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CLINRESREPORT   |    
The Clinical Analysis of General Paresis With 5 Cases
Wei Luo, M.D.; Zhiyuan Ouyang; Huayan Xu; Jiayan Chen, M.D., Ph.D.; Meiping Ding; Baorong Zhang, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2008;20:490-493.
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Received June 27, 2007; revised September 23 and October 6, 2007; accepted October 15, 2007. Drs. Luo, Ouyang, Xu, Ding, and Zhang are affiliated with the Department of Neurology, Second Affiliated Hospital, School of Medicine, at Zhejiang University, China. Dr. Chen is affiliated with the Zilkha Neurogenetic Institute at the University of Southern California. Address correspondence to Wei Luo, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; luoweirock@yahoo.com.cn (e-mail).

Copyright © 2008 American Psychiatric Publishing, Inc.

General paresis is considered to be a "treatable" dementia, in which early diagnosis and treatment play a very important role. In recent years, its occurrence might have increased significantly due to the increasing incidence of syphilis. The authors report five cases of general paresis in order to draw attention to this dementia.

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We retrospectively reviewed five diagnosed cases of general paresis between February 2000 and June 2006 at a university hospital in Zhejiang, China. Selected patients were diagnosed with general paresis using clinical features and the etiological test in serum and CSF. There were four men and one woman, with a mean onset age of 40.4 years and an average disease progression of 20 months. Among them, four cases exhibited cognitive impairment, two had urinary incontinence, and two had psychotic disorder; neurological exam showed tendon hyperreflexia in three cases and dysarthria in two cases (Table 1 ). Cerebral MRI showed cerebral atrophy in all five cases and the CSF was abnormal in all cases. All of the patients were treated with a high dose of penicillin. The clinical symptoms improved significantly in four cases, while the other patient showed little improvement resulting from the long duration from onset to treatment.

Five patients with general paresis were admitted to the Second Affiliated Hospital of Zhejiang University between February 2000 and June 2006. Four men and one woman, ranging from 31 years to 52 years of age, were all negative for HIV antibodies. Table 1 shows their clinical characteristics. The disease progressed slowly, with an average duration of 20 months from onset to treatment (range=6—48 months). Through clinical examinations, we found that most of their symptoms were mental disorders. The main symptoms included cognitive impairment in four patients, urinary incontinence in two patients, and psychotic disorder in two patients. Case 1 presented with hemiparalysis after 1 year of cognitive impairment without fever or headache. Neurological exam indicated tendon hyperreflexia in three cases, dysarthria in two cases, and intention tremor in one case (Table 1 ). The Treponema pallidum particle agglutination (TPPA) and rapid plasma reagin test (RPR) of the serum and CSF were positive in all cases. The CSF specimens submitted to the laboratory for testing had no visible blood contamination. Cell counts of CSF were increased in three cases, and protein levels were high in all cases. Other laboratory tests, including serum thyroid hormonal levels, serum vitamin B1 level, and immunoglobulin G antibody titer for herpes simplex virus type 1 in the CSF were all negative. Cranial MRI was performed in all patients before or during an early stage of the treatment. All cases showed abnormal results, mainly displaying cerebral atrophy, and two cases without history of hypertension, atherosclerosis, or diabetes exhibited lacunar infarction. The single photon emission computed tomography (SPECT) performed in Case 5 showed diffusely decreased cerebral blood flow (CBF). After 15 days of successful treatment, however, the SPECT showed more reduction in CBF compared to the previous test, predominantly in the right thalamus. Electroencephalograms (EEGs) performed on four of the patients showed diffuse disturbances in background rhythms marked by excessively slow activity.

All patients were treated with a large dose of penicillin G, ranging from 16 to 24 MU/day, administered intravenously every 4 to 8 hours. After about 2 weeks of treatment, the symptoms of four patients improved in varying degrees. Two of them could continue to work and another two could take care of themselves. For example, in Case 5, the titer of CSF rapid plasma reagent decreased from 1:16 to 1:8, the protein levels dropped significantly from 254 to 73.5 mg/dl (toward good direction though still above normal), and the score of Mini-Mental State Examination (MMSE) increased from 14 to 26 after 2 weeks of treatment. However, the symptoms for Case 3 did not significantly improve after 14 days of penicillin G treatment, which was possibly due to late treatment.

