ppt

1. HIV Neurology
Presenter :Reshid(NR2)
Moderator:Dr Abenet. T(Internist and
Consultant Neurologist)

2. Outline
• Introduction
• Neuropathogenesis of HIV Disease
• Disease Involving the Meninges
• Focal and Nonfocal Brain Conditions associated with HIV
• Spinal Cord Disease
• Neuromuscular Disorders

3. INTRODUCTION
• Clinically apparent neurological disease develops in
approximately half of HIV-infected patients.
• With the advent of ART, the overall incidence of the most
frequent human immunodeficiency virus (HIV)–associated
neurologic diseases has decreased.

4. Introduction Ctd …
• Neurologic manifestations in HIV infected individuals depend
on the degree of immunosuppression.
• Immune recovery associated with ART may be associated with
an inflammatory reaction within the CNS.
• Neurologic Complications in HIV may result from:
 Direct Viral Complications
 Immune Mediated complications
 Opportunistic Infections
 ART-associated toxicity
The neurological complications of HIV infection occur at all
stages of the disease

6. Keep in Mind…
• Neurological diseases are not infrequently the heralding
manifestation of AIDS.
• HIV-related neurological disease may present in unusual fashions .
• The simultaneous presence of two or more HIV-related neurological
disorders is frequently observed.
• Neurological disease occurring in the presence of HIV infection
need not be related to the HIV infection or associated
immunosuppression.

7. Neuropathogenesis of HIV Disease
• Neurons lack receptors for HIV binding and fusion and therefore are
not directly infected by the virus.
• The main cell types infected in the brain in vivo are those of the
monocyte-macrophage lineage.
• Monocytes
• Perivascular macrophages and resident microglial cells
• Astrocytes??
• Both white-matter changes and neuronal loss are observed in HIV
infection.

8. Neuropathogenesis Ctd...
• HIV-mediated effects on brain tissue are due to a combination
of indirect effects.
• toxic or function-inhibitory of virus or viral antigens on neuronal cells
• neurotoxins released from the infiltrating monocytes, resident
microglial cells and astrocytes.
• The fact that neuropsychiatric abnormalities decline upon
initiation of ART indicates HIV or its products are involved in the
neuropathogenesis of primary HIV neurological disorders

9. CSF Escape
• undetectable plasma HIV RNA with detectable CSF HIV RNA
• Occurs in 5% to 10% of individuals who are HIV infected
• sustained or non sustained and can occur repeatedly.
• Ongoing viral replication in the CNS may lead to higher rates of
HAND
• The virus detected in CSF is phylogenetically different than the
systemic viruses or
• May have developed unique resistance mutations

11. Aseptic Meningitis
• Aseptic meningitis occasionally accompanies or follows the flulike febrile
illness associated with HIV seroconversion
• Headache and other symptoms of meningeal inflammation with Preserved
alertness and cognition.
• Cranial nerve involvement may be seen , predominantly
cranial nerve VII
• The typical CSF profile consists of
• slightly elevated protein (< 100 mg) and
• mild lymphocytic pleocytosis (25/ml)
• with normal glucose levels

12. Aseptic meningitis Ctd..
• Aseptic meningitis may occur any time in the course of HIV
infection; however, it is rare following the development of AIDS
• principally a diagnosis of exclusion
• The prognosis in acute HIV meningitis is generally good, and it
requires no specific therapy.

13. Cryptococcal Meningitis
• Fungal meningitis is the leading infectious cause of meningitis
in patients with AIDS.
• The vast majority of these are due to C. neoformans, up to 12%
may be due to C. gattii.
• It is the initial AIDS-defining illness currently in ∼2% of patients
and generally occurs in patients with CD4+ T cell count less
than 100/μL.

14. • Most initial infections with Cryptococcus occur through
inhalation of small yeast or reproductive spores from the
environment.
• Once in the host, cryptococci develop large polysaccharide
capsules that strongly resist phagocytosis.
• The inflammatory reaction to inhaled cryptococci produces a
primary lung–lymph node complex.
• It has remarkable predilection to Infect the subarachnoid space.

