AIDS and CNS

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AIDS and CNS

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AIDS and CNS

  1. 1. CENTRAL NERVOUS SYSTEM IN AIDS Dr.T.V.Rao MD Dr.T.V.Rao MD 1
  2. 2. AIDS PATIENTS ARE ENCROHED BY MANY OPPORTUNISTIC AND UNCOMMON INFECTIONS Dr.T.V.Rao MD 2
  3. 3. Dr.T.V.Rao MD 3
  4. 4. AIDS complications Dr.T.V.Rao MD 4
  5. 5. 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
  6. 6. AIDS-Defining Illnesses• Kaposis sarcoma, HHV8• Lymphoma, Burkitts, 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
  7. 7. 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
  8. 8. HIV and the Nervous SystemHIV enters the nervous system early, at the time of initial infection, and mayimmediately cause symptoms, or may cause symptoms any time during the person’s lifetime. Dr.T.V.Rao MD 8
  9. 9. 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
  10. 10. Dr.T.V.Rao MD 10
  11. 11. Pathophysiology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, Chemokines and nitric oxide. Dr.T.V.Rao MD 11
  12. 12. HIV and the Nervous System Clinical Syndromes• BRAIN SYNDROMES –Meningitis –Dementia –Stroke –Seizures –Degenerative Disorders Dr.T.V.Rao MD 12
  13. 13. 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 Infections 2. Malignancies 3. Auto-immune and reconstitution diseases 4. Constitutional disease 5. Other /multi-factorial / poorly understood Dr.T.V.Rao MD 13
  14. 14. How being HIV+ leads to illness or impairment1. 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 viruses4. Constitutional Disease: The action of HIV at cellular level directly causing illness “constitutional symptoms” (not fully understood) Dr.T.V.Rao MD 14
  15. 15. 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 15
  16. 16. CNS Routes of penetration 5.Penetration of BBB 4. Disseminated Infection BBB Phagocytes Serum factors Blood streamSub mucosal nerve plexusNasal mucosa 3. Lung Penetration Skin ulcerations Nasal route Lungs microorganism Dr.T.V.Rao MD 16
  17. 17. Opportunistic infections with CNS involvement• Cerebral toxoplasmosis• PML• Meningitis (Cryptococcal meningitis, TB meningitis)• Encephalitis (CMV, HSV, VZV)• Neurosyphilis Dr.T.V.Rao MD 17
  18. 18. 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
  19. 19. HIV Associated Cryptococcal MeningitisClinical 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
  20. 20. HIV Associated Cryptococcal MeningitisDiagnosis• CSF, Indian ink/culture; yield about 75%• Cryptococcal antigen assays, CSF/serum• Blood culture Dr.T.V.Rao MD 20
  21. 21. HIV Associated Cryptococcal MeningitisTreatment• 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
  22. 22. 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
  23. 23. 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
  24. 24. Toxoplasmosis in Patients with HIVEpidemiology: Infection• 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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. 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 Dr.T.V.Rao MD 30
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. 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
  42. 42. 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
  43. 43. 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
  44. 44. 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
  45. 45. 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
  46. 46. 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
  47. 47. • 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
  48. 48. 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
  49. 49. 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
  50. 50. 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
  51. 51. 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
  52. 52. 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
  53. 53. 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
  54. 54. 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
  55. 55. 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 myelins sheath – mechanism is poorly understood Dr.T.V.Rao MD 55
  56. 56. (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
  57. 57. 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 understoodDr.T.V.Rao MD 57
  58. 58. 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
  59. 59. AIDS IS A PREVENTABLE DISEASE Dr.T.V.Rao MD 59
  60. 60. FOR MORE ARTICLES OF INTERST ON INFECTIOUS DISEASES VISIT ME .. Dr.T.V.Rao MD 60
  61. 61. • Programme Created by Dr.T.V.Rao MDfor Medical and Paramedical Students in the Developing World • Email • doctortvrao@gmail.com Dr.T.V.Rao MD 61

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