis,1·3 and medullary pyramid.4 Neurosyphilis has not been previously associated with PMH, pos¬ sibly because the PMH syndrome was formulated some 20 years after the peak incidence of neurosyphilis. A comparison of the usual clinical features of PMH with those in the present cases reveal that they fol¬ lowed a fairly typical course. Lacunar infarcts generally occur in the setting of risk factors for atherosclerosis, such as hypertension,1-3 but these are not prerequisite for the development of a severe arteropathy in the setting of neurosyphilis. The onset of PMH occurs usually in an intermit¬ tent, stepwise manner over several hours.1·3 The hallmark of PMH is a unilater¬ al motor deficit unaccompanied by other persistent neurologic abnormal¬ ities.1 However, subjective sensory phenomena at the onset of the deficit are relatively common.1 Additional evanescent neurologic signs and symptoms occur in the initial phases of pontine PMH, including dizziness, dysphagia,3 dysarthria, conjugate palsy, nystagmus, and forced gaze deviation of eyes.1 Headache is a rare occurrence in PMH1 and in our patients was probably secondary to the concomitant meningitis. Meningovascular neurosyphilis oc¬ curs predominantly in young males who had primary syphilis a few months to 12 years earlier (mean, seven years), although many patients do not recall previous syphilis infec¬ tion.8 There has been a recent increase in the incidence of primary syphilis and an increase in neurosyphilis inci¬ dence is therefore anticipated.9 This increase is seen in those forms of neurosyphilis with the shortest laten¬ cy periods, such as acute syphilitic meningitis and MVNS.913 Incidence of MVNS has been noted to be more frequent among the forms of neurosyphilis in the antibiotic1012 vs preantibiotic eras.8 Meningovascular neurosyphilis characteristically consists of a pro¬ dromal syndrome for weeks to months followed by a superimposed vascular event and an abnormal CSF formula.8 The prodromal symptoms include in¬ termittent headaches, dizziness, paresthesias, insomnia, emotional labili¬ ty, personality change, irritability, apathy, decreased memory, and giddi¬ ness.8-912 This constellation of symp¬ toms has been characterized as a form of "subacute encephalitis."' The vas- Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/15/2015 cular events are usually of acute apo¬ plectic onset but can be subacute.8·9 The neurologic deficits occur most commonly in the middle cerebral artery territory,812 with deficits in the basilar artery or its branches next highest in frequency.8 A number of midline brain-stem syndromes are known to be caused by MVNS, includ¬ ing the Millard-Gubler syndrome, which consists of contralateral PMH plus abducens or facial cranial nerve palsies.8 The CSF abnormalities, in conjunc¬ tion with the clinical state and blood syphilis serology, are crucial to the diagnosis of MVNS. The CSF shows a mononuclear pleocytosis with most patients having leukocyte counts of 11 to 100 X 106/L (11 to 100/mm3),8 al¬ though cell counts of greater than 200 X10VL (200/mm3) have been reported.9·10 There is a mild increase of total protein and discrete elevations of 7-globulin and IgG levels.'·10·14 The marked elevations of total IgG and more specific measures of central ner¬ vous system IgG levels (eg, CSF IgG index) seen in neurosyphilis are present in relatively few other condi¬ tions, such as some viral meningoencephalitides15 and in Lyme disease.16 Oligoclonal bands are present in the CSF in neurosyphilis1014 and have been shown to be intrathecally pro¬ duced IgG antibodies to Treponema pallidum.'4 Low CSF glucose levels occur in acute syphilitic meningitis8 and may be secondary to glycolytic activity of the tréponèmes. Alterna¬ tively, these patients may have had acute syphilitic meningitis with a localized arteritis leading to vascular occlusion. The CSF reactivity serves as an index of adequacy of therapy and examination of the CSF six months after treatment should show a normal cell count and falling protein content.11·12 The CSF nontreponemal tests (eg, VDRL and RPR) are highly specific but rather insensitive