17. Clinical features
• Presents with a picture of Subacute Meningoenchepalitis
• It presents as headache, fever, stiff neck and photophobia.
• Meningeal symptoms and signs may be minimal or absent in
over one half of the cases
Nejmedin M.(MD)

18. Diagnosis
• CSF findings include
• Markedly elevated opening pressure
• Microscopy
• Protein 30-150 mg/dl
• Mononuclear pleocytosis
• Low or normal glucose concentration
• Fungal CSF Culture –Gold Standard, but takes 2-3 weeks
-positive 75-90%
• Indian ink positive 70-80%
• CSF Cr Ag –Using LA or LFA
- >95 % sensitive and specific
• Serum Cr Ag –If LP is contraindicated

19. Diagnosis Ctd…

20. Diagnosis Ctd…
Neuroimaging
• Typically obtained to exclude focal cerebral disorders
• Sometimes reveals complications of cryptococcal meningitis,
such as hydrocephalus,gelatinous pseudocysts, infarction,
or cryptococcoma.
Nejmedin M.(MD)

22. Treatment
• Principles of Rx
• Antifungal therapy
• Rx of raised ICP
• ART
Nejmedin M.(MD)

23. Antifungal Therapy

25. Consolidation and Maintenance Treatment
Nejmedin M.(MD)

26. Monitoring and managing raised
intracranial pressure
• Raised intracranial pressure is a frequent and potentially life-
threatening complication.
• Occurs in up to 80% of people with HIV-associated cryptococcal
meningitis.
• Reduction of raised CSF pressure is associated with clinical
improvement and survival benefit, regardless of initial
opening pressure.

27. Raised ICP…
• The frequency of repeat therapeutic LP is determined by the
persistence or recurrence of symptoms or signs of raised ICP.
• Lumbar or ventricular shunts can be used if therapeutic Lumbar
punctures have failed to control raised ICP.
• Using drugs (mannitol, acetazolamide, furosemide or steroids)
for managing raised ICP is not recommended.

29. Timing O f ART initiation

30. Monitoring during Antifungal therapy
Clinical Response
Monitoring For Drug toxicity
CSF culture after Induction therapy

31. Crypto IRIS
• Paradoxical IRIS is associated with high mortality
• The median time to onset typically is 3–12 weeks after initiating
ART.
• Raised intracranial pressure is a common feature and an
important contributor to high mortality
• Management includes continuation of ART, antifungal therapy,
managing raised ICP and short course of corticosteroids.

32. Screening
• Any ART naïve patient with CD4 count<100 should be screened
with serum CrAg test
• If negative, no antifungal required and should be treated with ART
• If positive patients should be evaluated for signs and symptoms of
critical meningitis and should under undergo LP regardeless of signs
and symptoms
• If the LP is positive the patient should be treated for
Cryptococcal meningitis
• If the LP is negative (ie, negative CSF CrAg and culture),
antifungal therapy with fluconazole (400 mg daily) is warranted,
and ART can be started.

33. Prognosis
• Mortality in 10 weeks ranges from 10% to 25% in the developed
world and up to 43% in resource poor environments.
• Predictors of high mortality
• Impaired mental status
• Increased ICP
• CSF antigen titer >1:1024 by latex agglutination or >1:4000
by LFA)
• CSF cell count less than 20 cells/μL
• Extra CNS manifestation(especially pulmonary)

34. Cerebral Toxoplasmosis
• Is caused by the intracellular protozoan toxoplasma gondii
• Is the most common CNS OI in the pre-cART era
• Primary infection is acquired by ingestion of infectious oocyst
from contaminated food or under cooked meat
• RVI pts with CD4 count<100 and not ART/ prophyalaxis have
30% chance of developing CNS toxoplasmosis

35. Clinical feature
• The most common presentation is focal encephalitis with headache
and other focal deficits with or without fever
• Focal deficits include hemiparesis, seizure aphasia and progress to
coma and stupor if untreated
• Toxoplasmosis may present as a meningoencephalitis without any
identifiable intraparenchymal lesions
• Extracerebral manifestation
• Pneumonitis
• Retinitis
• Disseminated infection

