A brief description of the many neurological manifestations of HIV infection.

1. Neurological Manifestations
of
Human Immunodeficiency
Virus
Presenter - Dr.Garima Aggarwal
Moderator - Dr (Brig) Rajesh Kakkar
Dr.Manish Mittal

2.  HIV is the most common viral infection of the nervous
system, affecting both the CNS and PNS.
 Upto 50% of HIV patients have clinically apparent
neurological disease.
 Upto 20% of HIV patients present for the first time
with neurological manifestations.
 Upto 90% of HIV patients have neuropathological
changes on autopsy.
 India has the second largest burden of HIV related
pathology next to sub-Saharan Africa. Neurological
complications associated to HIV-1 infections, are very
common in our clinical setting.

3. NEUROPATHOGENESIS
Nervous System effects of HIV infection
DIRECT INDIRECT
HIV virus and its products Oppurtunistic infections
HIV associated Neoplasms
Cells affected by HIV -
 Perivascular Macrophages
 Monocytes from blood
 Microglial cells
 ?Astrocytes

4. NEUROPATHOGENESIS

5. CLASSIFICATION OF NEUROLOGICAL MANIFESTATIONS
OF HIV
HIV can involve disorders of both the CNS and PNS.
Classification based on the neuroanatomical localization and clinical
syndromes associated -
BRAIN
Dementia
Space occupying lesions
Encephalitis
Stroke like syndromes
MENINGES
Meningitis
SPINAL CORD
Myelopathy
Radiculopathy
PERIPHERAL NERVES
Peripheral Neuropathy
Inflammatory Demyelinating Polyneuropathies
Toxic Neuropathy
MUSCLE
Polymyosistis , Pyomyositis
HIV associated Wasting Syndrome

6. Neurological Manifestations of HIV
involving the
BRAIN
*AIDS defining illnesses are marked in RED

7. • HIV Encephalopathy/ ADC
• Progressive Multifocal Leuco-
DEMENTIA Encephalopathy
• Tuberculosis
• Neurosyphilis
B • Lymphoma
R • Abscesses
Tuberculosis
Listeria
A Nocardia
E.Coli
I • Infective Granulomas Toxoplasma
N SPACE Aspergillus
OCCUPYING Candida
Cryptococcus
LESIONS
• Neoplastic Primary CNS Lymphoma
Secondary Metastasis
Metastatic Kaposi’s Sarcoma
Glioma
• Others
PMLE, Varicella Zoster, CMV

8. • CMV Encephalitis
• PMLE
• HSV , VZV
ENCEPHALITIS • Toxoplasma Encephalitis
• Aspergillus encephalitis
B •
•
Metabolic Encephalitis
IRIS
R
I
A • Granulomatous Angitis – AIDS associated
• Infectious Vasculitis – Tb, Neurosyphilis,
S
C
I Aspergillus, Mucor
• Varicella Zoster Virus Vasculitis
H
E
• Bacterial Endocarditis, non bacterial thrombotic
N STROKE Like endocarditis
M
I
Syndromes • Venous thrombosis – Hypercoagulable states C
• HIV asso. Thrombocytopenia
• DIC H
• METASTATIC- Kaposi’s Sarcoma, PCNSL E
• Coagulopathy M
O.

9. Neurological Manifestations of HIV
involving the
MENINGES

10. M • HIV Seroconversion Illness-
Aseptic meningitis
E ACUTE • Pneumococcal, Meningococcal
N • E.Coli
• Klebsiella
I • Listeria
N
G • Mycobacterium tuberculosis
• Mycobacterium Avium complex
I • Cryptococcus
• Candida
T CHRONIC
• Syphilis
I • Nocardia
• Metastatic Meningitis -
S Lymphoma

11. Neurological Manifestations of HIV
involving the
SPINAL CORD

12. M HIV associated • Vacoular Myelopathy
Y
E • CMV Myelopathy
• Varicella Zoster Virus
L INFECTIONS • Herpes Simplex Virus
• HTLV 1 and 2
O • Neurosyphilis
P
NEOPLASTIC • Lymphoma/metastasis associated
A Myelopathy
T
H METABOLIC • Vitamin B 12 Deficiency
Y

