Man, 54, With Delusions and Seizures

A 54-year-old African-American man was brought by police officers to the emergency department (ED) after he called 911 several times to report seeing a Rottweiler looking into his second-story window. At the scene, the police were unable to confirm his story, thought the man seemed intoxicated, and brought him to the ED for evaluation.

The patient reported that he had been drinking the previous evening but denied current intoxication or illicit drug use. He denied experiencing symptoms of alcohol withdrawal.

Regarding his medical history, the patient admitted to having had seizures, including two episodes that he said required hospitalization. He described these episodes as right-hand “tingling” (paresthesias), accompanied by right-facial numbness and aphasia. The patient said his physician had instructed him to take “a few phenytoin pills” whenever these episodes occurred. He reported that the medication usually helped resolve his symptoms. He said he had taken phenytoin shortly before his current presentation.

According to friends of the patient who were questioned, he had had noticeable memory problems during the previous six to eight months. They said that he often told the same joke, day after day. His speech had become increasingly slurred, even when he was not drinking.

Once the patient’s medical records were retrieved, it was revealed that he had been hospitalized twice for witnessed grand mal seizures about six months before his current admission; he had been drinking alcohol prior to both episodes. He underwent electroencephalography (EEG) during one of these hospitalizations, with results reported as normal. On both occasions, the patient was discharged with phenytoin and was instructed to follow up with his primary care provider and neurologist.

The patient, who reported working in customer service, had no known allergies. He claimed to drink one or two 40-ounce beers twice per week and admitted to occasional cocaine use. Of significance in his family history was a fatal MI in his mother. Although the patient denied any history of rashes or lesions, his current delirium made it impossible to obtain a reliable sexual history; a friend who was questioned, however, described the patient as promiscuous.

On initial physical examination, the man was afebrile, tachycardic, and somewhat combative with the ED staff. He was fully oriented to self but only partially to place and time.

His right pupil was 3+ and his left pupil was 2+, with neither reactive to light. He spoke with tangential speech and his gait was unsteady, but no other significant abnormalities were noted. A full assessment revealed no rashes or other lesions.

Significant laboratory findings included a low level of phenytoin, a negative blood alcohol level, presence of cocaine on urine drug screening, and normal levels of thyroid-stimulating hormone (TSH), vitamin B12, and folate. The patient’s serum VDRL (venereal disease research laboratory) titer was positive at 1:256.

Electroencephalography showed diffuse slowing, and brain CT performed in the ED showed atrophy that was mild but appropriate for a person of the patient’s age, with no evidence of a cerebrovascular accident (CVA). Aneurysm was ruled out by CT angiography of the brain. MRI revealed persistent increased signal in the subarachnoid space.

The patient was admitted with an initial diagnosis of paranoid delusional psychosis and monitored for alcohol withdrawal. He was given lorazepam as needed for agitation. Consultations were arranged with the psychiatry service regarding his delusions, and with neurology to determine whether to continue phenytoin.

The patient showed little response during the next several days. Based on positive results on serum VDRL with high titer, the presence of Argyll-Robertson pupils on exam, and his history of dementia-like symptoms, a lumbar puncture was performed to rule out neurosyphilis. In the patient’s cerebral spinal fluid (CSF) analysis, the first tube was clear and colorless, with 72 cells (28% neutrophils, 59% lymphocytes); glucose, 64 mg/dL; and total protein, 117 mg/dL. The fourth tube had 34 cells (17% neutrophils, 65% lymphocytes) and a positive VDRL titer at 1:128. Results from a serum syphilis immunoglobulin G (IgG) test were positive, and HIV antibody testing was nonreactive, confirming the diagnosis of neurosyphilis.

The hospital’s infectious disease (ID) team recommended treatment with IV penicillin for 14 days. Once this was completed, the patient was discharged with instructions to follow up at the ID clinic in three months for a repeat CSF VDRL titer to monitor for resolution of the disease. His prescription for phenytoin was discontinued.

At the time of discharge, it was noted that the patient showed no evidence of having regained cognitive function. He was deemed by the psychiatry service to lack decision-making capacity—a likely sequelae of untreated neurosyphilis of unknown duration.

