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HIV Neurology
By:Dawit Ayele - July,2007
HIV AIDS
-Is
now second only to the Black Death as the largest
epidemic in history.
- kills about 2.9 million people a year, or about one person
every 11 seconds.
-The toll is worst in Africa, where millions of parents have
died, leaving children as orphans.
-about 1.4% of Ethiopians ages 15 to 49, or one million
people, are HIV-positive
-nearly 6% of adults in urban areas are HIV-positive, while
less than 1% of rural residents age 15 to 49 are HIVpositive. .(eth.demographic & health survey2005/daily
HIV/AIDS report sept,2006)
By 2015 life expectancy at birth of 7 african countries with
prevalence rate >20% will be 32 yrs.lower than in the
absence of AIDS
Neurologic diseases in HIV

Neurologic problems occur throughout the course of disease
irrespective of the immune status  The Brain infected as early
as first few weeks, low grade inflammation continues

Virtually all HIV infected patients have some degree of CNS
involvement:-evidence ~90%CSF abnormality even during
asymptomatic phase.

Affects all levels of the neuraxis

Overall,20 disease of CNS occur in ~1/3 of patients with AIDS.*But
this frequency is considerably less in patients receiving ART.

Nature of problem:-inflammatory
-demyelinating
-degenerative
Neuropathogenesis

Neurologic abnormalities in HIV infected
are due to
-opportunistic infections &
neoplasms.
-**direct efffects of HIV & products
 HIV is demonstrated in vivo in brain &
CSF of infected individuals.
 Main cell types infected causing effect in
CNS are:
-perivascular macrophages & microglial
cells.
-Monocytes already infected in the blood can
migrate & reside in brain or
-macrophages can be directly infected in the
brain.
 No convincing evidence that brain cells
other than those of monocyte/macrophage
lineage can be productively infected in
vivo
Neuropathogenesis:cellular tropism

HIV-1-utilizes 2 coreceptors along
CD4 to bind,fuse with and enter
target cells:CCR5&CXCR4
-V.Strains that utilize CXCR4X4
viruses
-Those that utilize CCR5R5 viruses
-Dual usingR5X4 viruses
 Early HIV transmitting virus(early
stage) is almost invariably an
R5virus
Note:R5 viruses are more efficient in
infecting monocyte/macrophages&
microglial cells of the brain.
Neuropathogenesis cont.
Eventually 40% of infected
individualspredominant X4
associated with rapid
progression.(no need of
gp120+CD4 interaction&
conformational  for co-receptor
affinity)
60%maintain R5 virus predominance.
 **HIV cytopathicity is low for
monocyte lineagecan replicate
extensively in cells.
 Hence-monocyte/macrophages are
normal in number(unlike T-helper
cells)&play role in dissemination
as reservoir—*represent an
obstacle to eradication of HIV by
ART.
Neuropathogenesis
**Chemotaxis of leucocytes(monocytes) into CNS
+endogenous neurotoxins from macrophages & lesser
extent astrocytes via indirect pathwaysis responsible
for manifestations of white matter lesions +neuronal
loss seen in infected individuals.

Development of neuro AIDS depends on:
– Immunosuppresion
– Neuro-virulence
– Genetic factors(E4 allele for apo-lipoproteinE ,CCR532)
– HAART
Disease Classification




Pathophysiologic (course of the disease)
-1ry HIV infection & Seroconversion
-sxic/asxic phase(CD4 > 200/mm3)
-AIDS defining (late HIV infection)
Neuroanatomic:brain parenchyma(diffuse/focal)
meninges(infectious/malignancy)
spinal cord(acute/subacute/chronic)
peripheral neuropathies(focal/poly)
myopathy( +/-inflammatory)
Radiologic appearance of CNS lesions:
-lesions with or without mass effect
Etiologic :HIV related
Non HIV related(stroke,degenerative dis..)
ART related
Approach to HIV infected patients with CNS lesions

