This document discusses the neurological manifestations of HIV infection, including: - Opportunistic infections like toxoplasmosis, cryptococcosis, and progressive multifocal leukoencephalopathy. - Neoplasms such as primary CNS lymphoma and Kaposi's sarcoma. - Direct results of HIV infection including HIV-associated neurocognitive impairment. - Specific conditions like aseptic meningitis, myelopathy, peripheral neuropathy, and myopathy.

1. Approach to Neurological manifestations of HIV infection Tanoy Bose Moderator: Dr. R. K. Kotokey Professor and In Charge ART Centre, AMCH, Dibrugarh The Department of Medicine , Assam Medical College

2. What’s wrong with this Lady? A 56F habitual blood donor presented with acute onset ascending type of burning paresthesia of all 4 limbs with calf muscle pain & urinary frequency 3 months after last donation. O/e She had loss of pain, position & vibration in a glove and stocking manner with preserved motor function but generalisedareflexia. Over next 3 days she rapidly developed weakness of her neck muscles as well as distal limb muscles and went into respiratory failure on day 5 & was put on ventilator. CSF showed elevated protein of 246.8 mg/dL and pleocytosis of 20 cells, with a lymphocyte predominance (L/N = 99/1). NCV showed conduction block, slowed conduction velocities, and prolonged F-wave latencies for all sampled nerves consistent with demyelinating polyradiculoneuropathy.

3. The only other positive finding in her investigation was that she was positive for HIV Ag by ELISA on day 5. During her last blood donation 3 months back her blood was negative for HIV Ag by ELISA.

4. Neurological Diseases in patients with HIV infection Opportunistic infections Toxoplasmosis Cryptococcosis Progressive multifocal leukoencephalopathy Cytomegalovirus Syphilis Mycobacterium tuberculosis HTLV-I infection Neoplasms Primary CNS lymphoma Kaposi's sarcoma Result of HIV-1 infection HIV-associated neurocognitive impairment, including HIV encephalopathy/AIDS dementia complex Aseptic meningitis Myelopathy Vacuolar myelopathy Pure sensory ataxia Paresthesia/dysesthesia Peripheral neuropathy Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) Chronic inflammatory demyelinating polyneuropathy (CIDP) Mononeuritis multiplex Distal symmetric polyneuropathy Myopathy

5. Neurologic complications in patients infected with HIV Brain Predominantly nonfocal AIDS dementia complex (subacute/chronic HIV encephalitis) Acute HIV-related encephalitis Cytomegalovirus encephalitis Varicella zoster virus encephalitis Herpes simplex virus encephalitis Metabolic encephalopathies Predominantly focal Cerebral toxoplasmosis Primary CNS lymphoma Progressive multifocal leukoencephalopathy Cryptococcoma Brain abscess/tuberculoma Neurosyphilis (meningovascular) Cerebrovascular disorders notably nonbacterial endocarditis, cerebral hemorrhages associated with thrombocytopenia, and Vasculitis Spinal cord Vacuolar myelopathy Herpes simplex or zoster myelitis Meninges Aseptic meningitis (HIV) Cryptococcal meningitis Tuberculous meningitis Syphilitic meningitis Metastatic lymphomatous meningitis Peripheral nerve and root Infectious Herpes zoster Cytomegalovirus lumbar polyradiculopathy, virus- or Immune-related Acute and chronic inflammatory HIV polyneuritis Mononeuritis multiplex Sensorimotor demyelinating polyneuropathy Distal painful sensory polyneuritis Diffuse infiltrative lymphocytic syndrome (DILS) Muscle Polymyositis and other myopathies (including drug-induced)

6. The Approach to a case Demography Risk factors History Serologic Confirmation Classification of HIV status Identification of the Anatomical Lesion Identification of the Pathology Confirmation of Diagnosis Management

7. Demography, Risks & History

8. Demography, Risks & History continued…

9. CLINICAL CASE DEFINITION OF AIDS IN INDIA (NACO) For Persons (Above 12 Yrs age): Two positive tests for HIV infection by ERS test and Any of the following; 1. (a)Significantweight loss ( 10 per cent or more of body weight) within last 1 month) and / or cachexia ( not known to be due to condition other than HIV infection ) and (b) Chronic diarrhoea ( intermittent or continuous) > 1 month (c) Prolonged fever ( intermittent or continuous) > 1 month 2. Tuberculosis: disseminated, miliary, extra-pulmonary and extensive pulmonary tuberculosis. 3. Neurological impairment preventing independent daily activities, not known to be due to the conditions unrelated to HIV infection (e.g. trauma).

11. Neuro-toxoplasmosis

12. Cytomegalovirus retinitis

13. Penicilliummarneffei infection

14. Recurrent Herpes zoster and multi-dermatomal, and

16. Serology & Classification

18. Encephalitis

19. Per Neuro

20. Myelopathy

21. OppertunisticInf

22. ADC

23. HIV myelopathy

24. Per Neuro

25. Myopathy ? AZTDrug induced Neurotoxicity ddI , ddC , d4T

26. Staging of HIV infection GB Syndrome Aseptic Meningitis Herpes Zoster Meningitis

27. Staging of HIV infection

28. How to localise & categorise the lesion?

29. How to localise & categorise the lesion? Contd…

30. So what was wrong with our patient ? A case of Acute DemyelinatingPolyradiculopathythat developed while the patient was having seroconversion as she was tested negative 3 months back while donating blood.