13. Neurological Manifestations of HIV
involving the
PERIPHERAL NERVES

14. • AIDP
• CIDP
N EARLY STAGES-
Immune
• Vasculitic Neuropathy
• Cranial Mononeuropathy
E Dysregulation • Multiple mononeuropathies
• Plexopathy – Brachial, Lumbosacral
U MID STAGE – HIV • Distal Sensory Polyneuropathy
R Replication driven • Autonomic Neuropathy
O • CMV polyradiculopathy, Mononeuritis
Multiplex
P LATE STAGES – • Syphilitic Polyradiculomyelitis
Oppurtunistic • Tuberculous Polyradiculomyelitis
A Infections, Neopla • Zoster ganglionitis
• Lymphomatous Polyradiculopathy
sms
T • AIDS Cachexic neuropathy
• ALS like motor neuropathy
H • Nucleoside Reverse Transcriptase Inhibitors –
ALL STAGES (TOXIC Didanosine, Zalcitabine, Stavudine
Y NEUROPATHY) • Other Concomittantly used drugs – Vincristine,
Isoniazid, Ethambutol, Thalidomide

15. Neurological Manifestations of HIV
involving the
MUSCLES

16. • HIV Polymyositis
M • CMV Polymyositis
Y INFECTION • Pyomyositis
• AIDS cachexia- HIV associated
O Wasting Syndrome
P
A
T
• ZIDOVUDINE
H DRUG INDUCED • Others especially NRTIS
Y

17. Some commonly encountered
Neurological Manifestations
Of HIV
In Clinical Practice

18. ASEPTIC HIV MENINGITIS
 10-15% of patients with Acute HIV Seroconversion illness present
with meningtis
PATHPHYSIOLOGY – Immune mediated illness
CLINICAL FEATURES
Headache – severe and protracted, isolated persistant headache
Signs of meningeal irritation – nausea, vomiting, photophobia
Acute Seroconversion illness – Flu like febrile illness
Preserved alertness and cognition
May be associated with features of Encephalitis
Cranial nerve Involvement may be seen – CN VII, rarely V and/or VIII
It is a diagnosis of exclusion.

19. ASEPTIC MENINGITIS continued
 INVESTIGATIONS
1. LP – CSF sugar - Normal (40-70mg/dl)
protein - Elevated but <100mg/dl (15-50mg/dl)
cells - lymphocytic pleocytosis (0-5 Mono/mm3)
2. Intrathecal anti HIV IgG
3. Serum P 24 capture assay, HIV RNA level
 TREATMENT
No specific therapy is needed.
Resolves in 2-4 months without treatment.

20. HIV ENCEPHALOPATHY/
AIDS DEMENTIA COMPLEX
 In the era of HAART, 10-20% of HIV patients are affected by it.
 It is the first manifestation of AIDS in upto 3 % of HIV patients
 Associated wth CD4+ T cell count of < 200/mm3
 It s considered part of the HIV associated Neurocognitive
Impairment spectrum
Minor Cognitive Motor
Assymptomatic AIDS Dementia Complex
Dysfunction
HIV associated NCI, progresses with increased viral load and immunosuppression
PATHOGENESIS – neuropathogenesis as described above.
White matter – pallor, multinucleated cell encephaltis, vacoular
changes, focal necrosis and neuronal loss.
The cerebral cortex is relatively spared.
Areas affected- subcortical structures of brain and spinal cord.

21. HIV ENCEPHALOPATHY continued
CLINICAL FEATURES
Cognitive impairment – Forgetfulness
Decreased Attention and Concentration
Inability to perform complex task
Decreased Sexual drive and disrupted Sleep
Mild mania and Agitation
Motor Dysfunction- Poor balance
Gait incoordination- slow and rigid gait
Slowness of movements
Postural tremors
Choreoform movements, myoclonic jerks
Vegetative state- Bowel and Bladder incontinence
Unable to Ambulate
lying in bed mute with vacant stare

22.  There are no specific diagnostic criteria for HIV Encephalopathy.
 Diagnosis of dementia – demonstrating a decline in cognition
CLINICAL STAGING OF HIV ENCEPHALOPATHY
STAGE Mental Function Motor Function
STAGE 0 Normal Normal
STAGE 0.5 Absent, Minimal or Equivocal Slowed ocular and extremity
symtoms movements
STAGE 1 Able to perform all but the Unequivocal motor
demanding aspects.Unequivocal impairment
func. and intellectual impairment Can walk without assistance
STAGE 2 Performs basic self care Ambulatory
Cannot work or maintain May require a single prop
demanding aspects of daily life
STAGE 3 Major Intellectual incapacity Major motor disability
Cannot walk unassisted
STAGE 4 Intellect, social comprehension and Paraparetic or paraplegic with
output at rudimentray level bowel, bladder incontinence