He did return to the ID clinic six months after his discharge. At that visit, a VDRL serum titer was drawn with a result of 1:64, a decrease from 1:128. His syphilis IgG remained positive, however.

Discussion
Definition and Epidemiology
Syphilis is commonly known as a sexually transmitted disease with primary, secondary, and tertiary (early and late latent) stages.¹ Neurosyphilis is defined as a manifestation of the inflammatory response to invasion over decades by the Treponema pallidum spirochete in the CSF as a result of untreated primary and/or secondary syphilis.² About one in 10 patients with untreated syphilis will experience neurologic involvement.^3,4 Before 2005, neurosyphilis was required to be reported as a specific stage of syphilis (ie, a manifestation of tertiary syphilis4), but now should be reported as syphilis with neurologic manifestations.⁵

A reportable infectious disease, syphilis was widespread until the advent of penicillin. According to CDC statistics,⁶ the number of reported cases of primary and secondary syphilis has declined steadily since 1943. In the late 1970s and early 1980s, the number of tertiary cases also began to plateau, likely as a result of earlier diagnosis and more widespread use of penicillin. Recent case reports suggest greater prevalence of syphilis among men than women and increased incidence among men who have sex with men.⁷

Pathogenesis
Syphilis is most commonly spread by sexual contact or contact with an infected primary lesion (chancre). Less likely routes of transmission are placental passage or blood transfusion. Infectivity is greatest in the early disease stages.⁸

Primary syphilis is marked by transmission of the spirochete, ending with development of secondary syphilis (usually two to 12 weeks after transmission). A chancre commonly develops but is often missed by patients because it is painless and can heal spontaneously.⁷ The chancre is also often confused with two other sources of genital lesions, herpes simplex (genital herpes) and Haemophilus ducreyi (chancroid). In two-thirds of cases of untreated primary syphilis, the infection clears spontaneously, but in the remaining one-third, the disease progresses.⁸

Secondary syphilis, with or without presence of a chancre, manifests with constitutional symptoms, including lymphadenopathy, fever, headache, and malaise. Patients in this disease phase may also present with a generalized, nonpruritic, macular to maculopapular or pustular rash. The rash can affect the skin of the trunk, the proximal extremities, and the palms and soles. Ocular involvement may occur, especially in patients who are coinfected with HIV.⁸ In either primary or secondary syphilis, infection can invade the central nervous system.¹

During latent syphilis, patients show serologic conversion without overt symptoms. Early latent syphilis is defined as infection within the previous year, as demonstrated by conversion from negative to positive testing, or an increase in titers within the previous year. Any case occurring after one year is defined as late or unknown latent syphilis.⁸

Tertiary syphilis is marked by complications resulting from untreated syphilis; affected patients commonly experience central nervous system and cardiovascular involvement. Gummatous disease is seen in 15% of patients.¹

The early stages of neurosyphilis may be asymptomatic, acute meningeal, and meningovascular.^1,4,8,9 Only 5% of patients with early neurosyphilis are symptomatic, with the added potential for cranial neuritis or ocular involvement.¹ The late stages of neurosyphilis are detailed in the table.^1,4,8

Diagnosis
A diagnosis of syphilis is made by testing blood samples or scrapings from a lesion. In patients with suspected syphilis, rapid plasma reagin (RPR) testing or a VDRL titer is commonly ordered. When results are positive, a serum treponemal test is recommended to confirm a diagnosis of syphilis. Options include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutinin assay for antibody to T pallidum (MHA-TP).⁵

If neurologic symptoms are present, a CSF sample should be obtained, followed by the same testing. A confirmed diagnosis of neurosyphilis is defined by the CDC as syphilis at any stage that meets laboratory criteria for neurosyphilis⁵; these include increased CSF protein or an elevated CSF leukocyte count with no other known cause, and clinical signs or symptoms without other known causes.⁷