for the diagno¬ sis of neurosyphilis, with a false-nega¬ tive rate that ranges from 19%8 to approximately 50%.'"" A nonreactive CSF VDRL titer does not preclude neurosyphilis, and therefore it must remain a diagnosis of exclusion when there are positive serum serologie test results, an active CSF, and the appro¬ priate clinical setting. The CSF VDRL tends to be of very low titer, typically less than or equal to 1:4." A negative FTA-ABS in the blood excludes the diagnosis of neurosyphilis and thus renders CSF examination unneces¬ sary.12 The pathologic lesion of MVNS is an endarteritis of the medium and large arteries (Heubner's) and of the small arteries and arterioles (Nissl-Alzheimer's). Hyperplasia of the subintimal fibrous tissue results in a patho¬ logically narrowed lumen, which becomes thrombotically occluded and causes an ischemie infarction.8 The basis pontis infarcts demonstrated on MRI (Figure, left) and subsequently on CT scan in case 1 (Figure, right) closely resemble those pathologically proven to be responsible for PMH.1 These lesions are most likely due to thrombosis of small paramedian branches of the basilar artery,' due to the Nissl-Alzheimer type of syphilitic arteritis. The differential diagnosis of stroke in a young man encompasses a wide variety of causes, including athero¬ sclerosis, embolus from a cardiac source or from an intracranial aneu¬ rysm, coagulopathy, complicated mi¬ graine, and inflammatory arteropa- thy (including syphilis, tuberculosis, amphetamine abuse, systemic lupus erythematosus, periarteritis nodosa, and rheumatoid arthritis).17 The patient in case 1 did have mild mitral valve prolapse detected on echocardio¬ gram, but the stuttering onset of his deficit and the location of the infarct are more consistent with a thrombotic rather than an embolie vascular occlusion. Both patients had only min¬ imal risk factors for atherosclerosis, normal coagulation parameters, and negative serologie test results for col¬ lagen vascular disease. Among the inflammatory arteropathies, only syphilis and tuberculosis are asso¬ ciated with meningitis. There were multiple negative mycobacterial CSF cultures in our patients. Patient 1 developed a penicillin-responsive case of meningitis in an endemic area for Lyme disease with low positive titers against the Lyme spirochete, but the dramatic central nervous system involvement and lack of other mani¬ festations of Lyme disease contradict the diagnosis. Cerebral infarctions have been noted in patients with AIDS. Some patients have had nonbacterial thrombotic (marantic) endocardi¬ tis,1819 while others had no identifiable source of embolus or atherosclerosis.18 An atypical aseptic meningitis, with a prolonged or recurrent course and prominent cranial nerve involvement, has been described as a neurologic complication of AIDS.18 " Most recent¬ ly, HIV has been cultured from the CSF of patients with AIDS with men¬ ingitis and other neurologic disor¬ ders.20 Patient 1 had a negative CSF viral culture including specific culture for HIV. Patient 2 had a positive CSF culture for HIV. Aseptic meningitis and subacute encephalitis have been noted as an early or even the initial manifestation of AIDS.1819·21 A recent case of cerebral granulomatous angiitis, which resulted in multiple cere¬ bral infarctions, was associated with isolation of HIV from the CSF.22 This raises the possibility that HIV may directly cause a vasculitis or may have acted in synergy with paliidum in patient 2 to shorten the latency to onset of MVNS. It is also possible that patient 2 had clinically occult primary syphilis months or years earlier and that the penile chancres four months prior to admission represented rein¬ fection. Case 2 may represent the first example of isolation of HIV in the active CSF of neurosyphilis, perhaps due to the virus having increased access to the central nervous system because of meningitic inflammation. Gay males are at increased risk for both syphilis and AIDS.1821 Repeated infection with venereal disease has been identified as a major risk factor for the subsequent development of AIDS.18 Cell-mediated