aids and cns

Dr.T.V.Rao MD 1

CENTRAL NERVOUS SYSTEM IN

AIDS Dr.T.V.Rao MD

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AIDS PATIENTS ARE ENCROHED BY MANY OPPORTUNISTIC AND

UNCOMMON INFECTIONS

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AIDS complications

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AIDS-Defining Illnesses• Candidiasis of bronchi, trachea, or lungs (see Fungal Infections) • Candidiasis, esophageal (see Fungal Infections) • Cervical cancer, invasive--HPV • Coccidioidomycosis, disseminated (see Fungal Infections) • Cryptococcosis, extrapulmonary (see Fungal Infections) • Cryptosporidiosis, chronic intestinal (>1 month duration) (see

Enteric Diseases) • Cytomegalovirus disease (other than liver, spleen, or lymph

nodes) • Cytomegalovirus retinitis (with loss of vision) • Encephalopathy, HIV-related† (see Dementia) • Herpes simplex: chronic ulcer(s) (>1 month duration) or

bronchitis, pneumonitis, or esophagitis • Histoplasmosis, disseminated (see Fungal Infections) • Isosporiasis, chronic intestinal (>1 month duration) (see

Enteric Diseases)

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AIDS-Defining Illnesses• Kaposi's sarcoma, HHV8 • Lymphoma, Burkitt's, EBV• Lymphoma, immunoblastic • Lymphoma, primary, of brain (primary central

nervous system lymphoma) • Mycobacterium avium complex or disease caused by

M. Kansasii, disseminated • Disease caused by Mycobacterium tuberculosis, any

site (pulmonary‡ or extrapulmonary†) (see Tuberculosis)

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AIDS-Defining Illnesses• Disease caused by Mycobacterium, other species

or unidentified species, disseminated • Pneumocystis carinii pneumonia (aka jiroveci)• Pneumonia, recurrent‡ (see Bacterial Infections) • Progressive multifocal leukoencephalopathy • Salmonella septicemia, recurrent (see Bacterial

Infections) • Toxoplasmosis of brain (encephalitis) • Wasting syndrome caused by HIV infection†

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HIV and the Nervous System

HIV enters the nervous system early, at the

time of initial infection, and mayimmediately cause symptoms, or maycause symptoms any time during the

person’s lifetime.

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HIV and the Nervous System• All levels of the neuraxis are

potential sites of involvement:»Meninges»Brain»Spinal cord»Cranial and peripheral nerves»Autonomic nervous system»Muscle

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HIV enters the CNS by infecting macrophages and monocytes that then cross the blood brain barrier, carrying the virus with them. What do you call this process?Immunohistochemistry studies show that the virus is most densely located in the basal ganglia, subcortical regions, and frontal cortex. Infected macrophages or microglial cells then elaborate proinflammatory diffusible cellular neurotoxins, including TNF-alpha, cytokines, interleukins, Chemokine's and nitric oxide.

Pathophysiology

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HIV and the Nervous SystemClinical Syndromes

• BRAIN SYNDROMES

–Meningitis–Dementia–Stroke–Seizures–Degenerative Disorders

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Classification system• To understand how neurological impairment

occurs in HIV, it is helpful to use a classification system of how impairment occurs generally in HIV disease

• One way is to divide in to the following five categories:

1. Opportunistic Infections2. Malignancies3. Auto-immune and reconstitution diseases4. Constitutional disease 5. Other /multi-factorial / poorly understood

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How being HIV+ leads to illness or impairment

1. Opportunistic infections: Immunosuppressed state renders individual susceptible to infections / illnesses “opportunistic infections” (most widely understood)

2. Autoimmune diseases and reconstitution diseases where the immune system is “overactive” e.g. joint disease (not fully understood)

3. Malignancies – Some malignancies much more prevalent with HIV – unsure why, some links to other viruses

4. Constitutional Disease: The action of HIV at cellular level directly causing illness “constitutional symptoms” (not fully understood)

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Neuropathogenesis• Neurological impairment can occur

through several routes:1. As a result of opportunistic infections2. As a result of HIV related malignancies3. As a result of autoimmune disorders4. Directly related to the action of HIV (can

be CNS or PNS related)5. Multifactorial / drug related / not

understood

Dr.T.V.Rao MD 16microorganism

Nasal route

5.Penetration of BBB

BBB

CNS

Skin ulcerations

Serum factorsPhagocytes

4. Disseminated Infection

Blood stream

3. Lung PenetrationNasal mucosa

Sub mucosal nerve plexus

Lungs

Routes of penetration

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Opportunistic infections with CNS involvement

