Neurosyphilis and neuro-AIDS

Neurosyphilis and neuro-AIDS - detailed technical article.

Topics covered:

  • Essentials
  • Neurosyphilis
  • Neuro-AIDS (the neurological complications of HIV infection)
  • Further Reading

Essentials 

Neurosyphilis

Invasion of the central nervous system occurs early in the course of syphilis infection. Neurosyphilis causes meningitis, myeloradiculopathy due to pachymeningitis, and gummatous cord and brain lesions; endarteritis may cause infarction.

Clinical features—these are protean: neurosyphilis should always be considered in the diagnosis of neurological disorders without a convincing explanation, including (1) stroke—especially in young patients; (2) ocular abnormalities—e.g. optic neuritis, choroidoretinitis, pupillary abnormalities; (3) unexplained cranial nerve disease, including sensorineural deafness and vertigo; (4) dementia—low-grade meningo-encephalitis is associated with generalized changes in the brain and occasionally with frontotemporal dementia; (5) tabes dorsalis—a sensory ataxia caused by disease of the dorsal roots, ganglia and posterior columns.

Diagnosis, treatment, and prognosis—diagnosis requires specific serological tests and examination of the cerebrospinal fluid. Treatment with antimicrobials is often curative in patients with meningitic or meningovascular disease, but is only partially effective in those with late forms of dementia or tabes. Follow-up after treatment should include repeat examinations of the cerebrospinal fluid until the cell count is restored to normal limits.

Neurological complications of HIV infection

The neurological sequel of HIV infection include (1) opportunistic infections—e.g. cryptococcal meningitis; toxoplasma encephalitis; tuberculous meningitis and tuberculomata; cytomegalovirus encephalitis, cauda equina syndrome; vasculitic neuropathy; progressive multifocal leucoencephalopathy (PML) and (2) neoplasms—e.g. primary CNS lymphoma.

HIV itself also affects the central and peripheral nervous systems causing HIV associated neurocognitive syndromes including dementia, vacuolar myelopathy and peripheral neuropathy.

The introduction of highly active antiretroviral therapies has greatly reduced the frequency of all such problems in patients with access to treatment. However, newer complications are now increasingly recognized—e.g. immune reconstitution inflammatory syndrome (IRIS).

Neurosyphilis

The incidence of primary and secondary syphilis in the United Kingdom (excluding Scotland) increased from 223 in 1999 to 2500 in 2008. It is more common in the United States of America, Russia, and eastern Europe, as well as in the developing world. As syphilis, similar to other ulcerating genital infections such as herpes and chancroid, is an independent risk factor for the acquisition and transmission of infection with the HIV, the disease has once again come under scrutiny. In addition, there are recent anecdotal reports of Treponema pallidum being more neurovirulent and with a greater risk of treatment failure in those dually infected with HIV.

Invasion of the CNS occurs early in the course of syphilis infection. T. pallidum has been isolated from the cerebrospinal fluid of up to 40% of neurologically asymptomatic patients with untreated primary and secondary syphilis. Despite this, cohort studies of untreated patients suggest that symptomatic late syphilis (neurosyphilis, cardiovascular syphilis, and gummas) occurs in 15 to 40% of such individuals; the Oslo study documented an incidence of clinical neurosyphilis in 9.4%. Thus, it would seem as if, at least in the immunocompetent patient, T. pallidum has a low virulence for the CNS.

Clinical features (Table 1)

Acquired syphilis is divided into an early, potentially infectious stage (primary, secondary, and early latent where less than 2 years have elapsed since infection) and a late, noninfectious stage (late latent where more than 2 years have elapsed—gummatous, cardiovascular, and neurosyphilis). Although there is a rough time course to the development of the various neurological syndromes, there is considerable overlap; these syndromes are, in reality, part of the spectrum of disease.

Neurosyphilis may include meningitis (acute and chronic), a myeloradiculopathy due to a pachymeningitis, and granulomatous lesions (gummas) that present as space-occupying lesions within the brain, spinal cord, or epidural space, causing compression. Meningovascular syphilis involves the small- and medium-sized arteries, typically causing an endarteritis (Heubner’s endarteritis obliterans), resulting in infarction. The so-called late manifestations of neurosyphilis result from a low-grade meningoencephalitis. In patients with general paralysis (also called general paralysis of the insane or dementia paralytica), the focus is on the frontotemporal cortex. Therefore, during the early stages, vague symptoms may include personality and mood changes, with impaired faculties of concentration and attention being the presenting features; memory difficulties develop later. 

In tabes dorsalis (taboparesis), which may coexist with general paralysis, the clinical presentation results from involvement of the dorsal roots and ganglia as well as the posterior columns within the spinal cord, with the resultant emphasis on a sensory ataxia. Diabetes may produce a similar clinical picture with a neuropathy and pupillary abnormalities (diabetic pseudotabes).