immunity has an important role in the host defense pallidum," and HlV-inagainst duced cell-mediated immunodeficien¬ cy may have adversely affected the course of primary syphilis in these patients and led to the development of neurosyphilis. It is also possible that dual infection with HIV and pallidum synergistically contributed to the vascular occlusions. The incidence of neurosyphilis in patients with AIDS is unknown but it may be a more common cause of neurologic illness in these patients than has been previous¬ ly appreciated. This is important since neurosyphilis is more readily treated than most opportunistic infections that involve the central nervous sys¬ tem in AIDS. The present cases illus¬ trate the fact that patients at risk for immunocompromise are susceptible to "traditional" as well as opportunis¬ tic pathogens. Clarification of a possi¬ ble interaction between AIDS and neurosyphilis awaits continued clini¬ cal observation, but we have recently encountered two other cases of neurosyphilis in young homosexual men with evidence of concurrent HIV infection.24 References 1. Fisher CM, Curry HB: Pure motor hemiplegia of vascular origin. Arch Neurol 1965;13:30\x=req-\ 44. 2. Ho K-L: Pure motor hemiplegia due to infarction of the cerebral peduncle. Arch Neurol 1982;39:524-526. 3. Rascol A, Clanet M, Manelfe C, et al: Pure motor hemiplegia: CT study of 30 patients. Stroke 1982;13:11-17. 4. Ropper AH, Fisher CM, Kleinman GM: Pyramidal infarction in the medulla: A cause of pure motor hemiplegia sparing the face. Neurology 1979;29:91-95. 5. Weisberg LA: Computed tomography and pure motor hemiparesis. Neurology 1979;29:490\x=req-\ 495. 6. Tapia JF, Kase CS, Sawyer RH, et al: Hypertensive putaminal hemorrhage presenting as pure motor hemiplegia. Stroke 1983;14:505\x=req-\ 506. 7. Weintraub MI, Glaser GH: Nocardial brain abscess and pure motor hemiplegia. NY State J Med 1970;70:2717-2721. 8. Merritt HH, Adams RD, Soloman HC: Neurosyphilis. New York, Oxford University Press Inc, 1946. 9. Holmes MD, Brant-Zawadski MM, Simon RP: Clinical features of meningovascular syphi- lis. Neurology 1984;34:553-556. 10. Aupy M, Benetier MP, Laporte A, et al: Neurosyphilitic arteritis: Clinical, paraclinical and therapeutic data: A review of six cases. Sem Hop 1982;58:1101-1106. 11. Burke JM, Schaberg DR: Neurosyphilis in the antibiotic era. Neurology 1985;35:1368-1371. 12. Simon RP: Neurosyphilis. Arch Neurol 1985;42:608-613. 13. Bayne LL, Schmidley JW, Goodin DS: Acute syphilitic meningitis. Arch Neurol 1986; 43:137-138. 14. Vartdal F, Vandvik B, Michaelsem TE, et al: Neurosyphilis: Intrathecal synthesis of oligoclonal antibodies to Treponema pallidum. Ann Neurol 1982;11:35-40. 15. Fishman RA: Cerebrospinal Fluid in Diseases of the Nervous System. Philadelphia, WB Saunders Co, 1980. 16. Pachner AR, Steere AC: The triad of neurologic manifestations of Lyme disease. Neurology 1985;35:47-53. 17. Hart RG, Miller VT: Cerebral infarction in young adults: A practical approach. Stroke 1982;17:110-114. 18. Levy RM, Bredesen DE, Rosenblum ML: Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): Experience Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/15/2015 at UCSF and review of the literature. J Neurosurg 1985;62:475-495. 19. Snider WD, Simpson DM, Nielsen S, et al: Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients. Ann Neurol 1983;14:403-418. 20. Ho DD, Rota TR, Schooley RT, et al: Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med 1985;313:1493-1497. 21. Koppel BS, Wormser GP, Tuchman AJ, et al: Central nervous system involvement in patients with acquired immune deficiency syndrome (AIDS). Acta Neurol Scand 1985;71:337\x=req-\ 353. 22. Yankner BA, Skolnick PR, Shoukimas GM, et al: Cerebral granulomatous angiitis associated with isolation of HTLV-III from the central nervous system. Ann Neurol 1986;20:362-364. 23. Pavia CS, Folds JD, Baseman JB: Cell\x=req-\ mediated immunity during syphilis: A review. Br J Vener Dis 1978;54:144-150. 24. Johns DR, Tierney M, Felsenstein D: Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus (HIV). N Engl J Med 1987;316:1569\x=req-\ 1572.