**Clinical challenge:-pt with change in mental status or abnormal
neurologic exam.
 Wide range of presentation:-subtle& non specific to life threatening
emergencies.
 Most important factor for DDX is degree of immunosuppression:
-CD4>500/lBenign& malignant brain tumors with metastasis(as
immunocompetent)
-CD4 200-500HIV associated cognitive & motor disorders.Usually
do not present with focal lesions
-CD4<200CNS mass lesions most common.The most likely dxic
consideration –OI & AIDS associated tumors.
 *Multiple etiologies can coexist:-one study 6%had >1etiology
established from histologic sampling.
Epidemiology

Thorough knowledge of the pattern of various etiologies
for CNS disease in HIV infected patient in particular
area is vital for evaluation&management.(eg-In
developed nations tuberculoma is rare)
 Patient not taking ART-may present initially with CNS
opportunistic infection
 Post ART & prophylaxis for PCP-same etiology but
different incidence & spectrum
Ex-Co-trimoxazole against PCP-effective for TE
prevention(72.2%18.6%from1991-1996)
-ART markedly HIV encephalopathy,PCNSL,PML
or new severe demyelinating leukoencephalopathy
Radiologic appearance of CNS lesions

CT&MRI +/-contrast
*Enhancementusually signifies
inflammation.(NB-steroid use can
enhancement)
 MRI advantage Vs CT
-much more sensitive in determining
truly solitary lesion
- sensitive for white matter lesions
in posterior fossa
- identify peripheral more
accessable lesion for biopsy.
 Ancillary imaging studies:
thallium SPECT,PET,perfusion
MRI,MR spectroscopy:
more sensitive than specific
not readily available
Radiologic appearance of CNS lesions

CNS lesions classified into 2 categories according to +/-mass
effect:
-CNS lesions with mass effect:
Characterized by swelling,edema&mass effect on surrounding
structures.In some esp.post fossa cerebral herniation occurs.
ass lesions usually enhance a/r the injection of contrast
material,indicating local inflammation& breakdown of BBB
Presenting feature can be headache,N,V,confusion,lethargy
ICP
Leading DDX-Toxoencephalitis,tuberculoma,PCNSL
-CNS lesions without mass effect
Usually do not enhance a/r injection of contrast material & are
not associated with risk of herniation.
Vast majority:PML or HIV associated encephalopathy
Additional vital diagnostic modalities

In addition to routine laboratory studies:
 CD4 count
 Serology(for toxo,VDRL…)
 CSF analysis(including CSF PCR)
 Brain biopsy are very important in reaching
specific diagnosis & management
SPECIFIC DISEASES—I)MENINGITIS


1)Cryptococcal meningitis
Leading infectious cause of meningitis in pts with AIDS ( CD4 <
100/mm3);particularly common in pts with AIDS in Africa occuring
in~20% of patients.
 AIDS-defining illness for 60 % of the HIV-infected patients in
whom it is diagnosed.
 In Ethiopia-Medical record review study done at TAH Jan1997Dec2003(int.conf.of AIDS jul.2004) revealed:-from total 102
microbiologically confirmed crypt.meningitis pts with HIV;median
age of 33.5yrs,67%M,in 82.4% it was 1st AIDS defining illness.
 C/P:
– Subacute meningoencephalitis:
 HA, fever, n &v, photophobia ,stiff neck; meningial signs
absent in 50%.(Similar figure in Ethiopian studies-HA,f,v
present in >90%of cases)
 Personality changes, cognitive impairment, altered mentation
and coma.
 Focal neurologic deficits & Seizure : less
frequentCryptococcomas
Cryptococcal meningitis diagnosis

Dx:CSF : Pressure > 200mmhg in 75 %
NL/modest Mononuclear
pleocytosis(5-100), prt(50-100) ;
low glucose
 CSF Culture +ve in > 95%( gold
standard)
 Indian ink +ve in 60-80%
 Crypt Ag +ve > 95%
 Biopsy for CNS cryptococcoma
– Blood culture +ve in 50-70%, Serum
cryp Ag +ve >95%
– MRI/CT:
 Excludes focal disorders
 Cerebral atrophy-related to advanced
HIV
 Hydrocephalus


