Neurological complications of HIV

1. Neurological complications of HIV Will Chegwidden, Senior Occupational Therapist & Emma McGettigan, Senior Physiotherapist Infection & Immunity Speciality Group Barts Hospital August 2005

2. Outline of session • Classification of HIV impairment and HIV neurological impairment • Neuropathogenesis of HIV • CNS involvement • PNS involvement • Issues for therapists and discussion

3. 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

4. How being HIV+ leads to illness or impairment • OI’s: Immunosupressed 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 Disease: The action of HIV at cellular level directly causing illness “constitutional symptoms” (not fully understood)

5. Disease groupings • OIs: • Viral Infections (CMV, HSV, PML, HPV) • Bacterial Infections (TB, MAI, Salmonella) • Protozoal Infections (PCP, Toxoplasmosis) • Fungal Infections (Cryptococcyl Meningitis, Candida) • Malignancies (KS, CNS lymphoma, Burketts, MCD) • Autoimmune diseases (Arthraligias, GBS) • Constitutional Conditions (HIVE/HAD/ADC, DSPN, Wasting Syndromes)

6. 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

7. Opportunistic infections with CNS involvement • Cerebral toxoplasmosis • PML • Meningitis (Cryptococcyl meningitis, TB meningitis) • Encephalitis (CMV, HSV, VZV) • Neurosyphilis

8. 2. 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)

9. 3. Autoimmune disorders withneuro involvement • Guillain-Barré Syndrome (GBS) • Inflammatory Demyelinating Polyneuropathy (IDP)

10. 4. Direct action of HIV • AIDS Dementia Complex (ADC) or HIV Associated Dementia (HAD) • Distal Symmetrical Polyneuropathy (DSPN) • Mononeuritis multiplex • Vacuolar Myolopathy • ?Wasting Syndromes (although cardiac system now implicated more)

11. 5. Multifactorial / drug related / poorly understood • “Neuromuscular weakness syndrome” • Role of drugs in peripheral neuropathy

12. Direct action of HIV in the CNS • HIV can easily cross the blood brain barrier • HIV thought to chiefly target phagocytic macrophages, but also astrocytes, microglia and monocytes • Do not affect directly affect CNS neurons or oligodendrocytes

13. Theories of how HIV crosses the blood brain barrier • Different theories including: • Infected monocytes and lymphocytes traffic across the BBB as part of their normal immune surveillance role • Blood brain barrier weakened by this process – leading to increased trafficking • Monocytes differentiate in to microglia and macrophages

14. Theories of how HIV crosses the blood brain barrier • Also theory that meningeal macrophages infiltrate the CNS through the CSF compartment • May also be a combination of these processes • Neurotoxic viral proteins released in to CNS by HIV infected cells resulting in neuronal injury / death

15. Direct action of HIV in the PNS • Thought that HIV cells can lead to axonal degeneration (resulting in DSPNs) • Thought that HIV can lead to inflammation / demylination (resulting in inflammatory demyelinating neuropathies)

16. Principles of HIV Neurology • Time Locking – Neurological compliocations are directly related to the duration of HIV disease, degree of advancement of HIV disease • Parallel Tracking – Existence of muliple pathologies in different parts of the nervous system (cerebral, spinal cord, peripheral nerves) • Layering – multiple complications in one part of the nervous system • Unmasking – previously compensated deficits may be unmasked by occurrence of an additional insult

17. Presentations • Vary wildly • Often multiple pathologies on different courses • Often hard to diagnose, especially if already treated empirically • May not be HIV related!

18. Conditions • Now going to present the most commonly seen conditions at BLT • Would be good to share all our experience on prevalence, experience of treating and progression of disease • We can collate and feed back to therapists who aren’t able to attend, especially those outside of London

19. HIV and CNS involvement

20. 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

21. Toxoplasmosis

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

23. Toxoplasmosis • Usually responds well to treatment • Usually the worse the initial presentation, the longer the recovery; may have some long term residual deficits • Can sometimes have multiple small lesions which present with quite specific / unusual sensory / motor / cognitive symptoms

24. Toxoplasmosis • Therapy usually “treat what you assess” – relearning gait / UL movement through normal movement approach; cognitive rehab; use of functional activity etc. • Need to be aware of visual field deficits • Great to work with as generally will recover • ?Impact of early intervention – usually recover quickly at first – may be more important where tone / positioning is an issue

25. 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

27. PML: Progressive Multifocal Leukoencephalopathy • Common presenting symptoms and signs • Hemiparesis • Gait abnormality • Speech disturbances • Cognitive dysfunction • Dysarthria • Ataxia • Sensory loss • Vertigo • Visual impairment

28. 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

29. 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.

30. Cryptococcyl meningitis, TB meningitis • Both quite common presentations • Crypto caused by fungal infection • TB may also cause focal lesions as well as the menigitis • Both may or may not have other systemic illness associated e.g. Cryptococcosis, TB lung, spine, miliary TB

31. Cryptococcyl 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

32. Cryptococcyl 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

33. 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

34. 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

35. 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)

36. 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

37. 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 palliatively with radiotherapy (usually palliative) or high dose methotrexate (chemo)

38. 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

39. HIV EncephalopathyHIVE / ADC / HAD • Number of terms used overlappingly 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

40. HIV EncephalopathyHIVE / 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

41. HIV EncephalopathyHIVE / 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

42. 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

43. HIV EncephalopathyHIVE / 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!)

44. HIV EncephalopathyHIVE / 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

45. 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 paraparesis 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

46. HIV and PNS Involvement

47. 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

48. DSPN • Often occurs in a glove and stocking distribution but there is great variance in self report • Can range from mild parasthesia / 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

49. 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

50. 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