36. Diagnosis
• Is made by in pt with CD4 count <100 and not on rx
• Compatible clinical syndrome
• Anti toxo IgG antibody positive
• Multiple ring enhancing lesions on brain imaging
• Most patients are positive for IgG antibodies but –ve test
doesn’t rule out infections
• CSF DNA PCR for toxo
• Imaging- MRI is preferred
• Multiple ring-enhancing brain lesions, often associated with edema
Bekalu L

38. Bekalu L

41. Treatment
Standard therapy in TE is sulfadiazine + pyrimethamine
Folic acid 10 mg/day is given to counteract pyrimethamine
bone marrow toxicity
Clindamycin (600 mg intra-venously or by mouth every day)
can be substituted for sulfadiazine in sulfa-allergic patients.
Adjunct Corticosteroids

42. PCL vs Cerebral toxo
• PCLS:
• single lesion
• subependymal spread
• solid enhancement
• no hemorrhage before treatment
• thallium SPECT positive
• MR perfusion: increased rCBV
• Cerebral toxoplasmosis
• multiple lesions
• scattered throughout the basal
ganglia and corticomedullary
junction
• ring or nodular enhancement
• hemorrhage occasionally occurs
mostly in the periphery of the
lesion
• thallium SPECT negative
• MR perfusion: decreased rCBV
Bekalu L

43. Bekalu L

44. • 1st line regimen in the Ethiopian context is:
Trimethoprim/sulfamethoxazole 80/400, oral, 4 tablets 12 hourly for 28
days, followed by 2 tablets 12 hourly for 3 months in adults.
• Secondary prophylaxis: use co-trimoxazole 960mg daily
• Steroids- in pts who have evidence mass effect
• No place of prophylactic anticonvulsants
• Some patients may develop IRIS
• ART naïve patients should be started ART with 2 weeks of anti
toxoplasmosis
Bekalu L

45. Response to Therapy
• Clinical improvement usually precedes radiographic
improvement.
• Lack of clinical and/or radiographic improvement within 7-10
days of starting empiric therapy for TE should raise the
possibility of an alternative diagnosis.
• Brain biopsy should be considered in such patients.

46. Prevention
• Primary prophylaxis
• Patients diagnosed with HIV infection should be
screened for IgG antibodies to T. gondii during the time of their
initial workup.
• Those who are seronegative should be counseled about ways to
minimize the risk of primary infection
• Patients with CD4+ T cell counts <100/μL and IgG antibody to
Toxoplasma should receive primary prophylaxis for toxoplasmosis.

47. Primary CNS Lymphoma
Primary CNS lymphoma accounts for ~20% of the cases of lym-
phoma in patients with HIV infection.
primary CNS lymphomas are usually positive for EBV.
Incidence appears to be increasing
The median CD4 ccount at the time of diagnosis is 50
It has poor prognosis

48. Clinical presentation
• progressive focal or multifocal neurological deficits
• presenting symptoms may include headache, hemiparesis, aphasia,
ataxia, behavioral changes, and altered mentation.
• The tempo of symptom evolution in PCNSL is generally slower than
in toxoplasmosis and faster than in PML
• Lymphomatous meningitis or ocular involvement occurs in about
15% of cases

49. Diagnosis
• PCNSL is generally considered following review of neuroimaging in the
appropriate clinical setting.
• MRI or CT generally reveals a limited number (one to three) of 3- to 5-cm
lesions with contrast enhancement
• Lesion location is typically deep in the brain, adjacent to the lateral
ventricles and often in white rather than gray matter.
• The definitive diagnosis of PCNSL generally requires brain biopsy

51. Treatment
• Treatment Options
• High dose Metothraxate( 3 g/m2 for four to eight cycles) with
concurrent ART
• Steroid
• Radiation

52. Progressive Multifocal
Leukoencephalopathy
JC virus, named after the initials of the patient (John Cunningham)
the causal agent for PML .
It Is a DNA containing human papillioma virus
Approximately 70%–90% of the adult population harbors antibodies
to JC virus
 less than 10% of healthy persons show any evidence of ongoing
viral replication.

