The document presents a clinical case of a 45-year-old female patient who was admitted with fever, headache, and altered sensorium. Investigations revealed HIV positivity and cryptococcal meningitis. The patient's condition deteriorated despite antifungal treatment and she expired. The discussion points covered neurological manifestations of HIV including opportunistic infections like tuberculous meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, cytomegalovirus infection, neurosyphilis, and cryptococcal meningitis. Treatment and diagnostic aspects of these infections were summarized.

1. Clinical Case Meet
Presented by : Dr. R.Rajesh
Moderator: Dr.Nidhi Bhardwaj

2. Patient Details
• Name: BR
• Age: 45/F
• CR no: 221105133
• Address: RAJPURA PATIALA, PUNJAB
• DOA: 09/11/2022
• DOD: 19/11/2022

3. Chief Complaints
• Fever since 30 days
• Head ache since 10 days
• Altered sensorium since 5 days

4. Background History
• Taken to local hospital
• Fever since 10 days
• Headache since 2 days
• Found to have HIV positive
• Patient condition worsened

5. HOPI
• Fever
1. since 30 days
2. Low grade with no chills and rigors.
• Head ache
1. since 10 days
2. All over head, a/w vertigo
3. No evidence of vomiting and decreased vision
• Weight loss of 6 kg over 2 months
• Altered mental status since 5 days

6. • Past history :
1. history of HTN
2. History of ? typhoid fever 2 months back
• Family, personal, social history : not significant

7. General examination
• BP : 130/90 mm of Hg
• RBS : 123
• SpO2 : 96% under RA
• PR : 81/ min
• Average built and nourished
• Pallor +

8. Systemic examination
• CVS, RESPI & per Abdo : wnl
• CNS:
1. Conscious not oriented E3V4M5
2. No signs of meningitis.

9. Blood
investigations
9/11 10/11 14/11 18/11
Hb 8.1 8.9
TLC 6400 7200
DLC (NLMEB) 73/19/7 82/10/7
Plt Ct 2,87,000 2,88,000
INR 1.08
Na 130 131 139
K 3.6 3.2 3.8
Ur 24 24 26
Cr 0.8 0.7 0.7
Ca 9.5 8.9 10.1
P 3.7 3.2 2.9
T.Bil 0.3
ALP 63
OT 18
PT 16
T.PRO 7.4
HIV POSITIVE
HEP B NEG
HEP C NEG

10. Hospital course
• Chest X-Ray- left upper zone cavity
• NCCT head: normal
• Patient was being evaluated for x-ray lesion and vertigo
• Was started on piptaz and doxy
• Found to have Tympanic Membrane perf. 1*1 mm.
• MRI done on 11. – acute infarct in left putamen
• On 13th patient developed 2 episodes of seizures and BP of 200/110mm of Hg.
• NCCT head: normal
• Fundus : R grade 3 & L grade 2 disc edema
• Lumbar puncture done on 13th.

11. SPUTUM CBNAAT TWICE NEG
CSF TLC 45 CELLS
CSF DLC FEW RBC. 5%N, 95%L
CSF GLUC 22
CSF PROT/ ADA 105/ 7.9
CSF C/S, INDIAN INK STERILE
CSF CBNAAT NEGATIVE

12. RADIOLOGICAL INVESTIGATIONS
• NCCT HEAD MRI BRAIN CECT Chest

13. Course and management
• Patient was started on ATT, dexa and Ceftriaxone 2g on 14th
• Cryptococcal antigen positive in serum on 16th
• On 16th patient developed 3rd CN palsy – grade 5 papilledema
• NS call no intervention.
• Started on Amphotericin + Flucytosine on 16th
• Intubated in view of gasping on 17th night
• Expired on 19th in ward.
• CD4- 7

14. Unit’s final diagnosis
• Raised intra cranial tension
• Cryptococcal meningitis
• Pulmonary TB > Cryptococcal pneumonia
• Acquired immuno deficiency syndrome

15. Points being discussed
• Neurological manifestations of HIV
• Opportunistic CNS infections in AIDS
• Cryptococcal meningitis

16. Neurological manifestations of HIV/AIDS
Neurological
manifestations
of HIV/AIDS
Virus – body
interaction
Immune
dysregulation
Virus itself
Effect of ART
Opportunistic
infections
Neurologic disease is the first manifestation of symptomatic HIV infection in roughly 10%–20% of
people, whereas about 60% of patients with advanced HIV disease will have clinically evident
neurologic dysfunction during their illness.

