Neurology India, Vol. 59, No. 3, May-June, 2011, pp. 344-350
Clinical spectrum of neurosyphilis in North East India
Ashok K Kayal, Munindra Goswami, Marami Das, Biswajit Paul
Department of Neurology, Gauhati Medical College, Guwahati, Assam, India
Correspondence Address: Ashok K Kayal Department of Neurology, Gauhati Medical College, Guwahati, Assam India firstname.lastname@example.org
Date of Submission: 23-Feb-2011
Code Number: ni11107
AbstractBackground : Symptomatic neurosyphilis (NS) can have varied syndromic presentations: Meningitis, meningovascular and parenchymatous involvement.
Aims : To evaluate the different types of clinical syndrome of NS in a tertiary care hospital.
Material and Methods : This was a study of clinical profile of 16 patients with NS, seen in between August 2008 and December 2010.
Results : There were 13 male and 3 female patients in the age group of 23-48 years. The clinical syndromes included: Neuropsychiatric syndromes (10), myelopathy (5), and posterior circulation stroke (1). Neuropsychiatric symptoms were dementia, behavioral abnormalities, chronic psychosis, and myelopathy syndromes included acute transverse myelitis (ATM), chronic myelopathy, and syphilitic amyotrophy. Thirteen patients had positive venereal disease research laboratory test (VDRL) and/or high Treponema pallidum hemagglutination titer in blood. Cerebrospinal fluid was positive for VDRL in 14 patients, raised protein was seen in 13 patients and lymphocytic pleocytosis was seen in 10 patients. Human immunodeficiency virus serology was negative in all the patients. Fourteen patients fulfilled the criteria of definitive NS and two of presumptive NS. All the patients except one received injection Procaine penicillin for 14 days. The patient with myelitis received a course of steroid, and one patient with associated hypothyroidism received thyroid supplement in addition to penicillin. On follow-up, dementia of short duration and ischemic stroke improved significantly and clinical status remained the same for ATM; others with mild symptoms improved with residual deficit.
Conclusion : Syphilis can affect any part of the neuraxis. A high index of clinical suspicion is required to diagnose NS and institute the treatment early, particularly in patients with promiscuous sexual behavior.
Keywords: Hemagglutination test, neuropsychiatric features, neurosyphilis, Treponema pallidum, venereal disease research laboratory test
Neurosyphilis (NS) is defined as an infection of the central nervous system (CNS), caused by Treponema pallidum. Up to 4-10% of patients with untreated syphilis may develop NS.  The clinical presentations of NS are extremely varied, and for practical purposes, they can be divided into early and late NS depending on the duration of illness. Clinical presentations of early NS include meningovascular diseases. Although overlap can be substantial, late NS refers to the neurological manifestations associated with chronic syphilis in which the brain and spinal cord parenchyma are involved.  Nowadays, it rarely presents in its classical forms, tabes dorsalis or general paresis, and often presents with atypical features.  Roberts and Emsley  reported that physicians failed to diagnose NS probably due to low index of suspicion. Several recent reports suggest a worldwide increase in the incidence of NS.  The clinical and laboratory features of NS have been classified into six categories.  The traditional terminology used for NS lacks precise definition, and pathologically many cases may have combined meningeal, vascular, and parenchymal involvement.  Human immunodeficiency virus (HIV) and syphilis affect similar patient groups and co-infection is common. Syphilis may present with non-typical features in HIV positive patients. There is a higher rate of non-symptomatic primary syphilis, and proportionately more HIV positive patients present with secondary disease. Secondary infection may be more aggressive and there is an increased rate of early neurological involvement. Relapse of infection is more likely in HIV positive patients and careful follow-up is required.  Penicillin remains the drug of choice for the treatment of late syphilis. The evidence for the use of non-penicillin regimens in the treatment of NS is relatively weak and some specialists recommend desensitization for all patients with NS who have penicillin allergy.  Ceftriaxone can be used as an alternative treatment for patients with NS.  The aim of the present study was to evaluate different types of clinical presentations of NS.