Axial section of the spinal cord showing syphilitic destruction (whitened area, upper center) of the posterior columns which carry sensory information from the body to the brain

Above: Axial section of the spinal cord showing syphilitic destruction (whitened area, upper center) of the posterior columns which carry sensory information from the body to the brain

The optic nerve could be involved with or without other evidence of neurosyphilis, but must always be treated as if it were part of a systemic infection. Uveitis, chorioretinitis, optic neuritis, papillitis, and optic atrophy have all been reported at different stages of the disease. Extraocular presentations include nerve palsies involving the eye muscles and a superior orbital fissure syndrome. Although the Argyll Robertson pupil may occur in any form of the disease, it is generally encountered in tabes dorsalis. The pupils are small and irregular, being unreactive to light, but constrict normally to accommodation and convergence. Unilateral involvement is rare. The light/near dissociation is the result of gliosis in the periaqueductal grey midbrain tegmentum, which may also account for the bilateral ptosis seen in some individuals.

argyll robertson pupil

Above: Argyll Robertson pupil - The pupils are small and irregular, they do not react to light but react to accommodation.

Diagnosis

Neurosyphilis has a myriad of neurological manifestations and therefore the diagnosis enters the differential of most neurological conditions (see Table 1). Treatment in the early stages of the disease (i.e. of the meningitic and meningovascular syndromes) may well result in recovery, whereas the late forms—with general paralysis and tabes dorsalis—may cease to progress with only partial recovery. These common neurological presentations include stroke, and should enter the differential diagnosis especially in younger patients, chorioretinitis, optic neuropathy of unknown cause, and single or multiple cranial neuropathies, particularly those involving cranial nerve VIII with vertigo and sensorineural deafness. Syphilis serology should be routinely performed in patients with dementia and psychiatric illnesses.

The serum reaginic tests, Venereal Diseases Research Laboratory (VDRL) test and rapid plasma reagin test (RPR), are always or almost always positive in secondary syphilis when the first neurological complications may be encountered. However, a false-negative result may occur due to the prozone phenomenon if undiluted serum is used. This occurs in 1 to 2% of cases of secondary syphilis and is due to blockage of agglutination caused by the saturation of antigenic sites by excess antibody. The specific serological tests—T. pallidum haemagglutination test (TPHA), T. pallidum particle agglutination test (TPPA), fluorescent treponemal antibody absorption test (FTA-abs), and the treponemal enzyme immunoassay (EIA)—are invariably positive.

In late syphilis (meningovascular syphilis, gummatous, general paralysis, and tabes dorsalis), the serum VDRL/RPR tests are negative in 30% of untreated cases. All the specific tests have a sensitivity approaching 100%, so that a negative treponemal antigen test has an extremely high predictive value for excluding neurosyphilis.

It is recommended that all patients with positive syphilis serology who have ocular and/or neurological symptoms and signs should undergo cerebrospinal fluid examination, as should patients with latent infection of unknown duration. In order for these tests to be correctly interpreted, it is important that the cerebrospinal fluid is not significantly (macroscopically) contaminated with blood.

In patients with neurosyphilis there is usually a lymphocytic pleocytosis (>5 cells/µl), with an elevated protein (>0.4 g/l). In the late stages, particularly in tabes, the cerebrospinal fluid may be quiescent. A reactive CSF VDRL establishes the diagnosis of active neurosyphilis, but a nonreactive test does not exclude it. The sensitivity of the CSF VDRL is 50%, with a specificity of 100%. A nonreactive CSF FTA-abs or TPHA excludes the diagnosis. However, a reactive CSF FTA-abs or TPHA does not establish the diagnosis because the presence of treponemal antibodies in the cerebrospinal fluid could result from passive transfer from the blood, or from a previous episode of treated syphilis. The sensitivity for the CSF FTA-abs is 100%, with a specificity of 30%.

Table 1 Clinical features of neurosyphilis
    Syphilitic meningitis Meningovascular General paralysis Tabes dorsalis
Time course Acute Within first year; may occur during secondary syphilis Months to years after infection, average 7 years 15–20 years 20–25 years
  Chronic 20–25 years      
Clinical features Acute Cranial nerve palsies (III, VI, VII, VIII), hydrocephalus Stroke (hemiparesis, dysphasia), seizures, cranial nerve palsies, encephalitic syndrome, anterior spinal artery syndrome Frontal–temporal dementia, psychiatric symptoms (delusions, apathy), personality change, seizures, dysarthria, tremor (tongue, face, hands), Argyll Robertson pupils, optic atrophy Lightning pains (limbs, viscera); loss of pain and temperature (Charcot’s joints), joint position (sensory ataxia, positive Romberg’s sign), areflexia, sluggish pupils(early), autonomic and sphincter dysfunction
  Chronic Myeloradiculopathy      

The role of the polymerase chain reaction (PCR) in the diagnosis of neurosyphilis is unclear at present, because the technique cannot discriminate between viable and nonviable organisms. T. pallidum DNA has been detected in cerebrospinal fluid up to 3 years after intravenous treatment with penicillin. 