17. Focal causes Diffuse dysfunction
Cerebral toxoplasmosis HIV- associated dementia
Progressive Multifocal
Leukoencephalopathy
Cryptococcal meningitis
Primary CNS lymphoma Tubercular meningitis
CMV ventriculoencephalitis Syphilitic meningitis
Brain abscess ( bacterial or fungal) Lymphomatous meningitis
Tuberculoma Bacterial meningitis
Meningovascular syphilis Multifocal brain disease
Angioinvasive Fungi Drug ingestion
VZV vasculopathy Metabolic encephalopathies
Bacterial endocarditis

18. Immune dysregulation

19. Manifestations caused by virus itself
HIV- associated neurocognitive disorder (HAND)
Vacuolar myelopathy
HIV associated vasculopathy (HAV)
Peripheral neuropathy and myopathy

20. • HIV- associated neurocognitive disorder (HAND)
Further divided into three categories of dysfunction: asymptomatic neurocognitive
impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated
dementia (HAD).
No proven treatment.
• Aseptic meningitis
• Vacuolar myelopathy
Pathogenesis: Metabolic disturbance of the trans-methylation pathway resulting in
extensive spongiform changes and vacuolation in spinal cord white matter.
Clinical features: spastic paraparesis, bladder incontinence, sensory involvement (no
clear cut level).
Radiology: Cervical and thoracic cord atrophy with T2 weighted hyperintense signal
affecting the posterolateral columns.
Treatment: ART introduction has decreased its prevalence.

21. HIV associated vasculopathy (HAV)
• Extracranial aneurysms:
1. May occur in the carotid, aorta, femoral and popliteal vessels.
2. Inflammation of vessel wall and atrophy of smooth muscle caused by virus
resulting in aneurysms.
3. Present as pulsatile mass or stroke from thrombus inside aneurysm.
• Intracranial aneurysms:
1. Presents as embolism or subarachnoid hemorrhage.
2. Fusiform variety is common variety, pathogenesis not known
• Treatment similar to any other aneurysm.

22. HIV associated vasculopathy (HAV)

23. • Accelerated atherosclerosis
Increased incidence of atherosclerosis in treatment naïve patients noted, but causal role
not proved.
• Vasculitis
Described in case series.
Benjamin et al suggested after ruling out all other causes and demonstrating trans mural
inflammation diagnosis can be made.3
HIV associated vasculopathy (HAV)

24. • Radiculopathy:
1. Progressive ventral lumbo-sacral radiculopathy is known to occur in
advanced HIV disease.
2. Improved with corticosteroids in case reports.
• Peripheral neuropathy:
1. Mononeuritis multiplex
2. Isolated cranial neuropathy especially facial palsy may be seen at seroconversion
3. Distal symmetric polyneuropathy (DSP) – mc / length dependant
4. AIDP and CIDP

25. • HIV- associated myopathy:
1. Is often an overlap of polymyositis and inclusion body myositis (IBM).
2. Patients present at a younger age than typical IBM with both proximal and distal
weakness.
3. Rimmed vacuoles on biopsy and antibodies to cytosolic 5 nucleotidase 1A
(NT5C1A).
4. Immunosuppressants give good response.

26. Effect of ART
• Adverse effects of drugs:
Zidovudine, Rilpivirine and Efavirenz causes directly neuropsychiatric side effects,
certain ART drugs causes dyslipidemia inturn resulting atherosclerosis.
• Immune reconstitution inflammatory syndrome:
Collection of inflammatory disorders associated with paradoxical worsening of a
preexisting infectious processes following the initiation of antiretroviral therapy.
CNS involvement is less common but with high morbidity and mortality.
Worsening of CNS TB or new emergence of PML or Cryptococcus can occur.
Treatment – treat underlying infection plus steroids plus continue ART.