Treatment
Treatment of syphilis generally consists of penicillin, administered intramuscularly (IM) or IV, depending on the stage. According to 2006 guidelines from the CDC,^10,11 treatment for adults with primary and secondary syphilis is a single dose of IM penicillin G, 2.4 million units. If neurosyphilis is suspected, recommended treatment is IV penicillin G, 18 to 24 million units per day divided into six doses (ie, 3 to 4 million units every four hours) or continuous pump infusion for 10 to 14 days.^10-12 Follow-up is recommended by monitoring CSF titers to ensure clearance of infection; retreatment may be required if CSF abnormalities persist after two years.¹¹

Patients with a penicillin allergy should undergo desensitization, as penicillin is the preferred agent; the potential exists for cross-reactivity with ceftriaxone, a possible alternative for patients with neurosyphilis.¹¹ All patients diagnosed with syphilis should also be tested for HIV and other sexually transmitted diseases.^10-12

The prognosis of patients treated for neurosyphilis is generally good if the condition is diagnosed and treated early. In patients with cerebral atrophy, frontal lesions, dementia, or tabes dorsalis, the potential for recovery decreases.^2,13,14

Teaching Points
There are several teaching points to take away from this case:

• Remember to rule out a CVA in any patient who presents with numbness, paresthesias, or slurred speech. In this case, a brain CT and CT angiography of the brain were both obtained in the ED before the patient was admitted. They both yielded negative results; because the patient’s history was consistent with alcohol and drug use and he had a history of seizures, he was monitored closely for signs of withdrawal or further seizure.

• Phenytoin is an antiepileptic agent whose use requires proper patient education and drug level monitoring. Appropriate follow-up must be ensured before phenytoin therapy is begun, as toxicity can result in nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, and possibly death.^15,16

• For patients with a suspected acute change in mental status, a workup is required and should be tailored appropriately, based on findings. This should include, but not be limited to, a thorough history and physical exam, CT of the brain (to rule out an acute brain injury¹⁷), and, if warranted, MRI of the brain. Also, a urine drug screen and alcohol level, a complete blood count, a TSH level (to evaluate for altered thyroid function that may explain mental status changes), comprehensive panel, RPR testing and/or a VDRL titer should be obtained, depending on the facility’s protocol^18,19; at some facilities, a treponemal test, rather than VDRL, is being obtained at the outset.²⁰ Levels of vitamin B12 (as part of the dementia workup), folate, thiamine, and ammonia (in patients with suspected liver disease) can also be obtained in patients with change in mental status.^18,19 Urinalysis should not be overlooked to check for a urinary tract infection, especially in elderly patients.²¹

• If primary syphilis is suspected, treatment must be undertaken.²⁰

Conclusion
Despite the decline seen since the 1940s in cases of primary and secondary syphilis, and the effectiveness of penicillin in treating the infection early, patients with late-stage syphilis, including those with neurosyphilis, may still present to the emergency care, urgent care, or primary care setting. Immediate treatment with penicillin is recommended to achieve an optimal prognosis for the affected patient.

A 54-year-old African-American man was brought by police officers to the emergency department (ED) after he called 911 several times to report seeing a Rottweiler looking into his second-story window. At the scene, the police were unable to confirm his story, thought the man seemed intoxicated, and brought him to the ED for evaluation.

The patient reported that he had been drinking the previous evening but denied current intoxication or illicit drug use. He denied experiencing symptoms of alcohol withdrawal.

Regarding his medical history, the patient admitted to having had seizures, including two episodes that he said required hospitalization. He described these episodes as right-hand “tingling” (paresthesias), accompanied by right-facial numbness and aphasia. The patient said his physician had instructed him to take “a few phenytoin pills” whenever these episodes occurred. He reported that the medication usually helped resolve his symptoms. He said he had taken phenytoin shortly before his current presentation.

According to friends of the patient who were questioned, he had had noticeable memory problems during the previous six to eight months. They said that he often told the same joke, day after day. His speech had become increasingly slurred, even when he was not drinking.

Once the patient’s medical records were retrieved, it was revealed that he had been hospitalized twice for witnessed grand mal seizures about six months before his current admission; he had been drinking alcohol prior to both episodes. He underwent electroencephalography (EEG) during one of these hospitalizations, with results reported as normal. On both occasions, the patient was discharged with phenytoin and was instructed to follow up with his primary care provider and neurologist.