Treatment

In patients with symptomatic neurosyphilis or ocular disease, the World Health Organization/United Nations Programme on HIV/AIDS (WHO/UNAIDS) as well as the Centers for Disease Control (CDC) recommend treatment with benzylpenicillin (2–4 MU intravenously every 4 h for 14 days). In the United Kingdom the preference is for procaine penicillin (1.8–2.4 MIU intramuscularly once daily, plus probenecid 500 mg by mouth four times daily, for 17–21 days). The alternative is intravenous benzylpenicillin (3 to 4 MU intravenously every 4 h for 17–21 days). In patients with a history of penicillin allergy one option is to perform skin testing to confirm the allergy and to then consider desensitization. The other is to treat with doxycycline 200 mg by mouth four times daily for 28 days.

After treatment of neurosyphilis, a repeat lumbar puncture should be performed at 6-monthly intervals until the cell count is normal. The cell count should have decreased by 6 months and be entirely normal by 2 years. The CSF VDRL may take years to become nonreactive.

Syphilis in the era of HIV

Since the onset of the AIDS epidemic there have been numerous reports of an accelerated course of syphilis and of treatment failures in patients who are dually infected. Compared with nonimmunosuppressed individuals there certainly does seem to be a higher than expected rate of cases of syphilitic meningitis and meninogovascular syphilis. To date, however, there are no denominator data. As cell-mediated immunity, which is necessary to eradicate T. pallidum, may be impaired in HIV infection, this seems plausible.

As a result of altered B-cell function there has been concern about serological tests. However, these are usually positive or may show a delayed response in the occasional case.

There is still debate as to whether or not patients with HIV and early syphilis who are neurologically asymptomatic should have a cerebrospinal fluid examination. Any cerebrospinal fluid cytochemical abnormalities could be due to either HIV or syphilis. In view of the treatment failures reported with benzathinepenicillin some authorities suggest that all HIV patients with early syphilis should be treated with neurosyphilis treatment regimens.

Neuro-AIDS (the neurological complications of HIV infection) 

Soon after the onset of the AIDS epidemic in 1981, it became clear that the nervous system was frequently involved. However, opportunistic infections such as toxoplasmosis and cryptococcal meningitis, as well as neoplasms (such as primary central nervous system lymphoma, PCNSL) accounted for only 30% of the neurological problems encountered. It also became evident that, in the later stages of the AIDS illness, patients developed neurological complications due to the HIV itself. This included a progressive decline in cognitive function in association with motor abnormalities—the HIV–dementia complex or as it is now known as HIV associated neurocognitive disorder (HAND).

Neurological disorders are the AIDS-defining illness in up to 20% of cases. Over the course of the illness the prevalence of neurological complications increases up to 70%. These include other opportunistic infections and tumours, as well as the HIV-related problems of dementia, vacuolar myelopathy, and distal sensory peripheral neuropathy (DSPN).

Prior to the advent of highly active antiretroviral therapies (HAART), at postmortem examination more than 90% of the brains from patients dying of AIDS show evidence of HIV encephalitis and/or of one of the opportunistic infections such as CMV.

During the last 10 years, with the introduction of HAART, there has been a dramatic decline in the incidence of neurological opportunistic infections as well as HIV-related disorders such as HIV–dementia. The downside has been an increase in the peripheral nerve complications of some of the antiretroviral drugs. However, these are expensive drugs and are out of reach for most HIV-infected individuals worldwide.

Clinical approach

All areas of the neuraxis are vulnerable in individuals infected with HIV. Differing pathological processes occur simultaneously in various parts of the nervous system. Thus, Occam’s razor—the principle of diagnostic parsimony, often used in medicine—does not always apply. Another aspect to be considered is the possibility of simultaneous infection with more than one organism, e.g. meningitis due to Mycobacterium tuberculosis or Cryptococcus neoformans. Mass lesions in the brain, with some not responding to antitoxoplasma therapy, could be due to lymphoma or another infective cause such as a tuberculoma.

The nervous system is involved early in the course of infection, as evidenced by neurological seroconversion illnesses such as an aseptic meningitis, encephalitis, and the Guillain–Barré syndrome. Furthermore, during the asymptomatic phase of the illness (i.e. when patients are well), the cerebrospinal fluid shows abnormalities in up to 60% of cases. This may be a lymphocytic pleocytosis of up to 50 cells/mm3, an elevated protein, or the presence of oligoclonal bands. The cerebrospinal fluid glucose level is usually normal. Therefore, these cytobiochemical markers are unhelpful in making a diagnosis of a meningitic or encephalitic illness. Reliance is therefore placed on specific markers such as the cryptococcal antigen or antibody tests such as the CSF VDRL or TPHA tests.

As a result of the impaired immune response, a rise in antibody titres to specific infections may not occur, especially during the later stages of HIV infection. Furthermore, the typical clinical picture—the presentation of which, at least in some infections, such as meningitis, is the result of a brisk inflammatory response such as fever—may not occur. In cryptococcal meningitis, only a third of patients exhibit the classic signs of meningism, i.e. neck stiffness, photophobia, and positive Kernig’s sign.