23. INVESTIGATIONS – testing done only to exclude other diagnosis
1. Neuropsychological testing – MMSE
It is advisabele in all patients with HIV to have a baseline MMSE.
2. CT / MRI - Diffuse cerebral atrophy
Patchy or diffusely abnormal signals esp on FLAIR –
(Hemispheric white matter +/- basal ganglia and thalamus)
Basal Ganglia calcification – in children
Non specific
3.CSF findings – sugar - normal
CSF changes
protein - mildly elevated
cells - lymphocytic pleocytosis
special tests – HIV IgG synthesis
Oligoclonal bands
HIV DNA amplification
Quantitative CSF-HIV Burden
others MCP1, neopterin, Quin. Acid, Beta2MG
The practical utility of special CSF testing is uncertain
No absolute correlation exists between CSF HIV burden and disease severity

25. TREATMENT
 HAART – HAART improves neuropsychological performance
(Larussa etal 2006)
- upto 50% reduction in HIV enceph. since HAART
- simpler regimens with least number of drug side effects
- Drugs with high CSF penetration should be used
(Zidovudine, Stavudine, Lamivudine, efavirenz, nevirapine)
 Neuroleptic medication- for patients with psychobehavorial dys.
- they have increased sensitivity to EPS
side effects of neurleptic drugs
- TCAs and SSRIs
- Clozapine and Haloperidol
 Anticonvulsant – Gabapentin and topiramate are preferred
 Psychological support, assisted living.

26. CRYPTOCOCCAL MENINGITIS
 Initial AIDS defining illness in 2% of patients
 More common with CD4+ T cell count of <100/mic.l
 CLINICAL FEATURES
Subacute onset
Signs of meningeal irritation – fever, stiff neck,vomiting, photophobia
Cryptococcomas and Cranial nerve involement rarely
Head to Toe examination for associated infection
 Skin lesions, like Molluscum contagiosum
 Palatal and oral ulcers
 Myocarditis
 Pulmonary involvement – in 1/3rd of case
 Gastroenteritis
 Prostatitis – prostate may serve as reservoir for smoldering infection

27. INVESTIGATIONS
1. CT/MRI – Hydrocephalus
Complications of
Gelatinous pseudocysts Cryptoccal
Cryptococcomas meningitis
only nonspecific Cerebral Atrophy
2. CSF - sugar - decreased
D/D TbM
protein - elevated protein
cells - monomuclear pleocytosis
India ink smear – nonspecific D/D Aspergillus,
C.immitus, Candida,
H.Capsulatum,
Naeglaeria
CSF cryptococcal antigen (CrAg) – sensitivity 95%
Fungal CSF culture for Cryptococcus – gold standard

28. CT brain showing -
1.Gelatinous
Pseudocyst
( formed by
confluence of dilated
perivascular spaces).
2.Sites: Basal
ganglia, cerebral
cortex, cerebellum
and midbrain.
 No contrast
enhancement
MRI: Cyst are of CSF
intensity

29. TREATMENT
Amphotericin B +/- Flucytosine
(0.5 to 0.7 mg/kg/day) ( 75 to 150 mg/kg/day)
Renal insufficiency Hematological
Hypokalemia x 2 to 3 weeks
Toxicity
Hypomagnesemia
Fluconazole 200mg P/O BD
x upto 3 months
Maintainence therapy -Fluconazole 200mg P/D OD (1st line)
Amphotericin/Itraconazole weekly (2nd line)
Continue till the CD4+T cell count >200cells/micr.l
 Increased ICP – Medical- corticosteroids and Acetazolamide
Repeated Lumbar punctures, Ventriculostomy
Acute mortality approaches 30% and is related to inceased ICP

30. TOXOPLASMOSIS of the BRAIN
 Associaterd with CD4+T cell count < 100cells/micr.l
 Most commmon cause of focal intracranial masses in patients with
AIDS
PATHOGENESIS
It almost always occurs as a Recrudescence of previously acquired
infection.
It is 10 times times more commmon in patients with Ab to Toxoplas.
CLINICAL FEATURES
FEVER
HEADACHE FOCAL NEUROLOGICAL DEFICITS
(Seizures/Hemiparesis/Aphasia)
Rarely patient may have Confusion, Dementia, Lethargy or Coma

31. INVESTIGATIONS
1. CT / MRI – ‘Multiple lesions in Multiple Locations’
Ring Encancing Lesions – inflammation and central
necrosis
2. IgG Ab to Toxoplasma – This should be done for all HIV patients
at the time of initial workup.
3. Brain Biopsy – only confirmatory test
- patients with failed 2-4 weeks of antitoxoplasma
therapy