53. PML contd…
PML is the only known complication of JC virus infection.
 seen in approximately 4%–5% of patients with AIDS.
The incidence seems declining currently but not as marked as
the other OI.

54. PML contd…
PML is a demyelinating disease of the CNS
 infection of oligodendrocytes with the JC virus
The lesions begin as small foci of demyelination in subcortical
white matter, often in the parieto-occipital area, that eventually
coalesce
cerebellum, the brainstem, and,very rarely, the spinal cord can be
affected .

55. Clinical presentation
Patients typically have a protracted course
 focal neurological deficit
Plus or minus changes in mental status
Visual field defects,
hemiparesis,
aphasia
language disorders, sensory deficits, and ataxia may occur

56. Lab ,imaging and histopathologies
CSF is usually normal or shows nonspecific changes
The viral DNA can be amplified from the CSF sample
 MRI typically reveals multiple, nonenhancing white matter
lesions that may coalesce and have a preference for
occipital or parietal lobe.
contrast enhancement on MRI was observed in as many as
15% of patients even before the ART era.

57. Diagnosis
 Is based on CSF PCR for JC virus DNA Coupled with the
appropriate clinical findings plus characteristic lesions of
PML on MRI .
In cases in which viral DNA is not detected in CSF, a brain
biopsy is necessary to confirm the diagnosis

59. Diagnosis Ctd…
Brain biopsy reveals:
Areas of Demyelination
Enlarged,Bizzarre Astrocytes
JCV-infected oligodendrocytes with enlarged amphophilic nuclei

60. Treatment
There is no specific therapy for PML
Mean survival in the pre-cART era was 2–4 months
However, in the cART era, as many as 50% of patients
experience median survival of 24 months
 Treatment mainly focuses on Immune Restoration using
HAART.

61. Favorable prognostic factors
higher CD4+ T cell counts
low HIV viral load, undetectable
Undetectable JC virus in CSF following cART
 contrast-enhancing lesions at the time of diagnosis

62. HIV-Associated Neurocognitive Disorder (HAND)
• A late complication of HIV infection that progresses slowly over months,
• Despite widespread ART use, HAND continues to affect up to 50% of patients with HIV
• Characterized by cognitive , behavioral, and motor dysfunction
• HIV-associated neurocognitive disorders (HAND) is a spectrum of disorders that range from
• Asymptomatic neurocognitive impairment (ANI) to
• Minor neurocognitive disorder (MND) to
• Clinically severe dementia (HAD)
• Characteristically, HAD and MND forms of HAND manifest after patients have
developed AIDS defining systemic illnesses.

63. Risk Factors
• Lower nadir CD4+ T-cell count and a history of AIDS
• Cardiovascular risk factors; hypertension, hyperlipidemia,
tobacco use, diabetes mellitus, central obesity, and higher
carotid intima-media thickness,
• Age older than 50 years
• Concurrent Hepatitis C infection
• Substance abuse, especially methamphetamine

64. (A) Pre ART era (B) ART era
Nejmedin M.(MD)

65. CLINICAL FEATURES
• ANI is the mildest form of HAND and occurs in about 30% of
individuals
• ANI is characterized by measurable neurocognitive impairment
• unrecognized by the patient or fails to impact function.
• ANI can be considered as a presymptomatic form of HAND

66. Clinical Features Ctd…
• MND is the symptomatic form of neurological impairment of ANI
• can be identified in about a quarter of HIV positive persons.
• Early symptoms usually consist of
• difficulties with attention and concentration.
• Recognized early if patients require a high level of concentration and
organization in their occupation or at home
• Many complain of slowness of thinking.
• Complex tasks become more difficult and take longer to complete
• forgetfulness and difficulty in concentration lead to missed appointments
• withdraw socially and appear apathetic and uncharacteristically quiet
• agitated organic psychosis and dysphoria are rare as presenting or
predominant aspects of this illness.