• Cerebral toxoplasmosis• PML• Meningitis (Cryptococcal meningitis,

TB meningitis)• Encephalitis (CMV, HSV, VZV)• Neurosyphilis

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HIV related malignancies withneuro involvement

• Primary lymphoma (most common)• Kaposi’s sarcoma with cerebral

involvement (rare)• Multiple lymphomas with either CNS

(including spinal cord compression) or rarely PNS involvement (ie secondary CNS/PNS lymphomas)

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HIV Associated Cryptococcal Meningitis

Clinical presentation:

• Occurs in persons with advanced immunodeficiency, CD4 <100/μl

• Subtle clinical presentation, headache, fever, malaise; absent meningeal signs

• Altered sensorium in 25%, and focal signs 5%

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Diagnosis• CSF, Indian

ink/culture; yield about 75%

• Cryptococcal antigen assays, CSF/serum

• Blood culture

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Treatment

• Induction: Amphotericin B; 0.7-1mg/kg/day IV, – With/without flu cytosine 100mg/kg/day PO

for 14 days,• Consolidation: fluconazole 400mg/day for 8-10

weeks,

• Maintenance: fluconazole 200mg/day, lifelong.

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Cerebral Toxoplasmosis• Most common CNS impairment seen in HIV• Is a reactivation of a latent protozoal infection• Can also affect myocardium, lung skeletal

muscle• Generally presents as multiple enhancing lesions

with perifocal oedema in the basal ganglia and grey-white matter interface of the cerebral hemispheres, although can be in any part of brain

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Toxoplasmosis• Common signs and symptoms

– Headache, fever – Confusion – Lethargy – Seizure (may be initial clinical manifestation) – Focal neurologic signs (50%-60% of HIV-infected cases)

• Usually hemiparesis or visual field defects

• Treatment– Antio-toxo drugs: Sulfadiazine, pyrimethamine,

clindamycin, pyrimethamine, folinic acid

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Toxoplasmosis in Patients with HIV Infection

Epidemiology:

• Toxoplasma gondii is a zoonotic infection• Cats are the definitive hosts, and excrete

T gondii oocysts in their feces• T gondii cysts are found in undercooked

meat• Prevalence of latent T gondii infection is

high 85% seropositive for anti-toxoplasma antibodies.

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Toxoplasmosis, clinical presentation:

• Typical presentation is an altered mental state, seizures, weakness, and cranial nerve abnormalities

• Onset is usually sub acute, nearly 90% of cases develop focal neurologic signs

• Commonly affected areas, basal ganglia, brain stem and cerebellum

• Extra cranial sites may occur, retina, myocardium, and lungs

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Diagnosis of toxoplasmosis:Neuro- radiologic imaging:• Contrast enhanced CT, hypo dense

multiple lesions with ring-enhancement after IV contrast

• Solitary lesions present with diagnostic difficulties

• Therapeutic trial, clinical / radiological response in two to three weeks

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Toxoplasmosis, diagnosis (contd.)

Serologic assays:• A negative Toxoplasma antibody

test makes the diagnosis of toxoplasmosis less likely.

Histologic diagnosis:• Brain biopsy; Wright-Giemsa,

fluorescent antibody staining

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Management of toxoplasma encephalitis

• Two major regimens:– Pyrimethamine plus sulfadiazine

OR– Pyrimethamine plus clindamycin

• both with folinic acid– duration of treatment six weeks– Suppressive/maintenance treatment continued

for life

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Management of toxoplasmosis (contd.)

• High rates of adverse reactions with pyrimethamine-sulfadiazine

• Experimental therapies: azithromycin, clarithromycin, trimetrexate, doxycycline, atovaquoune

• Corticosteroids may be used in patients with cerebral edema and increased intracranial pressure.