General paresis is a clinical type of late-stage syphilis and neurosyphilis. Symptoms vary among patients and there is no gold standard to diagnose at present. Diagnosis of general paresis depends on clinical evaluation, serologic testing, and CSF examination. The criteria for diagnosis of neurosyphilis recommended by the Centers for Disease Control and Prevention is as follows: CNS or ophthalmic signs or symptoms; serologic evidence (positive nontreponemal and positive treponemal test results) for syphilis infection plus either positive venereal disease research laboratory CSF, increased CSF protein (>40 mg/dl), or increased CSF leukocyte count (>5 mononuclear cells/μL).1 All five patients met the diagnostic criteria for general paresis. Clinical indications of the five cases were similar to those reported in recent literature, mainly exhibiting cognitive impairment, psychotic disorder, memory loss, and tendon hyperreflexia. There were two patients who displayed urinary incontinence, which is rarely reported in general paresis. Yet it can be seen in tabes dorsalis and may have hypocompliant detrusor hyperreflexia with detrusor-sphincter dyssynergia and postmicturition residual urine.2 The cranial MRI of Case 1, who exhibited hemiparalysis, revealed both acute and old lacunar infarction in the bilateral basal ganglia. The 31-year-old patient presented with hemiparalysis after 1 year of cognitive impairment, so we inferred that the patient might have general paresis combined with meningovascular syphilis. Case 3 exhibited old lacunar infarction without related symptoms. The infarction could also be seen in general paresis in Kodama et al.’s3 report. The longer the clinical course is, the more complicated the clinical manifestation and unfavorable prognosis. For example, Case 3, with 4 years of clinical course, presented with not only cognitive impairment and psychotic disorder, but also cerebellar signs such as intention tremor, broad-based gait, and glossopharyngeal paralysis. The cranial MRI revealed cerebral atrophy, primarily in the frontal and temporal lobe. It was reported that medial temporal lobe atrophy may be a poor prognostic sign in general paresis.3 In this patient, the personality change and general dementia remained after the complete penicillin G treatment, and the outcome for social function was poor. After the patient was treated with intravenous penicillin G for 14 days, the basic medical examination, neurological examination, and intelligence testing were the same as during original hospitalization. The cranial MRI performed in all five cases showed cerebral atrophy. The neuroimages of neurosyphilis generally are not very specific and thus of little value in making a diagnosis. SPECT has been employed to study cases of general paresis, as well as other natural mental disorders. The results of previous studies regarding the relationship between clinical status and CBF changes are still ambiguous. After 15 days of penicillin G treatment, the clinical symptoms had remitted, and laboratory results were improved, but the CBF still decreased. Kitabayashi et al.’s4 study suggested that in cases of general paresis, rapid marked decrease of quantitative CBF counts after penicillin treatment reflects the disappearance of encephalitis. Moreover, their slow recovery over 1 year reflects the gradual improvement of IQ and overall level of function.4 EEGs performed on four of the patients, three of whom had abnormal EEG manifestation, mostly revealed generalized arrhythmic slow activity. It is not specific and can be also seen in other diseases.

General paresis, the encephalitic form of neurosyphilis, typically presents as progressive dementia beginning 15—20 years after original infection (range 3—30 years). The clinical features of general paresis may include cognitive impairment, delusional or apathetic states, dysarthria, myoclonus, intention tremors, seizures, hyperreflexia, and Argyll Robertson pupils.5 After a decade of decline, rates of primary and secondary syphilis again began to rise in the United States in 2001.6 The increasing incidence among men who have sex with men in major cities accounted for the overall increase in incidence.7 In San Francisco, the increased incidence in early syphilis has been accompanied by increasing rates of neurosyphilis,8 and HIV infection also increases the risk of neurosyphilis.9 Similar trends have also been observed in Canada and Europe.10 At present, it is not known how many of those infected in recent syphilis outbreaks may go on to general paresis. A recent study showed that general paresis accounted for 25.6% of the 43 immunocompetent patients with neurosyphilis.11 It is quite possible that the incidence of general paresis might also increase correspondingly with the increased incidence of primary and secondary syphilis. In China, since the sexually transmitted diseases (STDs) were recognized as a public health problem during the early 1980s, the incidence of syphilis has gradually increased.12 General paresis increased correspondingly. The latter is considered to be a "treatable" dementia because it can be treated with antibiotics, mainly penicillin.13 However, early diagnosis and treatment are very important.

Sexually transmitted diseases were common before and during the early period of the foundation of the People’s Republic of China in 1949. They were virtually eliminated across the country by 1964,14 but reform and opening-up policies that started in 1978 have rapidly changed the situation, especially in the past 15 years. The number of STD cases reported has been increasing significantly since then. Similarly, syphilis incidence increased approximately 20 times during 1989 to 1998, at an average annual increase of 52.7%.12 This introduced a big health risk for the population and has been noticed by Chinese and foreign health researchers. General paresis should be seriously considered as one of the most severe outcomes of syphilis by doctors. If there is cognitive dysfunction or cerebral atrophy of unknown cause, general paresis should be considered.