67. Clinical Features Ctd…
• Psychomotor dysfunction is a major component of HAD
syndrome
• poor balance and incoordination may be the initial presentation
• Fine and skilled hand movements are affected early
• resulting in deterioration of handwriting.
• Gait incoordination may result in
• frequent tripping or falling or a need for extra caution in walking.
• a slow and somewhat rigid character of gait.

68. Clinical Features Ctd…
• Associated HIV VM causes worsening leg weakness, and
paraparesis limits walking.
• Bowel and bladder disturbances are late manifestations.
• End stage patients are vegetative, lying in bed mute with a vacant
stare, unable to ambulate and incontinent.
• Focal or lateralizing neurological deficit, such as hemiparesis or
aphasia are Characteristically absent.

69. Nejmedin M.(MD)

70. DIAGNOSIS
• HAND screening tools
• HIV Dementia Scale (HDS)
• InternationalHIV Dementia Scale (IHDS)
• Patients with screening results concerning for HAND
should be referred for formal neuropsychological testing
• Other causes of Cognitive impairment should be excluded
Nejmedin M.(MD)

71. HDS

72. IHDS

73. Neuroimaging
• can be helpful in ruling out other conditions
• Diffuse cerebral atrophy, generally greater centrally than
cortically.
• The classic MRI finding in HAND is patchy or confluent
symmetric subcortical T2 hyperintensities

74. HAND
T2-weighted axial magnetic resonance imaging section showing symmetrical white
matter abnormalities
Nejmedin M.(MD)

75. Diagnosis…
Cerebrospinal Fluid Analysis
• Used chiefly to exclude other diagnoses.
• Non specific findings of
• mild mononuclear pleocytosis and mildly elevated protein in approximately 60% of the
cases.
• evidence of intrathecal IgG synthesis and the presence of oligoclonal bands
• Detection of HIV or its antigens in the CSF is not useful for diagnosing HAD
• Quantitative HIV PCR to assess the CSF viral burden is perhaps the best
parameter that relates to HAD
• effective suppression of HIV in the CNS compartment is demonstrated to improve the
clinical status in HAD

76. Neuropathology
• Histopathological abnormalities in HAD include
• white-matter pallor
• perivascular mononuclear cellular infiltrates,
• multinucleated cell encephalitis
• vacuolar myelopathy.
• most common in the subcortical structures (i.e., hemispheric white
matter, basal ganglia, thalamus, brainstem, spinal cord).
• The cerebral cortex is relatively spared
Nejmedin M.(MD)

77. MANAGEMENT
• No specific treatments for HAND exist
• ART-in ART naïve patients
• Use of ART regimens with higher CNS penetrance has been proposed but no
beneficial effect is found.
• Modifiable risk factors for cognitive impairment should be identified and treated
• Depression screening should be undertaken as depression
often coexists with and worsens HAND.
Nejmedin M.(MD)

78. Spinal cord disease
• Spinal cord disease, or myelopathy, is present in ~20% of
patients with AIDS
• 90% of the patients with HIV-associated myelopathy have some
evidence of dementia
• Two main types of primary myelopathies are seen in
patients with AIDS:
Vacuolar Myelopathy
Dorsal column sensory tractopathy

79. HIV-Associated Myelopathy
• The most common cause of spinal cord dysfunction in untreated
patients with AIDS
• Causes the protective myelin sheath to pull away from nerve cells of
the spinal cord, forming small holes (vacuoles) in nerve fibers
• Apparent pathologically in 25% to 55% of AIDS autopsy series
• VM complicates late HIV infection and frequently coexists with HAD
and DSPN.