The specific type of opportunistic complications encountered depends on a number of factors, including the degree of immunosuppression. During the early stages when individuals are relatively immunocompetent, with CD4 counts above 500/µl, autoimmune disorders such as demyelinating neuropathies may occur. With CD4 counts of between 200 and 500/µl, multidermatomal herpes zoster infections and tuberculosis (TB) may present. Once the level declines below 200/µl, patients are vulnerable to all the major opportunistic infections and the complications due to HIV itself. Symptomatic infection with CMV tends to occur at very low levels below 50/µl. With the introduction of HAART, these guidelines are less robust because, despite immunreconstitution, pathogen-specific memory T-cell clones may not have been fully restored.

Opportunistic infections

Toxoplasmosis

Toxoplasma gondii, whose definitive host includes members of the cat family with humans as the intermediate hosts, is an obligate intracellular protozoan. Human infection occurs through the ingestion of tissue cysts in undercooked meat. Variations in dietary habits therefore explain the differing seroprevalence rates worldwide—90% in French adults compared with 50% of residents in the United Kingdom. Symptomatic toxoplasmosis is usually due to a reactivation of latent infection in individuals with HIV. The risk of an HIV-infected patient who is seropositive for IgG T. gondii antibody developing toxoplasmosis is around 25%.

Toxoplasmosis is the most common cause of mass lesions in the brains of patients with HIV infection, including those in areas where TB is endemic. The clinical presentation is variable, but headache, confusion, seizures, and focal neurological deficits such as hemiplegia, dysphasia, and visual field defects are the most common. Other presentations described include: a variety of movement disorders (choreoathetosis, dystonia, and hemiparkinsonism); psychiatric illness such as depression; brainstem syndromes; and a rapidly progressive diffuse encephalitis. Rarely, the spinal cord may be involved with myelitis or cauda equina syndrome.

A definitive diagnosis of toxoplasma encephalitis can be made only by brain biopsy. With increasing experience and pragmatism, it is now standard practice to treat any HIV-infected individual who has a low CD4 count and multiple lesions on imaging with antitoxoplasma therapy. A response, clinically and radiologically, confirms the diagnosis. Although a negative blood toxoplasma serology result makes the diagnosis less likely, this may occur in up to 17% of cases. This loss of seropositivity may be the result of impaired antibody synthesis with increasing immunosuppression. It is therefore useful to document an individual’s toxoplasma serostatus on first diagnosis of HIV positivity. For similar reasons, the expected rise in IgM and IgG levels does not occur. A single lesion on MRI is most likely to be due to lymphoma. A single lesion on CT should, if possible, be followed by MRI, which is a more sensitive method of detecting lesions, particularly in the posterior fossa.

The main differential diagnosis is that of primary CNS lymphoma (PCNSL), which presents at similar CD4 counts and has a similar presentation both clinically and on imaging studies (Bullet list 1 below).

A response is seen in 90% of patients by the second week of treatment (Table 2). It is necessary to reimage 2 weeks after treatment even if there is clinical evidence of improvement, because occasionally some lesions improve but others due to, for example, Mycobacterium tuberculosis, continue to enlarge, which then makes it necessary to consider a biopsy. The radiological improvement generally lags behind the clinical improvement. Secondary prophylaxis is required after resolution of the acute episode.

Patients infected with HIV who are seropositive for IgG against T. gondii should be offered primary prophylaxis with 980 mg co-trimoxazole (trimethoprim and sulfamethoxazole) when their CD4 count falls below 100/mm3. This will confer crossprotection against Pneumocystis jirovecii pneumonia. After the initiation of HAART, primary prophylaxis maybe discontinued after successful suppression of HIV viral replication and the CD4 counts exceed 200 cells/mm3 for 3 months. Maintenance therapy after an episode of toxoplasmosis may be discontinued after 6 months of successful suppression of HIV viral replication and a CD4 >200 cells/mm3. Cryptococcus neoformans This encapsulated yeast is a ubiquitous organism in the environment acquired by humans through inhalation. Although disseminated infection can involve the skin, bones, lungs, eyes, and prostate, symptomatic infection with C. neoformans most often presents as meningitis.

Cryptococcus neoformans

This encapsulated yeast is a ubiquitous organism in the environment acquired by humans through inhalation. Although disseminated infection can involve the skin, bones, lungs, eyes, and prostate, symptomatic infection with C. neoformans most often presents as meningitis.

Bullet list 1 Focal neurological syndromes

Infections

  • Toxoplasma gondii (abscesses, encephalitis)*
  • JC virus (PML)* 
  • Mycobacterium tuberculosis (tuberculoma)*
  • Fungal microabscesses (Cryptococcus neoformans
  • Histoplasma capsulatum, Candida albicans, Aspergillus fumigatus)
  • Cytomegalovirus

Neoplasms

  • Primary CNS lymphoma*
  • Metastatic tumours (non-Hodgkin’s lymphoma, Kaposi’s sarcoma)

Cerebrovascular

  • Ischaemic stroke (coagulopathies)
  • Embolic stroke (bacterial and nonbacterial endocarditis)
  • Vasculitis (meningovascular syphilis, herpes zoster) * Most common.