TABLE 1. Clinical Manifestation, Laboratory Test, and MRI of Five Patients Diagnosed with General Paresis
.
Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002; 51:1—78
 
.
Garber SJ, Christmas TJ, Rickards D: Voiding dysfunction due to neurosyphilis. Br J Urol 1990; 66:19—21
 
.
Kodama K, Okada S, Komatsu N, et al: Relationship between MRI findings and prognosis for patients with general paresis. J Neuropsychiatry Clin Neurosci 2000; 12:246—250
 
.
Kitabayashi Y, Ueda H, Narumoto J, et al: Cerebral blood flow changes in general paresis following penicillin treatment: a longitudinal single photon emission computed tomography study. Psychiatry Clin Neurosci 2002; 56:65—70
 
.
Walter GB, Robert BD, Gerald MF, et al: Neurology in Clinical Practice, 4th ed. Philadelphia, Butterworth-Heinemann, 2004, pp 1496—1498
 
.
Centers for Disease Control and Prevention: Primary and secondary syphilis—United States, 2002. MMWR Morb Mortal Wkly Rep 2003; 52:1117—1120
 
.
Peterman TA, Heffelfinger JD, Swint EB, et al: The changing epidemiology of syphilis. Sex Transm Dis 2005; 32:S4—10
 
.
San Francisco Department of Public Health: San Francisco sexually transmitted disease annual report, 2004. Available at http://www.dph.sf.ca.us/reports/std/sfstdannlsum2004.pdf
 
.
Marra CM: Syphilis and human immunodeficiency virus: prevention and politics. Arch Neurol 2004; 61:1505—1508
 
.
Hook EW III, Peeling RW: Syphilis control—a continuing challenge. N Engl J Med 2004; 351:122—124
 
.
Conde-Sendin MA, Amela-Peris R, Aladro-Benito Y, et al: Current clinical spectrum of neurosyphilis in immunocompetent patients. Eur Neurol 2004; 52:29—35
 
.
Chen XS, Gong XD, Liang GJ, et al: Epidemiologic Trends of Sexually Transmitted Diseases in China. Sex Transm Dis 2000; 27:138—142
 
.
Jay CA: Treatment of neurosyphilis. Curr Treat Options Neurol 2006; 8:185—192
 
.
Cohen MS, Henderson GE, Aiello P, et al: Successful eradication of sexually transmitted diseases in the People’s Republic of China: implications for the 21st century. J Infect Dis 1996; 174(suppl 2):S223—229
 
TABLE 1. Clinical Manifestation, Laboratory Test, and MRI of Five Patients Diagnosed with General Paresis
+

References

.
Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002; 51:1—78
 
.
Garber SJ, Christmas TJ, Rickards D: Voiding dysfunction due to neurosyphilis. Br J Urol 1990; 66:19—21
 
.
Kodama K, Okada S, Komatsu N, et al: Relationship between MRI findings and prognosis for patients with general paresis. J Neuropsychiatry Clin Neurosci 2000; 12:246—250
 
.
Kitabayashi Y, Ueda H, Narumoto J, et al: Cerebral blood flow changes in general paresis following penicillin treatment: a longitudinal single photon emission computed tomography study. Psychiatry Clin Neurosci 2002; 56:65—70
 
.
Walter GB, Robert BD, Gerald MF, et al: Neurology in Clinical Practice, 4th ed. Philadelphia, Butterworth-Heinemann, 2004, pp 1496—1498
 
.
Centers for Disease Control and Prevention: Primary and secondary syphilis—United States, 2002. MMWR Morb Mortal Wkly Rep 2003; 52:1117—1120
 
.
Peterman TA, Heffelfinger JD, Swint EB, et al: The changing epidemiology of syphilis. Sex Transm Dis 2005; 32:S4—10
 
.
San Francisco Department of Public Health: San Francisco sexually transmitted disease annual report, 2004. Available at http://www.dph.sf.ca.us/reports/std/sfstdannlsum2004.pdf
 
.
Marra CM: Syphilis and human immunodeficiency virus: prevention and politics. Arch Neurol 2004; 61:1505—1508
 
.
Hook EW III, Peeling RW: Syphilis control—a continuing challenge. N Engl J Med 2004; 351:122—124
 
.
Conde-Sendin MA, Amela-Peris R, Aladro-Benito Y, et al: Current clinical spectrum of neurosyphilis in immunocompetent patients. Eur Neurol 2004; 52:29—35
 
.
Chen XS, Gong XD, Liang GJ, et al: Epidemiologic Trends of Sexually Transmitted Diseases in China. Sex Transm Dis 2000; 27:138—142
 
.
Jay CA: Treatment of neurosyphilis. Curr Treat Options Neurol 2006; 8:185—192
 
.
Cohen MS, Henderson GE, Aiello P, et al: Successful eradication of sexually transmitted diseases in the People’s Republic of China: implications for the 21st century. J Infect Dis 1996; 174(suppl 2):S223—229
 
+
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