HIV Neurology

Question 1

Common neurologic complications of HIV (classified by the stage in which each occurs)

Answer 1

Question 2

Most common cause of meningitis in HIV

Answer 2

Cryptococcus

Question 3

Cryptococcal meningitis symptoms

Answer 3

Nonspecific headache and fever are the cardinal features of cryptococcal meningitis.

Nausea, vomiting, phonophobia, and photophobia (migraine symptoms) are rare early in the infection.

The clinical course is usually slow and insidious over several weeks

Seizures and, to a lesser extent, stroke are associated with cryptococcal meningitis.

As the infection advances and intracranial pressure increases, encephalopathy, cranial neuropathies (especially sixth nerve palsy), and papilledema develop.

Question 4

Cryptococcal meningitis: are there always
1) symptoms early in the disease
2) CSF findings

Answer 4

1) Early in the infection there is a paucity of neurologic signs.

Typical signs and symptoms of meningitis may be lacking because the immunosuppressed patient fails to mount a vigorous inflammatory response to the organism.
However, both the meninges and the brain can be infected, so focal neurologic findings may occur.

2) CSF indices can be normal or show just a mild mononuclear pleocytosis or mild elevation in protein, particularly in those with advanced AIDS; markedly abnormal indices warrant a search for an alternative or concomitant diagnosis.

Question 5

Cryprococcal meningitis laboratory findings

Answer 5

CSF analysis provides a definitive diagnosis in most cases.
A positive CSF culture for Cryptococcus or the presence of cryptococcal antigen establishes the diagnosis of cryptococcal meningitis.

Routine CSF indices usually reveal nonspecific abnormalities, including mild to moderate lymphocytic pleocytosis, elevated protein concentration, and a normal to moderately low glucose level.

The opening pressure is usually high (>250 mm H2O) and should be measured in all patients suspected of having cryptococcal meningitis to provide guidance during treatment.

Serum cryptococcal antigen and fungal cultures are sensitive tests for cryptococcemia.
When a lumbar puncture is contraindicated or CSF indices are normal, including the rare false-negative CSF cryptococcal antigen or culture, a positive serum antigen or culture supports a presumed diagnosis of cryptococcal meningitis.

Question 6

Serum cryptococcal antigen timing

Answer 6

Serum cryptococcal antigen is detectable in the blood 3 weeks before meningitis onset and is an independent predictor of clinical meningitis and death.

Question 7

Cryptococcal meningitis imaging

Answer 7

MRI may show enlarged perivascular (Virchow-Robin) spaces or enhancement of the meninges.
At least one imaging test, preferably with contrast, is indicated to exclude a cryptococcoma or other concomitant CNS process

Question 8

Cryptococcal meningitis in HIV patients treatment

Answer 8

Treatment of cryptococcal meningoencephalitis includes
1) antifungal therapy
i) induction therapy with amphotericin B and flucytosine for at least two weeks
ii) When patients transition to consolidation therapy, we suggest fluconazole rather than itraconazole for at least 8 weeks
iii) For patients who complete the induction and consolidation phases of therapy, we recommend fluconazole (200 mg daily) for maintenance for at least 1 year

2) control of intracranial pressure

3) immune recovery with HIV therapy

Question 9

Cryptococcal meningitis when to start ART

Answer 9

For patients with cryptococcal meningoencephalitis who are not receiving ART, we suggest initiation of ART be delayed at least two weeks after antifungal induction therapy has been started.

For patients with access to close medical follow-up and preventative therapy, we often start ART 10 weeks after the initiation of antifungal therapy to minimize the risk of drug interactions and development of an immune reconstitution inflammatory syndrome (IRIS).

However, for individuals without these resources, we typically start ART four to six weeks after induction therapy has been initiated.

Question 10

Most common cause of focal brain mass in HIV patients

Answer 10

CNS toxoplasmosis

Question 11

CNS toxoplasmosis clinical findings

Answer 11

A subacute presentation with headache, fever, focal neurologic deficit(s), and altered mental status is the most common presentation.

Acute symptomatic seizures occur in 25% of patients.

Rarely, toxoplasmosis presents with ocular pain and visual loss (toxoplasmic retinochoroiditis), myelopathic
signs (spinal cord toxoplasmosis), or diffuse encephalitis.

Unilateral chorea or ballism, along with other movement
disorders, have been reported, with toxoplasmic abscesses in the basal ganglia.