27. CNS Opportunistic Infections
Clinical syndrome Organism
Cerebrovascular disease Cytomegalovirus
Mycobacterium tuberculosis
Treponema pallidum
Varicella zoster virus
Dementia Treponema pallidum
Encephalitis Cytomegalovirus
Herpes simplex
West Nile virus
Mass lesion in brain Toxoplasma gondi
JC virus
Meningitis Cryptococcus neoformans
Mycobacterium tuberculosis
Treponema pallidum
Myelopathy/Radiculopathy Cytomegalovirus
Varicella zoster virus

29. CNS Tuberculosis
• Pathogenesis:
lung focus(Ghon focus) < meningeal focus(Rich focus) < spread based on immune
status.
• Presentation:
Meningitis, stroke, cerebral abscess, tuberculoma, hydrocephalus, spinal cord
compression.
• CSF:
White cell counts are raised, with lymphocytes as the predominant white cell type,
protein levels are often elevated, and hypoglycorrhachia is common. Index TB
guidelines doesn’t recommend ADA. C/S is gold standard +ve in 80% cases. The
Xpert MTB/RIF assay has a sensitivity of up to 80% and is the preferred initial
diagnostic option.

30. • CXR - In more than half of cases, evidence of old pulmonary lesions or a miliary
pattern is found.
• MRI: Basilar exudates, arachnoiditis, tuberculomas and meningeal enhancement
can be seen
• Treatment: 2HRZE + 7 HRE +/- steroids in sensitive cases. ART should be
delayed at least 4 weeks and initiated within 8 weeks
? Aspirin role in stroke. Anti-epileptics if seizure occurs. Anti edema measures +/-
VP shunting for hydrocephalus.
• Prophylaxis: 6 months daily Isoniazid.

31. Toxoplasmosis
• Pathogenesis:
Reactivation of tissue bradyzoites when CD4 falls less than 100 cells/mm3
• Presentation:
Cerebral abscess, diffuse encephalitis, chorioretinitis
• Diagnosis: IgG Ab in serum, CSF PCR using B1 sequence- highly specific (r/o JC
virus, EBV). Biopsy in treatment non responsive and r/o lymphoma
• Radiology: ring enhancing lesion (DD – lymphoma) predominantly in basal
ganglia, grey white matter junction.
• Prevention: Double strength co-trimoxazole daily for HIV +ve with CD4 < 350 or
WHO stage 3 / 4

32. • Treatment
1. Initial regimen:
Pyrimethamine 200mg po *1 dose, then 50mg (<60kg) or 75mg (>60kg) po daily +
sulfadiazine 1000mg (60kg) or 1500mg (>60kg) po q 6h + leucovorin (folinic acid)
10–25mg po daily for 6 weeks
2. Maintenance regimen:
Pyrimethamine 25–50mgpo daily + sulfadiazine 2–4g po qd (in 2–4 divided doses)
+ leucovorin 10–25mg po daily can be discontinued in patients who have responded
to ART and whose CD4+ T lymphocyte count has been >200/μL for 3 months

33. Progressive multifocal leukoencephalopathy
• Pathogenesis:
Reactivation of JC virus occurs when immunosuppression sets in, resulting in
infection of oligodendrocytes as well as astrocytes causing cell lysis and
demyelination.
• Presentation:
Focal or generalised weakness, gait abnormalities, cognitive dysfunction, impaired
coordination, seizures, visual and speech disturbances eventually coma.
• Diagnosis:
CSF PCR

34. • Radiology:
White matter hyperintensities are visible on T2-weighted and on T1 hypointensities
are seen in MRI.
• Treatment : no treatment

35. Cytomegalovirus infection
• Pathogenesis:
Reactivation of virus when CD4 less than 50.
• Presentation:
Dementia, Encephalitis with Ventriculo-encephalitis, Ascending
polyradiculomyelopathy and retinitis.
• Diagnosis:
CSF – neutrophilic pleocytosis with CMV DNA PCR.
MRI- symmetrical linear periventricular hyperintensity with gadolinium
enhancement

