Neurosyphilis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
Neurosyphilis refers to a site of infection involving the central nervous system (CNS). It may occur at any stage of syphilis. Before the advent of antibiotics, it was typically seen in 25-35% of patients with syphilis. Neurosyphilis is now most common in patients with HIV infection. Reports of neurosyphilis in HIV-infected persons are similar to cases reported before the HIV pandemic. The precise extent and significance of neurologic involvement in HIV-infected patients with syphilis, reflected by either laboratory or clinical criteria, have not been well characterized. Furthermore, the alteration of host immunosuppression by antiretroviral therapy in recent years has further complicated such characterization.
Historical Perspective
During the Napeoleonic Wars, General Paresis of the Insane(GPI) first appears to be reported in Paris. In 1836, Marshall Hall an English physician found a patient with loss of postural control in darkness caused by severely compromised proprioception, but He did not develop more information about it. In 1840, Moritz Heinrich Romberg, a german physician was the first who discovered tabes dorsalis which is the most prominent manifestation of neurosyphilis. He described excessive drinking and increase sexual activity may be the causes of tabes dorsalis. He named the disease as progressive locomotor ataxia. He was unable to find the relation between syphilis and tabes doesalis. In 1858, Guillaume Duchenne a French neurologist for the first time described the association between syphilis and neurosyphilis .In 1875, Jean-Alfred Fournier, a French dermatologist conclusively described the syphilis as the main cause of tabes dorsalis. In 1888, Sir William R. Gowers a British neurologist gave accurate details of the modern Romberg's test.
Classification
The forms of presentation of neurosyphilis can be grouped in two categories: early (asymptomatic which is the most common form, meningealand meningovascular neurosyphilis and late (progressive general paralysis and tabes dorsalis). Other less important forms are gummas, ocular forms of neurosyphilis and syphilitic amyotrophy or hypoacusis
Pathophysiology
Neurosyphilis is caused by Treponema pallidum, the bacteria that cause syphilis. It usually occurs about 10 - 20 years after a person is first infected with syphilis. Not everyone who has syphilis will develop this complication. Treponema pallidum is usually transmitted via direct contact with the infected lesion (sexual contact) or blood transfusion (rare). The incubation period varies with the size of innoculum (9-90 days). Following transmission, Treponema pallidum uses the intact or abraded mucous membrane to enter the body. It then disseminates to the lymphatics and blood stream to gain access to any organ of the body. Syphilis uses fibronectin molecules to attach to the endothelial surface of the vessels in organs resulting in inflammation and obliteration of the small blood vessels causing vasculitis (endarteritis obliterans). Organism has slow replication rate (30-33 hrs) and evades the initial host immune response. It may seed to different organs of the body especially the cardiovascular system and central nervous system resulting in tertiary syphilis. Different stages of syphilis results from the interaction between the antigen and the host immune response. The initial infection in primary syphilis is limited due to Th1 response and lack of the antibodyresponse. It is speculated that there is a shift from Th1 to Th2 response during secondary syphilis. Cytotoxic T cells and an incomplete humoral immunity response is mainly responsible for persistence of infection and tissue damage in tertiary syphilis. Ineffective type 4 delayed hypersensitivity reaction containing macrophages and sensitized T cells is mainly responsible for the gumma formation in various organs. There is no known genetic association of syphilis. However, neurosyphilis may be associated with the gene polymorphism for IL-10 production with increased levels seen in the patients with neurosyphilis. In neurosyphilis, the brain tissue and preganglionic portion of the dorsal roots of spinal nerves is infiltrated with lymphocytes and plasma cells, and invasion of treponema pallidum spirochetes to brain tissue and posterior columns of the spinal cord makes them atrophic. The demyelination of the axones of the neurons is the main cause of symptoms and it affects the neuronsin the brain, dorsal root ganglia and posterior columns of the spinal cord.
Causes
Neurosyphilis is a complication of late or tertiary syphilis infection. Syphilis is a sexually transmitted infectious disease. The infection damages the brain, spinal cord and peripheral nervous tissue.
Differentiating Neurosyphilis from Other Diseases
Neurosyphilis must be differentiated from other diseases that cause abnormal gait, blindness, confusion and depression, such as multiple sclerosis, brain tumors, Wernicke’s encephalopathy, CNS abscess, electrolyte disturbance, subdural empyema, subarachnoid hemorrhage, brain stroke, conversion disorder and drug toxicity.
Epidemiology and Demographics
Neurosyphilis is not a common disease now because syphilis is usually treated early. In 2012, the incidence of syphilis was estimated to be 6 million cases worldwide. From year 2005 to 2014, the incidence of syphilis in the United States increased from 2.9 to 6.3 cases/100,000/year. The rate of reported cases increased by 15.1% between 2013 and 2014 in the United States. In 2012, the prevalence of syphilis was estimated to be approximately 18 million cases in men and women aged 15-29 worldwide. Among infected patients with Treponema pallidum only 3 to 5% develop neurosyphilis and 5% of those individuals develop tabes dorsalis, 10–20 years later.
Risk Factors
The most potent risk factor in the development of neurosyphilis is HIV infection. Other risk factors include male gender, high serum RPR titer, advanced age, and African American race.
Screening
Screening guidelines for syphilis include all high risk non-pregnant individuals aged 15-65, all pregnant females, men who have sex with men, women who have sex with women, and HIV positive individuals. Routine screening of adolescents who are asymptomatic for syphilis is not recommended.