Question 12

CNS toxoplasmosis laboratory findings

Answer 12

A presumed clinical diagnosis is made by combining historical information with results from serum tests and brain imaging.
serum IgG antibody titer: indicates exposure to T gondii, thus raising the clinical probability of CNS toxoplasmosis,
(not everyone with a positive antibody will have CNS toxoplasmosis)
A negative titer does not rule out toxoplasmosis infection, as the antibody response may be attenuated in advanced AIDS or may not yet be mounted in newly acquired (primary) Toxoplasma infection.

A current CD4+ T-lymphocyte count should be obtained; greater than 300 cells/μL should suggest alternative diagnoses.

Lumbar puncture is often contraindicated; moreover, CSF
analyses seldom assist in the diagnosis of CNS toxoplasmosis.
Mild-to-moderate pleocytosis, elevated protein concentration, and normal-to-low glucose level are the usual findings.
A CSF Toxoplasma antibody titer is not helpful.

CSF analysis for Toxoplasma DNA by PCR lacks sensitivity but is helpful in confirming the diagnosis when positive.

Question 13

CNS toxoplasmosis imaging

Answer 13

MRI and CT brain scan typically show multiple ring enhancing, space-occupying lesions with surrounding vasogenic edema.

Toxoplasma has a predilection for the basal ganglia and the gray-white junction of the hemispheres.

Being more sensitive, MRI is the preferred imaging test.

Question 14

Comparison of CNS toxoplasmosis and primary CNS lymphoma imaging

Answer 14

Question 15

CNS toxoplasmosis in HIV patients treatment

Answer 15

The treatment of toxoplasmosis in patients with HIV includes antimicrobial therapy directed against T. gondii, as well as antiretroviral therapy (ART) for immune recovery.

Initial therapy – For most patients, we suggest an initial regimen containing sulfadiazine plus pyrimethamine or trimethoprim-sulfamethoxazole

For patients who respond to treatment, the duration of initial therapy is typically six weeks.

Maintenance therapy – For patients who complete initial therapy, we suggest maintenance therapy (ie, secondary prophylaxis) with sulfadiazine plus pyrimethamine or TMP-SMX. Relapse of infection can occur after initial therapy unless the patient has immunologic recovery.

Maintenance therapy can be discontinued in asymptomatic patients who are receiving ART, have a suppressed HIV viral load, and have maintained a CD4 count >200 cells/microL for at least six months.

● Antiretroviral therapy – Most patients with toxoplasmosis are not on ART at the time of diagnosis. We initiate ART within two weeks of starting treatment for toxoplasmosis, typically as soon as it is clear that the patient is tolerating toxoplasmosis therapy.

Question 16

Primary central nervous system lymphoma in HIV patients cause

Answer 16

strongly related to Epstein-Barr virus (EBV) infection

Question 17

Primary central nervous system lymphoma clinical findings

Answer 17

subacute focal neurologic deficits, encephalopathy, headaches, and seizures.

Fever is uncommon, in contrast to CNS toxoplasmosis.

The lymphoma is usually isolated to the CNS; therefore, systemic manifestations are not seen.

Question 18

Primary central nervous system lymphoma laboratory findings

Answer 18

CSF typically reveals mild, lymphocytic-predominant
pleocytosis, normal to mildly elevated protein concentration, and normal glucose level.

The most useful test is PCR amplification for EBV

Question 19

Primary central nervous system lymphoma diagnosis

Answer 19

The diagnosis of PCNSL in a person living with HIV should be made by stereotactic biopsy or CSF flow cytometry and/or cytology in the majority of patients.

In selected patients who cannot undergo biopsy and who have otherwise typical clinical and radiographic findings for PCNSL, detection of Epstein-Barr virus DNA in the CSF may provide enough clinical certainty to treat.

Question 20

Primary central nervous system lymphoma imaging

Answer 20

CT or MRI scans typically show an isolated enhancing
lesion or, less often, multiple enhancing lesions, commonly involving the frontal lobes and the periventricular region.

PCNSL may cross the midline through the corpus callosum.
Enhancement tends to be heterogeneous rather than the ringlike appearance seen with toxoplasmosis.
Vasogenic edema is variably present.

MRI is the preferred test.
Signal intensity on T2-weighted images is variable, but is often bright on diffusion-weighted images.
Perfusion-weighted images show areas of increased regional blood volumes, in contrast to the low-volume areas seen with toxoplasmosis.

Thallium SPECT imaging, which shows increased uptake with PCNSL, and magnetic resonance spectroscopy can be helpful in discriminating lymphoma from toxoplasmosis

Question 21

Primary central nervous system lymphoma in HIV patients management

Answer 21

*First-line chemotherapy – For most patients with HIV-related PCNSL, we suggest initial therapy with high-dose methotrexate (MTX) rather than radiation therapy or antiretroviral therapy (ART) alone.

