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Dr.T.V.Rao MD 3

AIDS complications:

AIDS complications Dr.T.V.Rao MD 4

AIDS-Defining Illnesses:

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) Dr.T.V.Rao MD 5

AIDS-Defining Illnesses:

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) Dr.T.V.Rao MD 6

AIDS-Defining Illnesses:

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† Dr.T.V.Rao MD 7

HIV and the Nervous System:

HIV and the Nervous System HIV enters the nervous system early, at the time of initial infection, and may immediately cause symptoms, or may cause symptoms any time during the person’s lifetime. Dr.T.V.Rao MD 8

HIV and the Nervous System:

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 Dr.T.V.Rao MD 9

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Dr.T.V.Rao MD 10

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11 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 Dr.T.V.Rao MD

HIV and the Nervous System Clinical Syndromes:

HIV and the Nervous System Clinical Syndromes BRAIN SYNDROMES Meningitis Dementia Stroke Seizures Degenerative Disorders Dr.T.V.Rao MD 12

Classification system:

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 : Opportunistic Infections Malignancies Auto-immune and reconstitution diseases Constitutional disease Other /multi-factorial / poorly understood Dr.T.V.Rao MD 13

How being HIV+ leads to illness or impairment:

How being HIV+ leads to illness or impairment Opportunistic infections : Immunosuppressed state renders individual susceptible to infections / illnesses “opportunistic infections” (most widely understood) Autoimmune diseases and reconstitution diseases where the immune system is “overactive” e.g. joint disease (not fully understood) Malignancies – Some malignancies much more prevalent with HIV – unsure why, some links to other viruses Constitutional Disea se : The action of HIV at cellular level directly causing illness “constitutional symptoms” (not fully understood) Dr.T.V.Rao MD 14


Neuropathogenesis Neurological impairment can occur through several routes: As a result of opportunistic infections As a result of HIV related malignancies As a result of autoimmune disorders Directly related to the action of HIV (can be CNS or PNS related) Multifactorial / drug related / not understood Dr.T.V.Rao MD 15

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16 microorganism Nasal route 5.Penetration of BBB BBB CNS Skin ulcerations Serum factors Phagocytes 4. Disseminated Infection Blood stream 3. Lung Penetration Nasal mucosa Sub mucosal nerve plexus Lungs Routes of penetration Dr.T.V.Rao MD

Opportunistic infections with CNS involvement:

Opportunistic infections with CNS involvement Cerebral toxoplasmosis PML Meningitis (Cryptococcal meningitis, TB meningitis) Encephalitis (CMV, HSV, VZV) Neurosyphilis Dr.T.V.Rao MD 17

HIV related malignancies with neuro involvement:

HIV related malignancies with neuro 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) Dr.T.V.Rao MD 18

HIV Associated Cryptococcal Meningitis:

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% Dr.T.V.Rao MD 19

HIV Associated Cryptococcal Meningitis:

HIV Associated Cryptococcal Meningitis Diagnosis CSF, Indian ink/culture; yield about 75 % Cryptococcal antigen assays, CSF/serum Blood culture Dr.T.V.Rao MD 20

HIV Associated Cryptococcal Meningitis:

HIV Associated Cryptococcal Meningitis 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. Dr.T.V.Rao MD 21

Cerebral Toxoplasmosis:

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 Dr.T.V.Rao MD 22


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 Dr.T.V.Rao MD 23

Toxoplasmosis in Patients with HIV Infection:

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. Dr.T.V.Rao MD 24

Toxoplasmosis, clinical presentation::

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 Dr.T.V.Rao MD 25

Diagnosis of toxoplasmosis::

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 Dr.T.V.Rao MD 26

Toxoplasmosis, diagnosis (contd.):

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 Dr.T.V.Rao MD 27

Management of toxoplasma encephalitis:

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 Dr.T.V.Rao MD 28

Management of toxoplasmosis (contd.):

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. Dr.T.V.Rao MD 29

Preventive therapies for Toxoplasmosis::

Preventive therapies for Toxoplasmosis : Indications CD4+ count < 100 cells/μl Positive T gondii serology Regimens TMP-SMX two tablets per day (single strength) Alternative regimens Dapsone 50mg daily, plus pyrimethamine 50 mg po weekly Dr.T.V.Rao MD 30

PML: Progressive Multifocal Leukoencephalopathy:

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 Dr.T.V.Rao MD 31

PML: Progressive Multifocal Leukoencephalopathy:

PML: Progressive Multifocal Leukoencephalopathy Common presenting symptoms and signs Hemiparesis Gait abnormality Speech disturbances Cognitive dysfunction Dysarthria Ataxia Sensory loss Vertigo Visual impairment Dr.T.V.Rao MD 32

PML: Progressive Multifocal Leukoencephalopathy:

PML: Progressive Multifocal Leukoencephalopathy 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 Dr.T.V.Rao MD 33

PML: Progressive Multifocal Leukoencephalopathy:

PML: Progressive Multifocal Leukoencephalopathy 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. Dr.T.V.Rao MD 34

Cryptococcal meningitis, TB meningitis:

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 Dr.T.V.Rao MD 35

Cryptococcal meningitis, TB meningitis:

Cryptococcal meningitis, TB meningitis 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 Dr.T.V.Rao MD 36

Cryptococcal meningitis, TB meningitis:

Cryptococcal meningitis, TB meningitis 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 Dr.T.V.Rao MD 37

CMV Encephalitis (and others):

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 Dr.T.V.Rao MD 38

CMV Encephalitis (and others):

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 Dr.T.V.Rao MD 39

CMV Encephalitis (and others):

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) Dr.T.V.Rao MD 40

Primary CNS Lymphoma:

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 Dr.T.V.Rao MD 41

Primary CNS Lymphoma:

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) Dr.T.V.Rao MD 42

Primary CNS Lymphoma:

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 Dr.T.V.Rao MD 43

HIV Encephalopathy HIVE / ADC / HAD:

HIV Encephalopathy HIVE / 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 Dr.T.V.Rao MD 44

HIV Encephalopathy HIVE / ADC / HAD:

HIV Encephalopathy HIVE / ADC / HAD 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 Dr.T.V.Rao MD 45

HIV Encephalopathy HIVE / ADC / HAD:

HIV Encephalopathy HIVE / ADC / HAD 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 Dr.T.V.Rao MD 46

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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 Dr.T.V.Rao MD 47

HIV Encephalopathy HIVE / ADC / HAD:

HIV Encephalopathy HIVE / ADC / HAD 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!) Dr.T.V.Rao MD 48

HIV Encephalopathy HIVE / ADC / HAD:

HIV Encephalopathy HIVE / ADC / HAD 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 Dr.T.V.Rao MD 49

Vacuolar Myopathy:

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 Dr.T.V.Rao MD 50

DSPN: Distal Symmetrical Sensory Polyneuropathy:

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 Dr.T.V.Rao MD 51


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 Dr.T.V.Rao MD 52


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 Dr.T.V.Rao MD 53


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 Dr.T.V.Rao MD 54

Inflammatory Demyelinating Polyneuropathy (IDP):

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 Dr.T.V.Rao MD 55

(Ascending) Neuromuscular Weakness Syndrome :

( Ascending) Neuromuscular Weakness Syndrome Presents as rapidly progressing sensorimotor neuropathy, can lead to respiratory failure Thought to be related to NRTI use Dr.T.V.Rao MD 56

Mononeuritis Multiplex :

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 Dr.T.V.Rao MD 57

AIDS Dementia and Antiretroviral Treatment:

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. Dr.T.V.Rao MD 58





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