Natural History, Complications and Prognosis
The symptoms of neurosyphilis usually develop secondary to long-term untreated syphilis, and include diplopia, impaired vision, hearing loss, hoarseness, persistent headache, dizziness, vertigo, lightning pains, impaired sensation and proprioception, hypesthesias, hemiparesis, homonymous hemianopsia, slurred speech and dysarthria. If left untreated, most patients with neurosyphilis may progress to develop paralysis, dementia, Charcot arthropathy, stroke and blindness. Common complications of neurosyphilis include meningitis, meningiovascular syphilis, Argyll-Robertson pupil, stroke, cranial nerve neuropathies, dementia, paralysis, Charcot arthropathy (Charcot joint) of the foot and sensory ataxic gait.
Diagnosis
Diagnostic Study of Choice
The first step laboratory test when there is a clinical suspicious toward neurosyphilis is a venereal disease research laboratory test (VDRL) or rapid plasma reagin (RPR). Fluorescent treponemal antibody absorbed (FTA-ABS) test is the gold standard test for the diagnosis of neurosyphilis.
History and Symptoms
The late forms of neurosyphilis (tabes dorsalis and general paresis) are seen much less frequently since the advent of antibiotics. The most common manifestations today are asymptomatic or symptomatic meningitis. Clinical signs of neurosyphilis (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities) warrant further investigation and treatment for neurosyphilis.
Physical Examination
Patients with neurosyphilis may be asymptomatic. Physical examination of patients with neurosyphilis is usually remarkable for: Argyll-Robertson pupils, impaired vibratory and proprioception sense, broad base and sensory ataxic gait and positive romberg's test.
Laboratory Findings
Approximately 35% to 40% of persons with secondary syphilis have asymptomatic central nervous system (CNS) involvement, as demonstrated by an abnormal leukocyte cell count, protein level, or glucose level or a demonstrated reactivity to Venereal Disease Research Laboratory (VDRL) antibody test on cerebrospinal fluid (CSF) examination. Laboratory testing is helpful in supporting the diagnosis of neurosyphilis; however, no single test can be used to diagnose neurosyphilis in all instances.
Electrocardiogram
There are no ECG findings associated with neurosyphilis.
X-ray
X-rays are not routinely recommended to detect neurosyphilis. However, complications associated with syphilis may be detected incidentally on x-ray. Cardiovascular manifestations of syphilis may be seen as a non-specific widening of the aortic or mediastinal silhouettes on PA and lateral chest x-ray. Linear calcification of the ascending aorta is an almost pathognomonic finding of syphlitic aortitis. This may prompt the clinician to order further imaging studies for confirmation. Additionally, on chest x-ray, secondary pulmonary syphilis may be characterized by the bilateral infiltrates, pleural effusion, subpleural nodules, and lymphadenopathy. X-ray findings may also include osteolytic bone lesions.
Echocardiography and ultrasound
There are no echocardiography/ultrasound findings associated with neurosyphilis.
CT
CNS CT scan may be helpful in the diagnosis of neurosyphilis. Findings on CT scan suggestive of of neurosyoohilis include areas of decreased density suggesting cerebral infarction, syphilitic gumma (appear hypodense with precontrast), focal or diffuse extraaxial enhancement and non-specific white matter lesions.
MRI scan
Spinal and brain MRI may be helpful in the diagnosis of neurosyphilis. Findings on MRI suggestive of neurosyphilis include non specific white matter lesions (cerebral gummas or arteritis), hyperintensity in mesiotemporal lobes, cortical atrophy , cerebral infarction, hippocampal atrophy, hyperintensities in multiple cortical areas and thalami, intramedullary hyperintensity and spinal cord atrophy, longitudinal T2-weighted hyperintensity in the dorsal columns of the spinal cord, narrowing between the cervical intervertebral discs and partial ankylosis of the cervical disc space, bilateral high intensity signals on the T2 weighted sequence located in mesiotemporal, insular, frontal regions and calcification of the ligamentum flavum.
Other imaging findings
Other imaging findings of neurosyphilis include novel PET/CT technology, multimodal ophthalmologic imaging and bone scintigraphy. In PET/CT scan, increased FDG uptake in lymph nodes may be seen. Multimodal ophthalmologic imaging combines ophthalmoscopy with spectral domain optical coherence tomography (SD-OCT) to produce high definition imaging of the posterior chamber of the eye. Bone scintigraphy allows clinicians to visualize bone uptake of Technetium-99 (T-99m) using x-ray technology.
Other diagnostic studies
Biopsy may be considered in some cases of neurosyphilis if clinical findings do not correlate with negative serological tests and there is a strong index of suspicion for neurosyphilis.
Treatment
Medical Therapy
CNS involvement can occur during any stage of syphilis. However, CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurological findings. No evidence exists to support variation from recommended treatment for early syphilis for patients found to have such abnormalities. If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis), a CSF examination should be performed. Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis and should be managed according to the treatment recommendations for neurosyphilis. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the recommended regimen for neurosyphilis; those with eye disease should be managed in collaboration with an ophthalmologist. A CSF examination should be performed for all patients with syphilitic eye disease to identify those with abnormalities; patients found to have abnormal CSF test results should be provided follow-up CSF examinations to assess treatment response.
Surgery
Surgical intervention is not recommended for the management of neurosyphilis.
Primary Prevention
There is no vaccine available for prevention of syphilis. However, effective measures for the primary prevention of syphilis include abstinence from intimate physical contact with an infected person, consistent use of latex condoms, limiting number of sexual partners, avoidance of sharing sex toys, practising safe sex, routine screening in pregnant females, individuals with high risk behaviours, and those residing in highly prevalent areas. In patients with diagnosed syphilis, early treatment with penicillin can widely prevent neurosyphilis.
Secondary Prevention
Secondary prevention strategies following syphilis include routine screening and follow up in patients with early syphilis to prevent complications, diagnosis and treatment of sexual partners of infected individuals, routine screening, diagnosis and treatment in pregnant females. In patients with diagnosed syphilis, early treatment with penicillin can completely prevent neurosyphlis.