32. D/D of Ring Enhancing Lesions

33. e d

34. TREATMENT
Sulfadiazine + Pyrimethamine
(05 to 1.5g P/O q 6th hrly) (200mg loading dose Day 1)
( 75mg P/O OD maintainence)
With Folinic Acid (10mg/day)
Long term Suppressive therapy – Sulfadiazine + Pyrimethamine
(2g/day) (25mg/day)
May need to continue maintainence therapy life long in some
Or until CD4+T cell count > 200cells/micr.l
Prophylaxis – HIV ,CD4+Tcell count <100c/mi.l, IgG toxoplasma +ve
Primary Prevention – HIV , but seronegative for toxoplasma

35. PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY
 It is a late manifestation, seen in 4% of patients with AIDS
PATHOGENESIS
Caused by the JC virus, DNA containing HPV. Only known complication
Approx 90% of general adult population is already exposed to this
virus in early childhood, and contains antibodies against it.
Lesions – small foci of demyelination in subortical white matter,
which coalesce. Areas – Occipital and parietal lobes, cerebellum,
brainstem and rarely Spinal Cord.
CLINICAL FEATURES
 Protracted course
 Multifocal Neurological deficits - Seizures
Visual Field defects
Aphasia
Ataxia, and occ. Sensory deficits
 With or without mental status changes

36. INVESTIGATIONS
1. CT / MRI – Multiple nonenhancing white matter lesions,
may coalesce, predilection for occipital and parietal.
MRI – decreased signal intensity on T1
- Hyperintensity on T2
2. CSF – non specific changes
- CSF PCR for JC virus DNA (sensitivity 76%, specificity 100%)
3. Brain Biopsy – if clinical diagnosis likely, but no viral DNA
detected on CSF
 Bizarre giant astrocytes with pleomorphic hyperchromic nuclei
 Altered oligodendrocytes with enlarged nuclei
 Cells with viral inclusions and myelin loss

37. FLAIR Images Showing
Progression of Progressive
Multifocal Leukoencephalopathy
a) Multifocal, high-signal-
intensity lesions (arrow) in the
right hemisphere of a patient The
CSF was positive for JC virus.
b) Contrast
enhancement is not evident
(arrow).
c ) 6 weeks later, progression
of the white matter lesions
(arrow) shows involvement of the
uncinate fibers.
d )Patchy enhancement with
gadolinium
(arrow) is noted (predominantly
in the right hemisphere

38. T2 flair MRI brain shows White matter hyperintensity of subcortical U fibers, splenium of
corpus callosum in posterior cerebral hemisphere
No contrast enhancement
No mass effect
Common sites: temporal and occipital white matter, Subinsular region, corpus callosum
and subcortical U fibers

39. TREATMENT
 No specific therapy available for PMLE
 Improved survival has been seen with HAART
HIV with PMLE
without HAART with HAART
Mean Survival- 3 – 6 months around 2.5 years (>7years*)
Patients on HAART may show paradoxical worsening due to IRIS
Only 50% of patients on HAART show any neurological improvement
 Other therapies tried – Cytosine, acyclovir, Vidrabine, IFN alpha
All these therapies have shown generally unsatisfactory results

40. PRIMARY CNS LYMPHOMA
 Complicate the course of AIDS in upto 5% of patients.
PATHOGENESIS
PCNSL of B cell origin are considered oppurtunistic neoplasms.
CLINICAL FEATURES
Similar to Toxoplasmosis – fever, headache , FNDs
PCNSL TOXOPLASMA
 Tempo of evolution slower presents as acute/subacute
several days to few weeks
 Fever usually absent may or maynot be present
 No response to antitox therapy Show clinical and
neuroimaging imrovement in
response to Antitox therapy

41. INVESTIGATIONS
1. MRI > CT – one or more deep lesions
- location – deep, adjacent to lateral ventricle
- White matter rather than gray matter
- subependymal extension
- predilection for Posterior fossa
- Mass effect may be present, surrounding edema rare
2. CSF – unhelpful
- Monoclonal B lymphocytes by flowcytometry Corroborative
evidence on
- CSF – EBV virus DNA amplification PCNSL
3. BRAIN BIOPSY – definitve diagnosis
- After a failed therapeutic trial for Toxoplasmosis
4. SPECT SCAN – may be useful.