36. Treatment:
Induction: Intravenous Ganciclovir, 5 mg/kg twice daily, in combination with Foscarnet,
90 mg/kg twice daily, typically for 3–6 weeks.
Start CMV treatment then ART after 2 weeks
Patient response & viral clearance / continue i.v. Foscarnet
Maintenance: oral Valganciclovir 900mg twice daily until CD4 count count ≥ 100 for
atleast 6 months

37. Neurosyphilis
• Pathogenesis:
Atypical and severe infection in pts with CD4 less than 350, as a part of tertiary
syphilis
• Presentation:
Asymptomatic, meningitis, stroke, tabes dorsalis, gumma as SOL, ocular and PNS
involvement
• Diagnosis:
Serum ELISA, TPHA, VDRL and CSF VDRL
MRI – meningeal, vascular phenomenon are common

38. • Treatment:
Preferred - Aqueous crystalline benzylpenicillin 18–24 million units IV daily in divided
doses given every 4 hours
Alternate - Ceftriaxone 2 g IV/IM QD for 10–14 days
Jarisch-Herxheimer reaction treatment – Prednisolone 40 mg from 1 day before to 2 days
after start of treatment

39. Cryptococcal meningitis (CM)
• Statistics :
1. 152,000 cases of CM occur among people with HIV/AIDS worldwide each year,
resulting in nearly 112,000 deaths.
2. 19% of AIDS-related deaths.
3. Most CM cases occur in sub-Saharan Africa.
• Host:
1. 90% of patients of CM are seen among patients with AIDS with CD4 ≤ 100
2. Non- HIV cases of CM are seen in patients on immunosuppressants or with
other immunodeficiency disorders like CGD.

40. • Agent:
1. Fungal infection is the leading cause of meningitis in HIV individuals.
2. 90% cases are due to Cryptococcus neoformans, others being C.gatti and
Histoplasma
3. C.neoformans is of 3 to 6 μm. Reproduces by budding. Has capsule.
• Pathogenesis :
1. Inhalation of C.neoformans spores f/b phagocytosis by alveolar macrophages
2. Then dissemination to multiple organs preferably to nervous system

41. 1. Sub acute presentation( 2 to 4 weeks)
2. Fever, nausea, vomiting, altered mental status(25% cases), headache, and
meningeal signs(25% cases). The incidence of seizures and focal neurologic
deficits is low. Raised ICP presenting as 6th CN palsy.
3. Lung: from asymptomatic colonisation to severe pneumonia with respiratory
failure.
4. Uncommon: Skin lesions that resemble molluscum contagiosum,
lymphadenopathy, palatal and glossal ulcers, arthritis, gastroenteritis,
myocarditis, and prostatitis.
Presentation

42. Laboratory diagnosis
• Serum :-
1. Cr Ag Positive in 95% cases of meningitis - screening test.
2. Antigen can be positive 22 days prior to symptoms.
• CSF :-
1. Increased opening pressure.
2. Can be normal 20 to 30% cases. Mild protein raise. Normal to low glucose. Increased
cells till 50.
3. Antigen positive in almost all cases.
4. PCR is costly and low sensitive in low fungal loads
5. Indian ink – encapsulated yeast in 60 to 80% cases. Follow up possible.
6. C/S – cream coloured mucoid colonies after 3 to 7 days.

43. • Blood fungal cultures: positive in 10 to 30% cases.
• Extra neural cultures positive in 30 to 60% cases.
Laboratory diagnosis

44. Radiology
• Initial CT & MRIs can be normal in 47 & 2-8% patients respectively.
• Lacunar strokes are present in up to 20%of patients, and cortical strokes are
equally common.
• Hydrocephalus, meningeal enhancement, cryptococcomas,dilated perivascular
spaces coalescing into gelatinous pseudocysts.
• The most common radiographic manifestations of pulmonary cryptococcosis
consist of single or multiple pulmonary nodules, segmental or lobar consolidation
or a reticulonodular pattern of opacities.
• Associated features include cavitation(40% cases), lymphadenopathy and pleural
effusion
• Rarely tree in bud apperance appearance

46. Treatment ( NACP guidelines )
• Induction:
1. IV amphotericin B deoxycholate1 mg/kg daily with flucytosine 25 mg/kg qid for
1 week followed by
2. Fluconazole 1200 mg/day for 1 week
• Consolidation:
1. Fluconazole 400 mg for 8 weeks
• Maintenance:
1. Fluconazole 200 mg/d for 1 year
• Start ART after 4 to 6 weeks of start of anti fungals.
• No role of corticosteroids.