32. Slowly or rapidly progressive dementia (loss of retentive memory, inattentiveness, language disorder, and apathy)accompanied by abnormalities of motor function.

33. Unable to follow conversations, taking longer to complete daily tasks, and becoming forgetful.

34. Inco-ordination of the limbs, ataxia of gait, and impairment of smooth pursuit and saccadic eye movements -early accompaniments of the dementia.

35. Heightened tendon reflexes, Babinski signs, grasp and suck reflexes, weakness of the legs progressing to paraplegia, bladder and bowel incontinence reflecting spinal cord or cerebral involvement, and abulia or mutism are prominent in the later stages of the disease

39. Clinical Staging of HIV encephalopathy (ADC)

40. Aseptic Meningitis Features: Seen in any but the very late stages of HIV infection. Syndrome of headache, photophobia, and meningismus. Rarely, an acute encephalopathy due to encephalitis Cranial nerve involvement may be seen, predominantly cranial nerve VII but occasionally V and/or VIII. Usually resolves spontaneously within 2–4 weeks; however, in some patients, signs and symptoms may become chronic. Rare following the development of AIDS. Investigation: CSF findings include a lymphocytic pleocytosis, elevated protein level, and normal glucose level

41. AIDS Myelopathy Features: Present in ~20% of patients with AIDS, often as part of HIV encephalopathy. 90% of the patients with HIV-associated myelopathy have some evidence of dementia Three main types of spinal cord disease are seen in patients with AIDS. Vacuolar myelopathy Pathologically similar to subacute combined degeneration of the cord Vitamin B12 deficiency can be seen:,it does not appear to be responsible for the myelopathy seen in the majority of patients Characterized by a subacute onset and often presents with gait disturbances, predominantly ataxia and spasticity May progress to include bladder and bowel dysfunction. Increased deep tendon reflexes and extensor plantar responses. The second form of spinal cord disease involves the dorsal columns and presents as a pure sensory ataxia. The third form is also sensory in nature and presents with paresthesias and dysesthesias of the lower extremities. In contrast to the cognitive problems seen in patients with HIV encephalopathy, these spinal cord syndromes do not respond well to ARV drugs, and therapy is mainly supportive

42. AIDS Neuropathy Features: Distal, symmetrical, axonal polyneuropathy, predominantly sensory and dysesthetic in type - the most common neuropathic pattern : may be a direct consequence of HIV infection or a side effect of dideoxynucleoside therapy. Painful burning sensations in the feet and lower extremities. Stocking-type sensory loss to pinprick, temperature, and touch sensation and a loss of ankle reflexes. Motor changes are mild and are usually limited to weakness of the intrinsic foot muscles Ganglionopathy : Due to Zoster Painful mononeuropathy multiplexoccurs, seemingly related to a focal vasculitis Subacute inflammatory caudaequina syndrome (a polyradiculitis)that is usually due to an accompanying CMV infection Inflammatory demyelinating peripheral neuropathy, of both the acute (Guillain-Barre´)and chronic types, in otherwise asymptomatic patients with HIV infection.

43. AIDS Neuropathy continued… Progressive or relapsing-remitting inflammatory neuropathy resembling chronic inflammatory demyelinatingpolyneuropathy (CIDP) : Patients commonly present with progressive weakness, areflexia, and minimal sensory changes All patients with inflammatory demyelinatingpolyneuropathies should now be tested for the presence of HIV infection Facial palsyis being reported with increasing frequency as a feature of AIDS; its relationship to the generalized polyneuritis of AIDS is uncertain. Investigations: Most of these patients had a mild pleocytosis in addition to an elevated CSF protein content. Also, all of the patients with inflammatory demyelinating neuropathy recovered either spontaneously or in response to plasma exchange suggesting an immunopathogenesis similar to that of the Guillain-Barre´ syndrome. Management: For distal symmetric polyneuropathy that fails to resolve following the discontinuation of dideoxynucleosides, therapy is symptomatic; gabapentin, carbamazepine, tricyclics, or analgesics may be effective for dysesthesias. Treatment-naive patients may respond to combination ARV therapy. Plasma exchange or IVIg has been tried with variable success. Because of the immunosuppressive effects of glucocorticoids, they should be reserved for severe cases of CIDP refractory to other measures.

44. AIDS Myopathy Features: Causes include HIV infection itself, zidovudine, and the generalized wasting syndrome. Range in severity from an asymptomatic elevation in creatinekinase levels to a subacute syndrome characterized by proximal muscle weakness and myalgias. Quite pronounced elevations in creatinekinase may occur in asymptomatic patients, particularly after exercise. Profound muscle wasting, often with muscle pain, may be seen after prolonged zidovudine therapy. This toxic side effect of the drug is dose-dependent and is related to its ability to interfere with the function of mitochondrial polymerases. It is reversible following discontinuation of the drug. Red ragged fibers are a histologic hallmark of zidovudine-induced myopathy. Investigation: Raised CreatinineKinase Muscle biopsy: Myofiber necrosis with inflammatory cells, nemaline rod bodies, cytoplasmic bodies, and mitochondrial abnormalities. Management: Discontinuation of Ziduvudine In some of these cases, the myopathy has improved with corticosteroid therapy

45. Oppertunistic Infections of CNS

46. Oppertunistic Infections of CNS continued…

47. Oppertunistic Infections of CNS continued…

48. Conclusion Clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection. The neurologic problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasm Among the more frequent opportunistic diseases that involve the CNS are toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma Frequency is considerably less in patients receiving effective ARV drugs

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