42. A)POST CONTRAST T1WI B) FLAIR T2WI A-B. 24 year-old man with AIDS
Show a solitary large ring-enhancing
lesion with mild mass effect and
moderate vasogenic edema.
The hypointensity of the lesion on
T2WI is
characteristic of lymphoma. Note
that the mass effect and edema is less
than expected given the size of the
lesion, as
is typical for primary brain lymphoma
while much more edema and mass
effect vs. lesion size is expected in
toxoplasmosis.
C) POSTCONTRAST T1WI D) T2WI
C-D. 30 year-old man with AIDS
show left temporal lobe vasogenic
edema,
related to a temporal lobe mass lesion
(not shown). There are also bilateral
lesions in the caudate nuclei on T2WI
(D)(red),
with periventricular and ependymal
extension of enhancement on the
right (C).(green)
The ependymal spread is
characteristic of PCNSL

43. TREATMENT
 HAART – vigorous attempts to suppress HIV replication are
recommended in all patients with PCNSL
 Mass effect – High dose corticosteroid therapy
 Radiotherapy – Palliative whole brain radiotherapy
 Chemotherapy – Its use remains controversial, trial stages.

44. VACUOLAR MYELOPATHY
 VM is the most common cause of spinal cord dysfunction in
untreated patients with AIDS.
 It is apparent in 25% to 55% of AIDS autopsy series
 It frequently coexists with HIV Encephalopathy and Distal
Sensory polyneuropathy
CLINICAL FEATURES
 Subacute onset – over weeks or months
 Gait disturbances, imbalance
 Ataxia
 Spasticicity
 Sphincter dysfunction
 Examination –Spastic parapareis, Hyperreflexia, Babinski +ve,
Loss of proprioception and vibration sense . No sensory level.
 Arms are typically spared

45. VACUOLAR MYELOPATHY VITAMIN B12- sacd
S. Vitamin B12 levels are Normal Decreased
Usually associated with Distal Sensory Not seen
neuropathy
Vacoular changes in myelin sheaths Decreased methylation of histidine
and phasphatidylcholine prod.
HIV infected patients may also present with Vitamin B 12 deficiency.

46. INVESTIGATION nonspecific , to exclude other etiologies
1. MRI SPINE – Cord swelling wtith intramedullary enhancement
- T2 signal changes
2. CSF – testing for Viral DNA – CMV, VZV, HSV, HTLV 1 & 2
TREATMENT
 HAART – Viral control can result in improved neurological
function is not well documented in VM.
 Assistance – Personal
Care of neurogenic bladder, bladder infection
Prevention of skin breakdown
Management of limb spasticity, etc.

47. Sagittal T2-weighted
images of the cervical
C2 spine-
Iintramedullary
signal
 increased signal on T2
C5 enhancement extending from C2
though approximately
C5.
The axial T2 image-
 Abnormal signal to be
symmetric within the
posterior columns of the
cord.

48. HIV associated NEUROPATHY
 Peripheral neuropathies complicate all stages of HIV.
 Symptomatic neuropathy is seen in 10-15% of patients but
pathological changes of peripheral nerve involvement - almost
all AIDS patients
HIV ass.
NEUROPATHY
Distal Sensory CMV assoc. NRTI assoc. TOXIC
AIDP and CIDP
PN POLYRADICULOPATHY NEUROPATHY

49. DISTAL SENSORY POLYNEUROPATHY
CLINICAL FEATURES
 Painful burning sensation, with numbness in both feet.Hands spared
 Depressed or absent ankle jerks, mild pain, temp., vibratory sense
loss in the feet.
 Symmetrical involvement is a characteristic clinica feature and hands
are usually spared.
INVESTIGATIONS – typical clinical features are diagnostic
TREATMENT
 Reduce exposure to NEUROTOXINS – Ethanol, NRTIs, INH,
Metronidazole, Dapsone, Vincristine
 Screen for Vitamin B 12 Deficiency, Diabetes Mellitus
 HAART
 Pain control – TCAs – Nortiptyline > Amitriptyline Help relieve
- Anticonvulsants – Gabapentin neuropathic pain

50. Thank you

51. References
1. Neurology in Clinical Practice – 3rd edition
(Bradley, Daroff, Fenchal)
2. Adams and Victor’s Principles of Neurology- 9th
edition
3. Harrison’s principles of Internal Medicine – 17th
edition
4. Textbook of neurology- Dounghey
5. NACO guidelines for management of AIDS- 2010
6.WHO guidelines for HIV/AIDS
7. World Wide Web