The patient, who reported working in customer service, had no known allergies. He claimed to drink one or two 40-ounce beers twice per week and admitted to occasional cocaine use. Of significance in his family history was a fatal MI in his mother. Although the patient denied any history of rashes or lesions, his current delirium made it impossible to obtain a reliable sexual history; a friend who was questioned, however, described the patient as promiscuous.

On initial physical examination, the man was afebrile, tachycardic, and somewhat combative with the ED staff. He was fully oriented to self but only partially to place and time.

His right pupil was 3+ and his left pupil was 2+, with neither reactive to light. He spoke with tangential speech and his gait was unsteady, but no other significant abnormalities were noted. A full assessment revealed no rashes or other lesions.

Significant laboratory findings included a low level of phenytoin, a negative blood alcohol level, presence of cocaine on urine drug screening, and normal levels of thyroid-stimulating hormone (TSH), vitamin B12, and folate. The patient’s serum VDRL (venereal disease research laboratory) titer was positive at 1:256.

Electroencephalography showed diffuse slowing, and brain CT performed in the ED showed atrophy that was mild but appropriate for a person of the patient’s age, with no evidence of a cerebrovascular accident (CVA). Aneurysm was ruled out by CT angiography of the brain. MRI revealed persistent increased signal in the subarachnoid space.

The patient was admitted with an initial diagnosis of paranoid delusional psychosis and monitored for alcohol withdrawal. He was given lorazepam as needed for agitation. Consultations were arranged with the psychiatry service regarding his delusions, and with neurology to determine whether to continue phenytoin.

The patient showed little response during the next several days. Based on positive results on serum VDRL with high titer, the presence of Argyll-Robertson pupils on exam, and his history of dementia-like symptoms, a lumbar puncture was performed to rule out neurosyphilis. In the patient’s cerebral spinal fluid (CSF) analysis, the first tube was clear and colorless, with 72 cells (28% neutrophils, 59% lymphocytes); glucose, 64 mg/dL; and total protein, 117 mg/dL. The fourth tube had 34 cells (17% neutrophils, 65% lymphocytes) and a positive VDRL titer at 1:128. Results from a serum syphilis immunoglobulin G (IgG) test were positive, and HIV antibody testing was nonreactive, confirming the diagnosis of neurosyphilis.

The hospital’s infectious disease (ID) team recommended treatment with IV penicillin for 14 days. Once this was completed, the patient was discharged with instructions to follow up at the ID clinic in three months for a repeat CSF VDRL titer to monitor for resolution of the disease. His prescription for phenytoin was discontinued.

At the time of discharge, it was noted that the patient showed no evidence of having regained cognitive function. He was deemed by the psychiatry service to lack decision-making capacity—a likely sequelae of untreated neurosyphilis of unknown duration.

He did return to the ID clinic six months after his discharge. At that visit, a VDRL serum titer was drawn with a result of 1:64, a decrease from 1:128. His syphilis IgG remained positive, however.

Discussion
Definition and Epidemiology
Syphilis is commonly known as a sexually transmitted disease with primary, secondary, and tertiary (early and late latent) stages.¹ Neurosyphilis is defined as a manifestation of the inflammatory response to invasion over decades by the Treponema pallidum spirochete in the CSF as a result of untreated primary and/or secondary syphilis.² About one in 10 patients with untreated syphilis will experience neurologic involvement.^3,4 Before 2005, neurosyphilis was required to be reported as a specific stage of syphilis (ie, a manifestation of tertiary syphilis4), but now should be reported as syphilis with neurologic manifestations.⁵

A reportable infectious disease, syphilis was widespread until the advent of penicillin. According to CDC statistics,⁶ the number of reported cases of primary and secondary syphilis has declined steadily since 1943. In the late 1970s and early 1980s, the number of tertiary cases also began to plateau, likely as a result of earlier diagnosis and more widespread use of penicillin. Recent case reports suggest greater prevalence of syphilis among men than women and increased incidence among men who have sex with men.⁷

Pathogenesis
Syphilis is most commonly spread by sexual contact or contact with an infected primary lesion (chancre). Less likely routes of transmission are placental passage or blood transfusion. Infectivity is greatest in the early disease stages.⁸