Cryptococcal infection is the most common infectious cause of meningitis in patients with AIDS (Bullet list 2). Although the presentation may be acute, it is usually subacute with symptoms of malaise, headache, fever, and vomiting. The classic signs of meningism—neck stiffness, photophobia, and Kernig’s sign—are present in only one-third of patients. Other, less common symptoms include altered mental status, seizures, and focal neurological signs. The last are the result of parenchymal cryptococcal abscesses.

Brain imaging is usually normal, although the basal meningitis may result in hydrocephalus or sometimes, particularly on MRI, small abscesses—cryptococcomas—may be evident.

Cerebrospinal fluid examination is essential for the diagnosis, with culture of the fungus being the ‘gold standard’. The cytochemical markers in the cerebrospinal fluid may be normal. India ink staining of the cerebrospinal fluid will reveal the fungal hyphae in 70 to 80% of cases and cryptococcal antigen is detected in over 90%. Cryptococcal antigen is also detected in the blood in over 90% of patients, and should be measured together with the cerebrospinal fluid level because in occasionally reported cases of fulminant cryptococcal meningitis the cerebrospinal fluid may be negative and the blood positive. The blood antigen measurement may be used as a screening test in patients presenting with symptoms of early infection such as headache. However, it should be appreciated that a negative result does not completely exclude the diagnosis of cryptococcal meningitis.

Treatment with amphotericin B remains the drug of choice for the treatment of severe cases of cryptococcal meningitis. The mortality rate still remains around 10%. Features that have been identified with a poor outcome include a relapse infection, abnormal mental status, cerebrospinal fluid cryptoccal antigen titre over 1:1024, cerebrospinal fluid white cell count more than 20 cells/mm3, positive India ink staining, hyponatraemia, and positive culture from an extrameningeal site. A cerebrospinal fluid opening pressure of more than 250 mmH2O is also a marker of poor prognosis. In milder cases, where none of these features is present, oral fluconazole may be used. Although combination with 5-flucytosine has been shown to improve outcome in non-AIDS patients, this has not been confirmed in patients with AIDS. However, the combination should be considered in fulminant cases.

A specific complication that requires close monitoring is the development of raised intracranial pressure due to obstruction of the arachnoid villi and cerebral oedema. This should be managed with repeated lumbar puncture or, if necessary, by the insertion of a lumbar or ventricular drain.

Maintenance therapy is essential, with relapse rates approaching 100% if secondary prophylaxis with oral fluconazole is not adhered to. The serum cryptococcal antigen titre is not useful in predicting relapse. The timing for the initiation of HAART after an episode of meningitis is not clear cut due to the risk of precipitation of the immune reconstitution syndrome (IRIS). After 6 months of HIV viral load suppression and a CD4 count less than 200 cells/µl with HAART, it seems safe to discontinue secondary prophylaxis.

JC virus

Progressive multifocal leucoencephalopathy (PML) is caused by the reactivation of latent JC virus (JCV). This polyomavirus infection is acquired by most of the population during childhood as a banal upper respiratory infection. The virus is frequently found in the urine of healthy individuals. Before the AIDS epidemic, PML was a rare condition encountered in patients immunosuppressed as a result of haematological malignancies, drugs used in the treatment of post-transplant recipients, autoimmune disorders such as systemic lupus erythematosus (SLE), and granulomatous disorders such as sarcoidosis. Nowadays, underlying HIV infection accounts for 85% of cases.

Table 2 Treatment of neurological opportunistic infections
Infection Drug Dose Duration Side effects Notes
Toxoplasmosis
Acute Pyrimethamine + Loading dose of 200 mg, then 75 mg orally 4–6 weeks Myelosuppression  
  Sulfadiazine 6–8 g/day orally or intravenously 4–6 weeks Nephrotoxicity, renal calculi, crystalluria Clindamycin 2.4 g/day oral or intravenously is an alternative to sulfadiazine. Side effect pseudomembranous colitis
  Folinic acid 15 mg/day orally 4–6 weeks   To counteract the myelosuppressive effects of pyrimethamine
Maintenance Pyrimethamine + 25–50 mg/day orally Indefinitely    
  Sulfadiazine + 2 g/day orally Indefinitely   Clindamycin 1.2 g/day
  Folinic acid 15 mg/day orally Indefinitely    
Primary prophylaxis Trimethoprim + 80 mg/day orally   Nausea, Stevens– Johnson syndrome, thrombocytopenia CD4 count < 200/µl and toxoplasma serology positive
  Sulfamethoxazole 400 mg/day orally      
Cryptococcal meningitis
Acute Amphotericin B ± 0.6–1.0 mg/kg per day intravenously At least 2–4 weeks until symptoms resolve and CSF culture negative Hypokalaemia, renal failure, anaemia Via central line because of thrombophlebitis. In mild cases fluconazole 400 mg initially i.v. then continued orally
  5-Flucytosine 100 mg/kg per day 2–4 weeks Myelosuppression  
Maintenance Fluconazole 200–400 mg/day orally Indefinitely Nausea, vomiting, abnormal liver function tests Amphotericin 1 mg/kg per week if intolerant or relapse on fluconazole

Before the introduction of HAART, the incidence of PML was 4%. The clinical presentation is subacute, with progressive focal neurological deficits such as a hemiparesis, visual field defects, and a cerebellar syndrome. The disorder is not restricted to the white matter because patients may also develop dysphasia and seizures. Occasional patients may present with a progressive dementia with focal neurological signs.