Material and Methods
This study was performed in a tertiary teaching hospital between August 2008 and December 2010. Patients presenting with CNS disease, with history of promiscuous sexual behavior, underwent the following investigations: Blood Venereal Disease Research Laboratory test (VDRL), blood T. pallidum hemagglutination (TPHA), cerebrospinal fluid (CSF) biochemistry, cell count and VDRL. Other relevant investigations like thyroid and collagen profiles were also done in selected cases to exclude other etiologies causing the syndrome or as comorbid conditions. Patients who fulfilled the diagnostic criteria of NS were included in the analysis [Table - 1].  Patients were grouped as per the mode of presentation [Table - 2].  TPHA test was performed in the blood of 14 patients. CSF leukocytosis was defined as >5 leukocytes/mm 3 and protein concentrations of >40 mg/dl were considered abnormal. Neuroimaging was done in 15 patients. Serology for HIV was done in all the 16 patients and was negative.
All the patients except one received Inj. Procaine penicillin for 14 days. The patient with myelitis received a course of steroid and one patient with dorsal myelopathy who had associated hypothyroidism received thyroid supplement. On follow-up, repeat CSF investigations were done, and depending on CSF pleocytosis and/or CSF VDRL, course of Inj. Procaine penicillin was repeated. We could not follow any disability scale to ascertain the prognosis.
Details of patients' clinical features, investigations, treatment and follow-up are given in [Table - 3], [Table - 4] and [Table - 5]. Of the 16 patients, 14 met the diagnostic criteria for definite NS and 2 had presumptive NS. Thirteen patients (81.2%) were males and the mean age at presentation was 36.7 years (ranging from 23 to 48 years). Three males were unmarried. Ten patients had definite history of promiscuous sexual behavior; rest of the patients had denied any such behavior. Four had history suggestive of primary syphilis in the form of genital ulcer. History of substance abuse was found in 11 patients.
Neuropsychiatric disorders were seen in 10 patients, posterior circulation stroke in 1 patient and myelopathy in 5 patients. The different neuropsychiatric symptoms were dementia, behavioral abnormalities and chronic psychosis. Case 8, a 38-year-old unmarried male presented with cortical and extrapyramidal symptoms mimicking corticobasal degeneration and his brain magnetic resonance imaging (MRI) showed cortical atrophy. Case 14 presented with behavioral abnormalities and brain MRI features were mimicking herpes simplex encephalitis.
The different myelopathic features were acute transverse myelitis (ATM) in two patients and chronic myelopathy in three patients. One patient with chronic myelopathy (case 12) had features suggestive of motor neuron disease (amyotrophy). This patient presented with weakness, wasting, hypotonia, hyporeflexia of left upper limb and spasticity, hypereflexia of lower limbs with flexor planter reflex. On follow-up examination after 6 months, he showed clinical stability. Case 13 presented with acute onset of cortical blindness and imaging features were suggestive of posterior circulation ischemic stroke. Associated diseases were rheumatoid arthritis in one patient (case 6) and hypothyroidism in another patient (case 4).
CSF analysis: Cell count 0-170 cells/mm 3 (average 40 cells/mm 3 ), predominantly lymphocytes; protein 30-164 mg/dl (average 86.3 mg/dl); glucose 47-75 mg/dl (average 64.2 mg/dl), CSF VDRL reactive in all the patients with definite NS. Blood VDRL was reactive in 14 patients and non-reactive in 2 patients (cases 5 and 15) but TPHA was reactive in both of them. Blood VDRL was reactive in the spouse of one presumptive NS. HIV serology was negative in all the patients.
Patients with neuropsychiatric features were found to have cortical atrophic changes predominantly in the fronto-temporal region. In one patient (case 14) who presented with dementia and behavioral changes with occasional aggressive behavior and myoclonus of right leg, MRI brain revealed T2W and FLAIR hyperintensities in bilateral medial temporal lobes including hippocampus, parahippocampal gyri and insular cortex with diffuse cerebral atrophic changes mimicking herpes simplex encephalitis [Figure - 1],[Figure - 2],[Figure - 3]. His CSF antibody was negative for herpes simplex virus type 1 and 2 (both IgG and IgM antibody), and CSF VDRL was reactive. Two patients with ATM were found to have longitudinal extensive spinal cord lesions. Patient with cervical amyotrophy were found to have focal cord atrophy with increased signal in T2W MRI in the anterior horns of cervical cord extending from C5 to C7 level.