Primary syphilis is marked by transmission of the spirochete, ending with development of secondary syphilis (usually two to 12 weeks after transmission). A chancre commonly develops but is often missed by patients because it is painless and can heal spontaneously.⁷ The chancre is also often confused with two other sources of genital lesions, herpes simplex (genital herpes) and Haemophilus ducreyi (chancroid). In two-thirds of cases of untreated primary syphilis, the infection clears spontaneously, but in the remaining one-third, the disease progresses.⁸

Secondary syphilis, with or without presence of a chancre, manifests with constitutional symptoms, including lymphadenopathy, fever, headache, and malaise. Patients in this disease phase may also present with a generalized, nonpruritic, macular to maculopapular or pustular rash. The rash can affect the skin of the trunk, the proximal extremities, and the palms and soles. Ocular involvement may occur, especially in patients who are coinfected with HIV.⁸ In either primary or secondary syphilis, infection can invade the central nervous system.¹

During latent syphilis, patients show serologic conversion without overt symptoms. Early latent syphilis is defined as infection within the previous year, as demonstrated by conversion from negative to positive testing, or an increase in titers within the previous year. Any case occurring after one year is defined as late or unknown latent syphilis.⁸

Tertiary syphilis is marked by complications resulting from untreated syphilis; affected patients commonly experience central nervous system and cardiovascular involvement. Gummatous disease is seen in 15% of patients.¹

The early stages of neurosyphilis may be asymptomatic, acute meningeal, and meningovascular.^1,4,8,9 Only 5% of patients with early neurosyphilis are symptomatic, with the added potential for cranial neuritis or ocular involvement.¹ The late stages of neurosyphilis are detailed in the table.^1,4,8

Diagnosis
A diagnosis of syphilis is made by testing blood samples or scrapings from a lesion. In patients with suspected syphilis, rapid plasma reagin (RPR) testing or a VDRL titer is commonly ordered. When results are positive, a serum treponemal test is recommended to confirm a diagnosis of syphilis. Options include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutinin assay for antibody to T pallidum (MHA-TP).⁵

If neurologic symptoms are present, a CSF sample should be obtained, followed by the same testing. A confirmed diagnosis of neurosyphilis is defined by the CDC as syphilis at any stage that meets laboratory criteria for neurosyphilis⁵; these include increased CSF protein or an elevated CSF leukocyte count with no other known cause, and clinical signs or symptoms without other known causes.⁷

Treatment
Treatment of syphilis generally consists of penicillin, administered intramuscularly (IM) or IV, depending on the stage. According to 2006 guidelines from the CDC,^10,11 treatment for adults with primary and secondary syphilis is a single dose of IM penicillin G, 2.4 million units. If neurosyphilis is suspected, recommended treatment is IV penicillin G, 18 to 24 million units per day divided into six doses (ie, 3 to 4 million units every four hours) or continuous pump infusion for 10 to 14 days.^10-12 Follow-up is recommended by monitoring CSF titers to ensure clearance of infection; retreatment may be required if CSF abnormalities persist after two years.¹¹

Patients with a penicillin allergy should undergo desensitization, as penicillin is the preferred agent; the potential exists for cross-reactivity with ceftriaxone, a possible alternative for patients with neurosyphilis.¹¹ All patients diagnosed with syphilis should also be tested for HIV and other sexually transmitted diseases.^10-12

The prognosis of patients treated for neurosyphilis is generally good if the condition is diagnosed and treated early. In patients with cerebral atrophy, frontal lesions, dementia, or tabes dorsalis, the potential for recovery decreases.^2,13,14

Teaching Points
There are several teaching points to take away from this case:

• Remember to rule out a CVA in any patient who presents with numbness, paresthesias, or slurred speech. In this case, a brain CT and CT angiography of the brain were both obtained in the ED before the patient was admitted. They both yielded negative results; because the patient’s history was consistent with alcohol and drug use and he had a history of seizures, he was monitored closely for signs of withdrawal or further seizure.