80. Clinical Features
• Affected patients develop
• gait difficulty caused by spasticity, leg weakness, and impaired
proprioception
• often accompanied by sphincter dysfunction
• evolve over several months.
• Back pain not a prominent feature

81. CFs Ctd…
• Examination reveals spastic paraparesis with
• Babinski signs and hyperreflexia, ataxia, and an abnormal Romberg
sign are common
• Sensation in the legs, particularly proprioception and vibratory sense
usually impaired
• but a discrete sensory level should suggest another etiology
• Pathological findings are most striking in the dorsolateral
thoracic cord and include vacuolar changes in myelin sheaths.

82. Diagnosis
• Vacuolar Myelopathy is a diagnosis of exclusion
• Infectious, neoplastic, and metabolic disorders
occasionally cause myelopathy in patients with HIV infection
• . Compared with VM, these disorders:
May progress Rapidly
often have associated back or radicular pain
Discrete sensory level-In Extrinsic Cord compression
MRI –usually normal
CSF analysis –to exclude alternative etiologies
Bekalu L

83. Neuropathies
• Peripheral neuropathies are common in HIV infection and they occur
at all stages of illness and take a variety of forms.
• Cause considerable morbidity and disability in HIV-infected
individuals and AIDS patients.
• There are five major clinical types of HIV-associated neuropathies:
1. DSPN
2. nucleoside-associated toxic neuropathies.
3. acute inflammatory demyelination polyradiculoneuropathies (AIDP) and
4. chronic inflammatory demyelination polyradiculoneuropathies (CIDP),
5. CMV-associated polyradiculomyelopathy

84. Distal Sensory Polyneuropathy (DSPN)
• The most common peripheral nerve syndrome that complicate
HIV infection
• Develops in approximately one-third of patients with AIDS
• It is Axonal, predominantly sensory and length-dependent
polyneuropathy
• Affects 30% to 50% of individuals who are HIV infected

85. Clinical Manifestations
• Mild pain, temperature, and vibratory sensory loss in the feet,
with or without associated foot paresthesia and numbness
• Less frequently, severe burning pain and paresthesia develop in
the feet .
• Symmetrical involvement is a characteristic clinical feature.
• Depressed or absent ankle jerks

86. Diagnosis and Treatment
• The rather typical clinical features of DSP usually obviate the
need for EMG and NCS.
• Exposures to neurotoxins, including ethanol, should be reviewed.
• Screening for Vitamin B12 deficiency and DM is Important.
• Treatment goals in DSPN
• Minimizing neurotoxic exposures
• Virus suppression by HAART and
• Management of pain
• When Choosing drugs for the neuropathic pain side effect profile and
drug Interactions should be considered

87. Lumbosacral Polyradiculomyelitis
• Subacute lumbosacral polyradiculomyelitis with variable cord involvement
• Uncommon syndrome that results from a variety of infectious agents most
notably CMV
C/F :
• a rapidly developing cauda equina syndrome with leg weakness
• later sphincter dysfunction, sacral and leg paresthesias and sensory loss, and
areflexia
• typically evolve over several days.
• CMV PCR or branched DNA assay in CSF is a helpful confirmatory test
• Treatment
• intravenous ganciclovir
Other causes of polyradiculomyelopathy in AIDS include tuberculosis,
neurosyphilis, HSV type 2, and lymphomatous meningitis.

88. Myopathies
• can arise from
• toxic (zidovudine)
• dysimmune (polymyositis)
• AIDS cachexia (muscle wasting syndrome)

89. HIV associated polymyositis
• proximal weakness and, less commonly, myalgia
• Is ascribed to a polyclonal hyperimmune response following HIV
infection Or may occur with immune restoration following HAART
• Serum creatine kinase is elevated in most cases
• Muscle biopsy reveals fiber-size variability, fiber degeneration, and
endomysial infiltrates.
• Treatment: immunomodulatory medications (steroids, IVIg or plasma
exchange)

90. Neurologic complication of ART

92. References
• Harrisons Principles Of Internal Medicine 21St Edition
• Bradley Neurology 8th Edition
• Continuum Neuroinfectious Disease,2021
• WHO Guidelines for Diagnosing,Preventing and Managing
Cryptococcal Disease ,2022
• Infectious Disease Of CNS, Fourth Edition

93. •
• Thank you