Treatment and follow-up
All patients were treated with Inj. Procaine penicillin 2.4 million units per day for 14 days and patients with ATM also received steroid for 5 days. Case 13 had hypersensitivity to penicillin and was given ceftriaxone 2 g 12 hourly for 14 days, followed by doxycycline 200 mg 12 hourly for 28 days. On follow-up of 12 patients for an average 9.8 months (3 months to 2 years), it was found that dementia of short duration and ischemic stroke improved significantly and clinical status was same for ATM, and others had partial improvement. Repeat CSF investigation done in six patients showed partial improvement of lymphocytic pleocytosis and protein level except in one (case 12) patient, who improved partially but CSF parameter did not change. MRI was repeated in two patients (cases 8 and 14) showed reduction in hyperintensity lesions.
This was a prospective study of 16 patients with NS seen within 2.5 years from North East India. Other series  from South India had reported 132 cases collected over a period of 5 years. Another series reported seven cases collected over a period of 7 months.  A study from North India reported 25 cases of NS collected over a period of 13 years. In the series by Srinivasan and Ranganathan,  the age group was 20-50 years, particularly in those with meningovascular syphilis with male gender predominance (124 of 132 cases).
Although NS has been divided into five major categories, i.e., asymptomatic, meningeal, meningovascular, parenchymatous, and gummatous, these entities represent a continuum and frequently overlap  and it is difficult to classify clinically patients into these different pathological groups. Neuropsychiatric features were the commonest form of presentation and NS can present with any type of neuropsychiatric symptoms. Kraft-Ebbing first reported general paresis of insane (GPI).  Commonly, the condition begins with mild nonspecific personality changes and amnesia, which may evolve into dementia with psychiatric symptoms such as delusions, hallucinations, mood disorders, delirium and aggression. The computer tomograph and MRI scan of brain in our patients revealed cortical atrophy predominantly in the fronto-temporal region and one case was mimicking herpes simplex encephalitis in keeping with published literature.  Psychiatric symptoms improved with addition of antibiotic therapy to the antipsychotic medication, similar to the case series by Sanchez and Ziesseiman.  One patient presented with features suggestive of corticobasal degeneration, similar to the case reported by Benitoleon et al.
Two patients had features suggestive of ATM, a known presentation of NS.  Three patients had features of chronic myelopathy, two presented with chronic myelopathy in the form of dorsal myelopathy and one presented with features like motor neuron disease. One of the patients with chronic myelopathy (case 15) had associated sensorineural deafness. He also had past history of chronic headache and MRI brain was suggestive of multiple chronic ischemic lesions. This reflects a continuum of meningovascular to parenchymatous form. Sensorineural deafness is a known feature of NS.  One patient presented with features like a motor neuron disease. This type of entity may be labeled as syphilitic amyotrophy.  Muscular atrophy in syphilis is due to a progressive degeneration of the anterior horn cells in the spinal cord and may result from any type, parenchymatous or meningovascular, of syphilis of the spinal cord, but the term syphilitic amyotrophy is usually reserved for the muscular atrophy which occurs in meningomyelitis.  Meningovascular syphilis involving cerebral vessels is a recognized cause of stroke.  One patient presented with posterior circulation stroke.
Ischemic stroke improved fully and clinical status was same for ATM, and others had partial improvement. Patients with NS should be reviewed clinically and follow-up CSF examinations should be done at 6-month intervals over the first 2 years or until the CSF becomes normal.  Resolving pleocytosis should occur over the first 6 months, while the CSF VDRL titer (if initially high) should decline fourfold within 1 year. It is noteworthy that the CSF VDRL titer may take years to revert to negative.  In our case series, on follow-up CSF examination, six patients were found to have lymphocytic pleocytosis with positive CSF VDRL and five patients were retreated with Inj. Procaine penicillin. One patient (case 12) refused to continue this treatment.
In conclusion, syphilis, a treatable condition, can involve any part of the neuraxis and the clinical picture can be divergent. Parenchymatous NS can present with neuropsychiatric syndromes and chronic myelopathy. Meningovascular NS can present with stroke and acute transverse myelitis. High index of suspicion of NS is required. Prognosis depends on the duration of illness, parenchymal or meningovascular involvement.
Copyright 2011 - Neurology India
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