• Phenytoin is an antiepileptic agent whose use requires proper patient education and drug level monitoring. Appropriate follow-up must be ensured before phenytoin therapy is begun, as toxicity can result in nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, and possibly death.^15,16

• For patients with a suspected acute change in mental status, a workup is required and should be tailored appropriately, based on findings. This should include, but not be limited to, a thorough history and physical exam, CT of the brain (to rule out an acute brain injury¹⁷), and, if warranted, MRI of the brain. Also, a urine drug screen and alcohol level, a complete blood count, a TSH level (to evaluate for altered thyroid function that may explain mental status changes), comprehensive panel, RPR testing and/or a VDRL titer should be obtained, depending on the facility’s protocol^18,19; at some facilities, a treponemal test, rather than VDRL, is being obtained at the outset.²⁰ Levels of vitamin B12 (as part of the dementia workup), folate, thiamine, and ammonia (in patients with suspected liver disease) can also be obtained in patients with change in mental status.^18,19 Urinalysis should not be overlooked to check for a urinary tract infection, especially in elderly patients.²¹

• If primary syphilis is suspected, treatment must be undertaken.²⁰

Conclusion
Despite the decline seen since the 1940s in cases of primary and secondary syphilis, and the effectiveness of penicillin in treating the infection early, patients with late-stage syphilis, including those with neurosyphilis, may still present to the emergency care, urgent care, or primary care setting. Immediate treatment with penicillin is recommended to achieve an optimal prognosis for the affected patient.

A 54-year-old African-American man was brought by police officers to the emergency department (ED) after he called 911 several times to report seeing a Rottweiler looking into his second-story window. At the scene, the police were unable to confirm his story, thought the man seemed intoxicated, and brought him to the ED for evaluation.

The patient reported that he had been drinking the previous evening but denied current intoxication or illicit drug use. He denied experiencing symptoms of alcohol withdrawal.

Regarding his medical history, the patient admitted to having had seizures, including two episodes that he said required hospitalization. He described these episodes as right-hand “tingling” (paresthesias), accompanied by right-facial numbness and aphasia. The patient said his physician had instructed him to take “a few phenytoin pills” whenever these episodes occurred. He reported that the medication usually helped resolve his symptoms. He said he had taken phenytoin shortly before his current presentation.

According to friends of the patient who were questioned, he had had noticeable memory problems during the previous six to eight months. They said that he often told the same joke, day after day. His speech had become increasingly slurred, even when he was not drinking.

Once the patient’s medical records were retrieved, it was revealed that he had been hospitalized twice for witnessed grand mal seizures about six months before his current admission; he had been drinking alcohol prior to both episodes. He underwent electroencephalography (EEG) during one of these hospitalizations, with results reported as normal. On both occasions, the patient was discharged with phenytoin and was instructed to follow up with his primary care provider and neurologist.

The patient, who reported working in customer service, had no known allergies. He claimed to drink one or two 40-ounce beers twice per week and admitted to occasional cocaine use. Of significance in his family history was a fatal MI in his mother. Although the patient denied any history of rashes or lesions, his current delirium made it impossible to obtain a reliable sexual history; a friend who was questioned, however, described the patient as promiscuous.

On initial physical examination, the man was afebrile, tachycardic, and somewhat combative with the ED staff. He was fully oriented to self but only partially to place and time.

His right pupil was 3+ and his left pupil was 2+, with neither reactive to light. He spoke with tangential speech and his gait was unsteady, but no other significant abnormalities were noted. A full assessment revealed no rashes or other lesions.

Significant laboratory findings included a low level of phenytoin, a negative blood alcohol level, presence of cocaine on urine drug screening, and normal levels of thyroid-stimulating hormone (TSH), vitamin B12, and folate. The patient’s serum VDRL (venereal disease research laboratory) titer was positive at 1:256.

Electroencephalography showed diffuse slowing, and brain CT performed in the ED showed atrophy that was mild but appropriate for a person of the patient’s age, with no evidence of a cerebrovascular accident (CVA). Aneurysm was ruled out by CT angiography of the brain. MRI revealed persistent increased signal in the subarachnoid space.