47. Discontinuing Fluconazole
• 4 criteria
1. Adherent to ART and free of cryptococcal disease
2. Fluconazole received for 1 year
3. CD4 count ≥ 100 cells/mm3
4. Suppressed viral load < 1000 copies/ml

48. Dealing with drugs
Prevention of amphotericin B deoxycholate related
toxicities
1. Pre-hydrate with 1 litre of NS with 1 ampoule
of KCL (20 mmol) over 2 hours before.
2. Twice-daily oral potassium and magnesium
supplementation should be given.
3. To minimize the risk of phlebitis, lines should
be flushed with normal saline immediately
after the Am B infusion
Administration of amphotericin B deoxycholate Am B powder should be reconstituted in sterile
water; add to 1 litre of 5% D and administer within
24 hours in a peripheral line over 4 hrs
Monitoring of patients receiving amphotericin B Day 0,3,7 – Na, K, Mg, Creatinine
Day 0,7 – full blood count

49. Dealing with drugs
Management of Am B toxicities
1. Febrile reaction
2. AKI
3. Electrolyte disturbances
1. Paracetamol 1 g (if severe,
hydrocortisone 25 mg)
2. Normal saline, avoiding nephrotoxic
drugs, continue/ use better options if
available.
3. Correct, look for magnesium levels.
CKD 1. No dosage modification for Am B
2. Dosage modify for Flucytosine,
Fluconazole

50. Management of raised ICP
• NO role of acetazolamide, mannitol and corticosteroids.
• Daily LPs till patient become asymptomatic/ reduce opening pressure
less than 20cm
• If CSF pressure is more than 50cm, reduce to half of initial.
• Lumbar or ventricular drains.

51. Prognosis
In specific populations, mortality in HIV-associated CM can reach 70%.
1. Early screening for and treatment of cryptococcal antigenaemia reduces
mortality by 30%.
2. Acute mortality from CM has been directly correlated with
• Altered mental status at presentation
• CSF antigen titer > 1:1024 by latex agglutination(high burden of disease)
• CSF WBC < 20 cells/mm3(poor host response)

52. TAKE HOME MESSAGE
• Serum CrAg is indicated in all PLHIV presenting with CD4 counts <200
cells/mm3 with or without symptoms suggestive of cryptococcal meningitis.
• A negative result on India ink does not rule out cryptococcal meningitis.
• Role of therapeutic lumbar puncture in reducing ICT
• ART initiation after 4-6 weeks of starting antifungal treatment
• OIs need to be thoroughly ruled out before attributing the clinical and
diagnostic findings to the direct effects of HIV virus on CNS
• High index of suspicion for CM should be there so that early treatment can
be initiated and mortality reduced.

53. References
• Ho EL, Jay CA. Altered mental status in HIV-infected patients. Emerg Med Clin
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• Paruk HF, Bhigjee AI. Review of the neurological aspects of HIV infection. J
Neurol Sci. 2021;425:117453.
• Benjamin LA, Bryer A,Lucas S, Stanley A, Allain TJ, Joekes E, et al. Arterial
ischemic stroke in HIV: Defining and classifying etiology for research studies.
Neurol Neuroimmunol Neuroinflamm 3 (4) (2016) e254.
• Index TB guidelines for extra- pulmonary tuberculosis in India-2016.
• Hobbs E, Vera JH, Marks M, Barritt AW, Ridha BH, Lawrence D. Neurosyphilis
in patients with HIV. Pract Neurol 2018;0:1–8.

54. • Collazos J. Opportunistic infections of the CNS in patients with AIDS: diagnosis
and management. CNS Drugs. 2003;17(12):869-887.
• Bilgrami M, O'Keefe P. Neurologic diseases in HIV-infected patients. Handb Clin
Neurol. 2014;121:1321-1344.
• Uptodate – cryptococcal meningitis

55. THANK YOU