MRI characteristically shows multiple areas of high signal on T 1-weighted images and a low signal on T 2-weighted ones. There is little or no enhancement, with no mass effect or oedema around the lesions. Blood serological testing is unhelpful because 80% of the general population is seropositive. It is possible to confirm the diagnosis of PML by isolating JC viral DNA in cerebrospinal fluid by PCR techniques. This has a sensitivity of 75% with a specificity of 95%. In PCR-negative cases it may be necessary either to repeat the cerebrospinal fluid examination or to perform a brain biopsy. The typical histological features show areas of focal demyelination, bizarre enlarged astrocytes, and abnormal oligodendrocytes with inclusion bodies that stain for JC viral antigens.

There is, to date, no specific treatment for PML. Cytosine arabinoside, both intravenous and intrathecal, has been shown to be ineffective. However, improving immune function with HAART has been shown to improve survival times from a median survival of 10 weeks to 40 weeks. Cidofovir, an anti-CMV drug, in one multicentre study showed no significant additional benefit over HAART alone. Recently, there are anecdotal data suggesting that the anti-malarial drug mefloquine and the antidepressant mirtazipine may have some beneficial effecs. Adequate trial results are awaited.

Cytomegalovirus

The neurological complications from this herpesvirus results from reactivation in severely immunocompromised patients. Almost all patients infected with HIV are seropositive for CMV. Postmortem studies of the brains of patients who died from AIDS show evidence of CMV in 25% of cases. However, clinical CMV disease, apart from CMV retinitis, is rare.

Bullet list 2 Meningitis in HIV infection

Infections 

  • Cryptococcus neoformans
  • Mycobacterium tuberculosis
  • Listeria monocytogenes
  • Treponema pallidum

Neoplasms

  • Metastatic non-Hodgkin’s lymphoma

CMV retinitis is the most common manifestation of CMV disease and can affect up to 20% of patients with AIDS. The slowly progressive necrotizing retinitis results in characteristic white irregular lesions with central necrosis and haemorrhages—the cheese and tomato ketchup appearance. Retinal detachment may occur in patients with extensive retinal involvement. The retinitis presents with symptoms of reduced visual acuity, floaters, and loss of peripheral vision. As the condition may be asymptomatic in the early stages, regular ophthalmological screening is recommended for high-risk patients with CD4 counts below 50 cells/µl.

A necrotizing ventriculoencephalitis has been described, usually in patients with evidence of CMV disease elsewhere (Bullet list 3). The onset is subacute over a period of days or weeks with confusion, seizures, and brainstem signs such as internuclear ophthalmoplegia, ataxia, and cranial nerve palsies. Imaging studies typically show periventricular enhancement.

CMV polyradiculopathy presents over a period of days with back pain, leg weakness, sensory impairment, and sphincter disturbance. The differential diagnosis includes syphilitic polyradiculopathyand infiltration with metastatic lymphoma. The cerebrospinal fluid reveals a polymorphonuclear leucocytosis which is unusual for a viral infection. Early recognition and treatment are necessary to stabilize and, in some cases, improve the neurological impairment.

Bullet list 3 Encephalitis in HIV

Virus

  • Cytomegalovirus
  • Herpes simplex
  • Herpes zoster
  • Human herpesvirus 6?

Protozoa

  • Toxoplasmosis

Drugs licensed for the treatment of CMV disease include ganciclovir, cidofovir, and foscarnet. Oral ganciclovir is prescribed for secondary prophylaxis.

Opportunistic tumours

Primary central nervous system lymphoma (PCNSL) is the second most common cause of mass lesions after toxoplasmosis in adults, and the most common in children with AIDS. Histologically, this is a high-grade, non-Hodgkin’s, B-cell lymphoma. Recent evidence suggests that the Epstein–Barr virus is causally linked to primary central nervous system lymphoma (PCNSL), with the identification of the viral DNA incorporated into that of the neoplastic cells. 

The common presenting symptoms are those of headache with focal neurological deficits, altered level of consciousness, and seizures.

Brain imaging reveals enhancing mass lesions with surrounding oedema and mass effect. These are similar to those found in toxoplasmosis. PCNSL is more likely to present as a single mass lesion than toxoplasmosis and is also more likely to invade the ventricular walls. Recent studies using thallium-201 single photon emission computed tomography (SPECT) suggest that it may be possible to differentiate between an abscess and a tumour, with the former having little uptake compared with the high uptake of the mitotically active lymphoma.