The patient was admitted with an initial diagnosis of paranoid delusional psychosis and monitored for alcohol withdrawal. He was given lorazepam as needed for agitation. Consultations were arranged with the psychiatry service regarding his delusions, and with neurology to determine whether to continue phenytoin.

The patient showed little response during the next several days. Based on positive results on serum VDRL with high titer, the presence of Argyll-Robertson pupils on exam, and his history of dementia-like symptoms, a lumbar puncture was performed to rule out neurosyphilis. In the patient’s cerebral spinal fluid (CSF) analysis, the first tube was clear and colorless, with 72 cells (28% neutrophils, 59% lymphocytes); glucose, 64 mg/dL; and total protein, 117 mg/dL. The fourth tube had 34 cells (17% neutrophils, 65% lymphocytes) and a positive VDRL titer at 1:128. Results from a serum syphilis immunoglobulin G (IgG) test were positive, and HIV antibody testing was nonreactive, confirming the diagnosis of neurosyphilis.

The hospital’s infectious disease (ID) team recommended treatment with IV penicillin for 14 days. Once this was completed, the patient was discharged with instructions to follow up at the ID clinic in three months for a repeat CSF VDRL titer to monitor for resolution of the disease. His prescription for phenytoin was discontinued.

At the time of discharge, it was noted that the patient showed no evidence of having regained cognitive function. He was deemed by the psychiatry service to lack decision-making capacity—a likely sequelae of untreated neurosyphilis of unknown duration.

He did return to the ID clinic six months after his discharge. At that visit, a VDRL serum titer was drawn with a result of 1:64, a decrease from 1:128. His syphilis IgG remained positive, however.

Discussion
Definition and Epidemiology
Syphilis is commonly known as a sexually transmitted disease with primary, secondary, and tertiary (early and late latent) stages.¹ Neurosyphilis is defined as a manifestation of the inflammatory response to invasion over decades by the Treponema pallidum spirochete in the CSF as a result of untreated primary and/or secondary syphilis.² About one in 10 patients with untreated syphilis will experience neurologic involvement.^3,4 Before 2005, neurosyphilis was required to be reported as a specific stage of syphilis (ie, a manifestation of tertiary syphilis4), but now should be reported as syphilis with neurologic manifestations.⁵

A reportable infectious disease, syphilis was widespread until the advent of penicillin. According to CDC statistics,⁶ the number of reported cases of primary and secondary syphilis has declined steadily since 1943. In the late 1970s and early 1980s, the number of tertiary cases also began to plateau, likely as a result of earlier diagnosis and more widespread use of penicillin. Recent case reports suggest greater prevalence of syphilis among men than women and increased incidence among men who have sex with men.⁷

Pathogenesis
Syphilis is most commonly spread by sexual contact or contact with an infected primary lesion (chancre). Less likely routes of transmission are placental passage or blood transfusion. Infectivity is greatest in the early disease stages.⁸

Primary syphilis is marked by transmission of the spirochete, ending with development of secondary syphilis (usually two to 12 weeks after transmission). A chancre commonly develops but is often missed by patients because it is painless and can heal spontaneously.⁷ The chancre is also often confused with two other sources of genital lesions, herpes simplex (genital herpes) and Haemophilus ducreyi (chancroid). In two-thirds of cases of untreated primary syphilis, the infection clears spontaneously, but in the remaining one-third, the disease progresses.⁸

Secondary syphilis, with or without presence of a chancre, manifests with constitutional symptoms, including lymphadenopathy, fever, headache, and malaise. Patients in this disease phase may also present with a generalized, nonpruritic, macular to maculopapular or pustular rash. The rash can affect the skin of the trunk, the proximal extremities, and the palms and soles. Ocular involvement may occur, especially in patients who are coinfected with HIV.⁸ In either primary or secondary syphilis, infection can invade the central nervous system.¹

During latent syphilis, patients show serologic conversion without overt symptoms. Early latent syphilis is defined as infection within the previous year, as demonstrated by conversion from negative to positive testing, or an increase in titers within the previous year. Any case occurring after one year is defined as late or unknown latent syphilis.⁸

Tertiary syphilis is marked by complications resulting from untreated syphilis; affected patients commonly experience central nervous system and cardiovascular involvement. Gummatous disease is seen in 15% of patients.¹