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Preventive therapies for Toxoplasmosis:

Indications• CD4+ count < 100 cells/μl• Positive T gondii serologyRegimens• TMP-SMX two tablets per day (single

strength)Alternative regimens• Dapsone 50mg daily, plus pyrimethamine 50

mg po weekly

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PML: Progressive Multifocal Leukoencephalopathy

• Used to be more common and was nearly always fatal; now not seen that often

• Is a reactivation of a latent JC virus (due to immunosuppression) – often seen more in more severely immunocompromised people

• Appears as patchy white matter on scans, often bilateral, asymmetrical scalloped lesions in sub-cortical white matter, often in parietal lobe

• Usually gradual onset

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• Common presenting symptoms and signs – Hemiparesis – Gait abnormality – Speech disturbances – Cognitive dysfunction – Dysarthria – Ataxia – Sensory loss – Vertigo – Visual impairment

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• No specific PML treatment; aim is to improve immune health therefore usually treatment is with ARVs (although cidofovir sometimes used)

• Still often fatal; survivors tend to have residual dysfunction in some or all of the presenting deficit areas

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• Therapy approach is again to treat what you find – in more advanced disease may need to look at positioning to discourage poor movement or even prevent contracture; or looking at managing advanced dementia / behaviour

• If patient does survive may require some compensation on discharge e.g. supervision, wheelchairs etc.

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Cryptococcal meningitis, TB meningitis

• Both quite common presentations• Crypto caused by fungal infection• TB may also cause focal lesions as well as

the meningitis• Both may or may not have other systemic

illness associated e.g. Cryptococcosis, TB lung, spine, miliary TB

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• Symptoms – Headache (without focal signs) – Fever – Altered mental status – Nausea and/or vomiting– May have some focal deficits, cranial nerve features

• Therapy input may be around focal deficits / cranial nerve involvement; patients also typically become deconditioned and lack balance as they recover so often benefit from general functional / activity tolerance approach

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• Crypto treated with IV amphotericin / fluconazole

• TB treated with standard TB therapy• Both generally respond reasonably well;

crypto quite often relapses a few times before treated successfully

• Either sometimes may require a shunt top effectively manage the raised ICP

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CMV Encephalitis (and others)• CMV= cytomegalovirus• Quite common; CMV encephalitis is a

reactivation of latent CMV infection - features cell death in meninges and peri-ventricular area

• Often associated with a CMV retinitis• Rapidly progressing; responds well to

treatment if caught in time otherwise responds poorly

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CMV Encephalitis (and others)

• Treatment is usually IV Ganciclovir, valganciclovir, foscarnet, cidofovir – these drugs can be quite toxic

• Presentations vary, however usually involve confusion, headache, delirium

• Can have focal neurology, cranial nerve deficits

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CMV Encephalitis (and others)

• Therapy approach again is treat what presents; often complicated by permanent visual field loss

• Other encephalitis presentations include HSV (Herpes Simplex Virus) and VZV (Varicellar Zoster Virus)

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Primary CNS Lymphoma• 1000-4000 times more common in HIV+

population than in immunocompetent population

• Doesn’t correlate with low CD4 counts• Pathogenesis not fully understood but known

to be linked to the Epstein-Barr Virus• Thought that long term low level immune

system damage may be contributing factor

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Primary CNS Lymphoma• Is generally non-Hodgkin’s B-cell type with high mitotic

rate; tumours usually double in size in 14 days. (can also be a Burkitt or more rarely a Primary Effusion Lymphoma)

• Can be multifocal (50%) and appear in uncommon locations with greater frequency than in non-HIV population

• Studies have average survival rates from diagnosis between 3 and 24 months

• May be treated actively or palliative with radiotherapy (usually palliative) or high dose methotrexate (chemo)

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Primary CNS Lymphoma

• Disagreement between researchers whether discontinuing or continuing ARVs throughout treatment is most beneficial

• Therapy input is usually initially around advice / treatment to help maintain function / independence and planning for deterioration / palliative approach

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HIV EncephalopathyHIVE / ADC / HAD

• Number of terms used over to describe poorly understood syndromes of long term infiltration of HIV into the CNS

• Names include:– HIV-1-associated dementia complex (HAD)– AIDS Dementia Complex (ADC)– HIV encephalitis / HIV Encephalopathy (HIVE)– multinucleated giant-cell encephalitis

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• Can be seen in early disease but more common later• Severe form less common since the introduction of HAART• Many long term diagnosed however do report mild

cognitive problems e.g. memory problems, and show some general brain atrophy on scans

• On scans often higher concentrations changes in the basal ganglia - ?due to numbers of microglia in the brain – thought to be why high rates of extra-pyramidal signs / symptoms seen