There is no effective treatment for primary central nervous system lymphoma (PCNSL). Whole-brain radiotherapy provides, at best, only a modest benefit, with most patients succumbing within 2 months. Current evidence suggests that HAART may improve survival in this group of patients.

HIV associated neurological disorders (HAND)

(Previously known as HIV–dementia complex)

Before the introduction of HAART (and in areas of the world where these drugs are still unavailable) approximately 15 to 20% of individuals infected with HIV developed a variably progressive dementia with associated motor deficits. HAND is now classified to three degrees – asymptomatic neurocognitive disorder (ANI), mild neurocognitive impairment (MND) with only mild functional effects and HIV dementia (HAD) where there is marked functional impariment. In children, a similar HIV-1-associated progressive encephalopathy occurs more frequently than with opportunistic infections. This usually occurs within the context of severe immunosuppression in those with a CD4 count of less than 200/mm3. In around 3% of cases, HIV–dementia is the AIDS-defining illness. Large cohort studies, using clinical, MRI, and neuropsychological methods, have largely discounted the early reports of evidence of cognitive changes in asymptomatic HIV-positive patients.

The clinical presentation in the early stages is with vague symptoms of apathy, mood changes, and difficulty with memory and concentration. These are features of a subcortical dementia with no features of cortical involvement such as language, visuospatial, or calculation difficulties. This picture may be mimicked by depression, metabolic encephalopathy, and drugs, both therapeutic and recreational. At this stage, there may be few physical signs apart from brisk reflexes, impaired fine finger movements, and unsteady gait.

Later, the memory impairments are obvious, as is the psychomotor retardation—which may progress to frank mutism and a global dementia. Some patients develop seizures. The motor signs due to the associated vacuolar myelopathy with a spastic paraparesis and sphincter disturbances are also present in a significant number of patients (Bullet list 4). In addition, some patients will have the HIV-related distal sensory peripheral neuropathy. Thus, this group will have absent ankle jerks and extensor plantar responses.

The diagnosis of the HIV–dementia is made by clinical assessment—there are usually no focal signs and the tempo of the disorder is an insidious one. Investigations are performed to exclude other infection or neoplastic pathologies, and therefore necessitate imaging, preferably with MRI, and a cerebrospinal fluid examination. MRI may show evidence of cerebral atrophy with compensatory ventricular dilatation, a diffuse white-matter high signal on T 2-weighted images with no enhancement. A cerebrospinal fluid examination may be nonspecifically abnormal with a pleocytosis, elevated protein level, and oligoclonal bands. It important to exclude cryptococcal and tuberculous meningitis as well as neurosyphilis. The HIV RNA viral load in cerebrospinal fluid correlates with the severity of clinical dementia, but there is too much overlap between nondemented and demented patients for the measurement to be of use as a diagnostic aid. There is no correlation between the plasma HIV RNA viral load and dementia. Electroencephalography (EEG) may be normal in the early stages, with nonspecific diffuse slowing developing shown later.

The pathology of the HIV–dementia is a spectrum ranging from diffuse myelin pallor, microglial nodules—which are nonspecific and may be found in CMV encephalitis—to multinucleated giant cells that are indicative of productive brain infection and cortical neuronal loss. There is no clear correlation between the clinical and pathological findings.

Bullet list 4 Myelopathy in HIV

Infections

  • HIV-associated vacuolar myelopathy*
  • Herpes zoster*
  • Cytomegalovirus
  • HTLV-1 (coinfection)
  • Treponema pallidum
  • Toxoplasmosis
  • Epidural abscess

Neoplasm

  • Metastatic non-Hodgkin’s lymphoma

Other causes

  • Vitamin B12

HTLV-1, human T-cell leukaemia/lymphoma virus-1.

* Most common.

The mechanisms of disease in the HIV–dementia are still unclear. It is, however, evident that HIV predominantly infects the microglial and astrocytic cells rather than neurons or oligodendrocytes. One hypothesis for the entry of the virus into the CNS is the ‘Trojan horse’ theory, with invasion occurring by infected peripheral blood monocytes penetrating a blood–brain barrier that has been disrupted by damage to the capillary endothelial cells. Neuronal damage is subsequently caused by viral toxins (e.g. Gp120) and cytokines (e.g. tumour necrosis factor α) released from activated macrophages.

After the introduction of zidovudine in 1987, there was a dramatic reduction in the incidence of HIV-associated dementia. One clinical study looking specifically at the effect of zidovudine on cognitive function confirmed its beneficial effect, albeit at dosages much higher than those currently used. With the introduction of the newer antiretroviral drugs—most of which have poor penetration into the cerebrospinal fluid and presumably the brain—there is concern that, despite the reduction of plasma HIV viral loads, the CNS may develop into a safe sanctuary for the virus from which reinfection could occur. It is clear, however, that suppressing the systemic viral load is important in the prevention and progression of HIV-associated dementia perhaps by reducing the trafficking of virus into the CNS. Recently published studies confirm that these newer therapies improve cognitive function and it seems prudent, until further data become available, to use drug combinations to which the virus is sensitive with those that best penetrate the cerebrospinal fluid to treat HIV–dementia.