The early stages of neurosyphilis may be asymptomatic, acute meningeal, and meningovascular.^1,4,8,9 Only 5% of patients with early neurosyphilis are symptomatic, with the added potential for cranial neuritis or ocular involvement.¹ The late stages of neurosyphilis are detailed in the table.^1,4,8

Diagnosis
A diagnosis of syphilis is made by testing blood samples or scrapings from a lesion. In patients with suspected syphilis, rapid plasma reagin (RPR) testing or a VDRL titer is commonly ordered. When results are positive, a serum treponemal test is recommended to confirm a diagnosis of syphilis. Options include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutinin assay for antibody to T pallidum (MHA-TP).⁵

If neurologic symptoms are present, a CSF sample should be obtained, followed by the same testing. A confirmed diagnosis of neurosyphilis is defined by the CDC as syphilis at any stage that meets laboratory criteria for neurosyphilis⁵; these include increased CSF protein or an elevated CSF leukocyte count with no other known cause, and clinical signs or symptoms without other known causes.⁷

Treatment
Treatment of syphilis generally consists of penicillin, administered intramuscularly (IM) or IV, depending on the stage. According to 2006 guidelines from the CDC,^10,11 treatment for adults with primary and secondary syphilis is a single dose of IM penicillin G, 2.4 million units. If neurosyphilis is suspected, recommended treatment is IV penicillin G, 18 to 24 million units per day divided into six doses (ie, 3 to 4 million units every four hours) or continuous pump infusion for 10 to 14 days.^10-12 Follow-up is recommended by monitoring CSF titers to ensure clearance of infection; retreatment may be required if CSF abnormalities persist after two years.¹¹

Patients with a penicillin allergy should undergo desensitization, as penicillin is the preferred agent; the potential exists for cross-reactivity with ceftriaxone, a possible alternative for patients with neurosyphilis.¹¹ All patients diagnosed with syphilis should also be tested for HIV and other sexually transmitted diseases.^10-12

The prognosis of patients treated for neurosyphilis is generally good if the condition is diagnosed and treated early. In patients with cerebral atrophy, frontal lesions, dementia, or tabes dorsalis, the potential for recovery decreases.^2,13,14

Teaching Points
There are several teaching points to take away from this case:

• Remember to rule out a CVA in any patient who presents with numbness, paresthesias, or slurred speech. In this case, a brain CT and CT angiography of the brain were both obtained in the ED before the patient was admitted. They both yielded negative results; because the patient’s history was consistent with alcohol and drug use and he had a history of seizures, he was monitored closely for signs of withdrawal or further seizure.

• Phenytoin is an antiepileptic agent whose use requires proper patient education and drug level monitoring. Appropriate follow-up must be ensured before phenytoin therapy is begun, as toxicity can result in nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, and possibly death.^15,16

• For patients with a suspected acute change in mental status, a workup is required and should be tailored appropriately, based on findings. This should include, but not be limited to, a thorough history and physical exam, CT of the brain (to rule out an acute brain injury¹⁷), and, if warranted, MRI of the brain. Also, a urine drug screen and alcohol level, a complete blood count, a TSH level (to evaluate for altered thyroid function that may explain mental status changes), comprehensive panel, RPR testing and/or a VDRL titer should be obtained, depending on the facility’s protocol^18,19; at some facilities, a treponemal test, rather than VDRL, is being obtained at the outset.²⁰ Levels of vitamin B12 (as part of the dementia workup), folate, thiamine, and ammonia (in patients with suspected liver disease) can also be obtained in patients with change in mental status.^18,19 Urinalysis should not be overlooked to check for a urinary tract infection, especially in elderly patients.²¹

• If primary syphilis is suspected, treatment must be undertaken.²⁰

Conclusion
Despite the decline seen since the 1940s in cases of primary and secondary syphilis, and the effectiveness of penicillin in treating the infection early, patients with late-stage syphilis, including those with neurosyphilis, may still present to the emergency care, urgent care, or primary care setting. Immediate treatment with penicillin is recommended to achieve an optimal prognosis for the affected patient.