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• Symptoms generally develop over weeks to months in the following domains:

• Cognition – Decreased concentration – Forgetfulness, particularly daily or recent events – Slowing of thought processes – Global dementia – Psychomotor slowing: verbal responses delayed, near or

absolute mutism, vacant stare – Unawareness of illness, disinhibition – Confusion, disorientation – Organic psychosis

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• Motor function – Unsteady gait – Clumsiness – Tremor – Leg weakness (legs more than arms) – Loss of coordination, impaired handwriting

• Behaviour – Social withdrawal – Apathy – Personality change – Agitation – Hallucinations

• Other – Headaches – Generalized seizures – Ataxia

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• Treatment is via reducing viral load and viral activity in the CNS, therefore treatment is primarily HAART

• Need to consider ARVs with best CNS penetration e.g. Zidovudine (AZT), abacavir, nevirapine

• Difficult to measure drug levels as not known whether CSF drug levels always correlate with cerebral levels; (not practical to brain biopsy!)

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• Therapy input more akin to treating someone with dementia; early treatment may be looking at memory strategies; later stages may require behavioural management and reality orientation / validation

• Severe HIVE may require 24 hour supervision

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Vacuolar Myopathy• “Holes” in spinal cord• Clinical Features – onset over weeks-months of:

– Bilateral lower extremity stiffness and weakness with variable sensory disturbances

– Gait unsteadiness – Bladder and erectile dysfunction – Hyperreflexia and Babinski signs – Spastic Para paresis with no definite sensory involvement – Loss of proprioception and vibration sense

• Thought to be secondary to overactive immune system producing excessive cytokines, or some poorly understood metabolic imbalance; may be related to HTLV-I and HTLV-II

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DSPN: Distal Symmetrical Sensory Polyneuropathy

• Occurs in many HIV+ patients with varying severity

• Poorly understood aetiology but could be related to malnutrition and resultant wasting of peripheral nerves, or could be neurotoxic effect of cytokines

• Can also be secondary to NRTI use e.g. AZT

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DSPN• Often occurs in a glove and stocking

distribution but there is great variance in self report

• Can range from mild paraesthesia / numbness / pins and needles through to severe hypersensitivities, or dysesthesias (burning, stabbing pain)

• Can lead to poor upper limb coordination or mildly impaired mobility / clumsiness, attributable to reduced sensory feedback

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DSPN• Can progress to actual muscle weakness,

particularly foot intrinsics (result of long term de-inervation)

• Sometimes use EMG studies to diagnose• Often treated with quite high dose analgesics

which can interact with other medications or have lifestyle implications

• Can be very disabling

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DSPN• Therapy input can be looking at

– Psychogenic management of pain e.g. relaxation– Task planning – how to avoid parts of tasks that

elicit pain– Safety aspects e.g. temperature sensation,

retraining to be aware of feet catching on stairs– Padded / built up equipment to reduce / alter

sensory input to help mange pain, or provide more gross proprioceptive feedback

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Inflammatory Demyelinating Polyneuropathy (IDP)

• IDP, and it’s more severe Guillain- Barre Syndrome sometimes occur acutely in otherwise well HIV+ patients, or in HIV+ patients with advanced disease.

• Seems to be some sort of auto-immune response that attacks the myelin's sheath – mechanism is poorly understood

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(Ascending) Neuromuscular Weakness Syndrome

• Presents as rapidly progressing sensorimotor neuropathy, can lead to respiratory failure

• Thought to be related to NRTI use

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Mononeuritis Multiplex • Can present as multifocal sensory and/or

motor abnormalities and is due to asymmetrical involvement of individual peripheral and cranial nerves; may be a mixed neuropathy (motor, sensory, autonomic)

• Thought to be directly related to action of HIV

• Poorly understood

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AIDS Dementia and Antiretroviral Treatment

• AIDS dementia complex, or ADC, is mental decline caused by HIV infection. It is also called HIV-associated dementia. ADC occurs most often in the advanced stages of AIDS. It is not common in people who have taken antiretroviral therapy. Mental problems can make it hard to follow the planned routines for care and make it difficult to protect the person with AIDS from infections.

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AIDS IS A PREVENTABLE DISEASE

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FOR MORE ARTICLES OF INTERST ON INFECTIOUS DISEASES VISIT ME ..

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