*Antiretroviral therapy – In addition to tumor-directed therapy, all patients should receive concurrent treatment of HIV with ART.
Every effort should be made to find an antiretroviral regimen that is effective, since enhancement of the immune system is a key therapeutic intervention against PCNSL.

*Refractory disease – The field has moved increasingly away from whole brain radiation therapy (WBRT) as first-line therapy in PCNSL due to poor durability of responses, poor survival when used as a standalone therapy, and risks of irreversible neurocognitive decline in survivors.
WBRT remains reasonable to consider in patients with chemotherapy-refractory disease and those who cannot tolerate systemic therapy.
Focal irradiation and immunomodulatory therapies may also be options in selected patients.

Question 22

PML pathogenesis

Answer 22

A reactivation of JC virus, either within the CNS or at extraneural sites such as the kidneys or lymphoid tissue with subsequent spread to the CNS, in the setting of an immune-compromised state leads to a productive infection within oligodendrocytes, resulting in their apoptosis and subsequent demyelination.

Question 23

Does a negative CSF PCR for JCV exclude PML diagnosis?

Answer 23

No
(Sensitivity 65-90% / Specificity 90-100%)

Question 24

Most common form of dementia in people under 40

Answer 24

HIV

Question 25

HIV neurocognitive disorder: types

Answer 25

HIV-associated dementia –
HAD occurs predominantly in untreated patients with advanced HIV infection. In its classic form, it is primarily characterized by subcortical dysfunction, with attention-concentration impairment, depressive symptoms, and impaired psychomotor speed and precision. The onset of the impairments is typically subacute.
Cerebral atrophy is typically evident on brain imaging, which can also demonstrate diffuse or patchy white matter hyperintensity.

Milder neurocognitive deficits –
The main cognitive deficits reported in milder presentations of HAND include difficulty with attention and working memory, executive functioning, and speed of informational processing. The onset and time course is generally more indolent than the typically subacute presentation of HAD, and deficits may remain stable or seemingly unchanged for years.
There are no specific imaging findings.

Question 26

HIV associated myelopathy: clinical findings

Answer 26

HIV-associated myelopathy is a chronic disorder with an insidious, often asymmetric onset characterized by urinary and erectile dysfunction, spastic paraparesis, and gait ataxia from posterior column involvement.

Because the thoracic segments of the cord are affected first, arms are spared until late in the disease.

Examination reveals a spastic paraparesis and attenuated vibratory and proprioception sensation in the toes, reflecting posterior column dysfunction.
Pain and temperature sensation are relatively preserved. Additional signs include exaggerated ankle and patellar stretch reflexes, extensor plantar responses, gait spasticity, and a Romberg sign.
As the disease progresses, similar signs and symptoms involve the arms.

Question 27

HIV associated myelopathy: diagnosis

Answer 27

clinical based on symptoms

Question 28

HIV associated myelopathy: treatment

Answer 28

B12, Glucocorticoids and IVIg
ARE NOT effective

Question 29

Differential diagnosis of nonacute myelopathy

Answer 29

Question 30

Causes of HIV aseptic meningitis

Answer 30

1) during primary HIV dissemination as part of the acute conversion syndrome
2) after cessation of antiretroviral therapy (retroviral rebound syndrome) less commonly

Question 31

VZV vasculitis in HIV: clincial findings

Answer 31

• fever
• headache
• encephalopathy
• cranial neuropathies (especially oculomotor palsy)
• focal stroke-like neurologic deficits
• seizures

Question 32

VZV vasculitis in HIV: laboratory and imaging findings

Answer 32

CSF
generally shows mild to moderate lymphocytic or monocytic pleocytosis, elevated protein concentration, and normal to low glucose level.
CSF should be analyzed for both VZV DNA (via PCR) and antibody (IgM and IgG).

The presence of VZV DNA or IgM antibody in CSF or an elevated CSF-to-serum IgG antibody ratio confirms the diagnosis.

MRI
typically shows multiple areas of hyperintensity on T2- and diffusion-weighted images, suggestive of acute or subacute infarcts.
Some of these areas may become hemorrhagic.

Transcranial Doppler and magnetic resonance angiography
may show asymmetric increased flow velocities and focal stenoses, respectively, particularly in the distal arteries

Question 33

Most common cause of neurologic morbidity in HIV patients

Answer 33

Peripheral neuropathy

Question 34

Peripheral nervous system complications of HIV infection

Answer 34