HIV-associated neuropathy

The most common neurological complication encountered in patients infected with HIV is DSPN, which may occur in 30% of those with AIDS (Bullet list 5). It is a significant cause of morbidity.

Typically, patients complain of numbness of the soles of the feet together with shooting pains and paraesthesiae developing over a period of months. There is little or no weakness. The hands are infrequently involved. The ankle jerks are depressed or absent. Sensory testing reveals impaired pain and temperature perception as well as vibration.

Further investigations are usually unnecessary in a patient with a CD4 count below 200 and showing the typical clinical picture, but it is always worth checking the blood sugar, vitamin B12 level, and syphilis serology. It is important to enquire about alcohol intake and the possibility of an excess intake of vitamin B6.

Neurophysiological and pathological studies suggest this to be a length-dependent axonal neuropathy. Productive HIV infection has not been found in pathological specimens and the underlying mechanisms, similar to those for HIV dementia, are linked to macrophage activation products.

As antiretroviral therapy has no benefit, treatment is symptomatic with the use of tricyclic antidepressants and anticonvulsant drugs such as gabapentin.

The nucleoside analogues didanosine (ddI), zalcitabine (ddC), and stavudine (d4T) cause a dose-dependent sensory neuropathy that may be indistinguishable from DSPN. Clues to this drug-induced neuropathy include the shorter history of weeks rather than months, and the improvement on stopping the offending drug. However, there may be a continued worsening of symptoms for a period of 4 to 8 weeks after stopping—the phenomenon of ‘coasting’. The underlying mechanism appears to be the impairment of mitochondrial protein synthesis.

Bullet list 5 Peripheral nerve complications in HIV infection

HIV related

  • Axonal neuropathy (distal sensory peripheral neuropathy)*
  • Demyelinating neuropathy—acute (Guillain–Barré syndrome), chronic (chronic inflammatory demyelinating neuropathy)
  • Vasculitic (mononeuritis multiplex)
  • Diffuse inflammatory lymphocytic syndrome
  • Lower motor neuron syndrome (resembling motor neuron disease)

Drugs

  • Antiretrovirals (ddI, ddC, d4T)*
  • Isoniazid
  • Thalidomide
  • Dapsone
  • Metronidazole (high dose)
  • Vincristine

CMV related

  • Vasculitic (mononeuritis multiplex)
  • Lumbosacral polyradiculopathy

Others

  • Syphilis (polyradiculopathy)
  • Metastatic non-Hodgkin’s lymphoma (polyradiculopathy)
  • Ganglioneuritis
  • Autonomic neuropathy

* Most common.

Neurological immune reconstitution inflammatory syndrome (IRIS)

The introduction of HAART results in the recovery of CD4 T lymphocytes including memory T-cells. This may result in the ‘paradoxical deterioration of clinical or laboratory markers including imaging studies despite a favourable response in the viral load and CD4 count’ due to reaction against latent antigens. Neurological immune reconstitution inflammatory syndrome has now been described with Mycobacterium tuberculosis causing meningitis and brain abscesses, cryptococcal meningitis, CMV with the development of vitritis, uveitis, and cystoid macular oedema, and PML with MRI showing enhancement and biopsies inflammatory infiltrates.

The management in such cases is difficult but includes treatment of the appropriate organism and may warrant corticosteroids. In life-threatening situations stopping the HAART may be necessary.

Further reading

Top

Brew B (2001). HIV neurology. Oxford University Press, Oxford.

Clinical Effectiveness Group (1999). National guideline for the management of early syphilis. Sex Transm Infect, 75 Suppl 1, S29–33.

Clinical Effectiveness Group (1999). National guideline for the management of late syphilis. Sex Transm Infect, 75 Suppl 1, S34–7. 

French P (2007). Syphilis. Clinical review. BMJ, 334, 143–7.[Abstract/Full Text]

Gendleman H, et al. (eds) (2005). The neurology of AIDS, 2nd edition. Oxford University Press, Oxford.

Harrison MJ, McArthur JC (1995). AIDS and neurology. Clinical Neurology and neurosurgery monographs. Churchill Livingstone, Edinburgh.

Koralnik I (2006). Progressive Multifocal Leucoencephalopathy Revisited: Has the Disease Outgrown Its Name. Ann Neurol, 60, 162–173.

Letendre S, et al. (2008). Validation of the CNS Penetration Effectiveness Rank for Quantifying Antiretroviral Penetration into the Central Nervous System. Arch Neurol, 65(1), 65–70. 

Seminars in Neurology (1999). Vol. 19. Thieme Medical Publishers, Amsterdam. [Whole volume devoted to HIV neurology.]

Stoll M, Schmidt RE (2003). Immune Restoration Inflammatory Syndromes: The Dark Side of Successful Antiretroviral Treatment. Current Infectious Disease Reports, 5, 266–276.

Swartz MN, Healy BP, Musher DM (1999). Late syphilis. In: Holmes KK, et al. (eds) Sexually transmitted diseases, pp. 487–509. McGraw-Hill, New York.