Cxn: Hydrocephalus, Gelatinous
pseudo-cyst, Infarction, cryptococcoma
Cryptococcal meningitis Cont…
Treatment: Standard;
 Induction: Amp B + 5 FC x 2 wks
 Consolidation: Fluconazole 400mg x 8 wks /until CSF sterile
 Suppressive phase: Fluconazole 200mg
Lower ICP –
 LP, V-P shunt, optic nerve sheath fenestration
 Repeat LP at 2 wks if no response
 Monitor fluconazole level in Renal failure
Alternatives:
– Fluconazole alone for acute Rx as effective as Amp B –delayed
CSF clearancepreserved for mild disease
– Fluconazole+ 5 FC x 6-10 wks
– Ambisome 4 mg/kg IV x 2wks
– Consolidation –iatraconazole
*FC combination with AMP B does not improve immediate out come
but prevents relapse
Cryptococcal meningitis Cont…

Response:
– CSF culture –ve at 2wks in 70%
– CSF cryp Ag used to follow response

Poor prognostic factors:
–
–
–
–

Altered level of consciousness
CSF cell < 20/ul
CSF crypt Ag > 1:1024
High DBP
Treatment failure:
**No clinical response at 2 weeks
– Continue with same treatment
– Higher dose of Fluconazole with FC
– Voriconazole
 Death inevitable w/o Rx( > 90% in first 2 wks, 40% in wk3-10)
(*Even with proper Rx overall mortality is 6-14%.Mortality rate in the Ethiopian
study >46% being rxed with amphotericin (45.1%) , Fluconazole(17.6%),no
antifungal(39.2%))


Exclude IRS as a cause of failure
Sxs may recur with HAART initiation as IRIS
Tb meningitis


1/3 of all AIDS related deaths due to Tb.Untreated universally fatal.
Seropositivity in Zaire study 88% in those with confirmed Tb
meningitis.
 Accelerates the course of HIV so needs index of suspicion.
 *HIV co-infection doesn’t alter c/f,CSF findings,response to therapy
 CNS Tb exists in three forms:
– Meningitis
– Intracranial tuberculoma
– Spinal Tb arachinoditis

Inflammation
– Proliferative arachinoditis at the base-CN & vessels
– Vasculitis-thrombosis & infarction
– Hydrocephalus-communicating

Three phases
– Prodromal phase-2-3 wks : malaise, fever , HA, personality changes
– Meningeal phase: meningismus, confusion, focal signs (CNpalsies or
hemiparesis)
– Paralytic phase: Stupor, coma, Seizure & dense hemiplegia
Tb meningitis cont….

CSF - AFB : yield 37% with initial smear, 87% with upto 4 serial
specimens examined,
– elevated prt & low glucose with a mononuclear pleocytosis
Recommended that a minimum 3 LPs be performed at daily intervals .
** Key points to sensitivity of CSF AFB smear:
1-use large volume(10-15ml) &best to use the last fluid removed at LP
2-Smear of clot or sediment most readily demonstrates org.(if no clot;
add 2ml of 95%alcohol form heavy protein ppt carrying bacilli)
3-~.02ml of centrifuged slide </=1cm diameter&stain with ZiehlNeelsen method.
4-200-500 HPF should be observed(2observers)~30minute
PCR 60% sensitivity
 Radiological clue (CT)
-*Communicating hydrocephalus
– Basilar arachnoiditis,Cisternal enhancement
– Cerebral edema and infarction/ BG infarction
– Multiloculated abscess/Tuberculomas ( common in HIV (60 VS 14
%)among pts with TB meningitis)
Treatment of Tb meningitis
•
•
Anti TB (HRZ+E/STM)x2 + (HR)x10 months w/o delay
Dexamethasone:
-Has no mortality benefit in HIV
-Reduces basal inflammation and arteritis
– Administration depends on grading
Grade I (GCS 15 , no focal deficit)
 Grade II focal deficit, GCS 11-14
 Grade III coma GCS < 10
Gen.Dose recommendation:
Dexa-1st 3wks (initially IV 0.4mg/kg/day, tapering to 0.1
mg/kg/day) followed by –PO beginning with 4 mg per day, tapered
over 3-4 weeks at the rate of 1 mg decrease in the daily dose each
week.
Prednisone 60 mg per day tapered gradually over six weeks


Surgery — Patients with hydrocephalus
Neuro syphilis
Share risk factors-coexists: 25 – 70 %
 Affects brain, meninges, spinal cord & nerve root
 Peculiarity with HIV:
- *Manifestations may be altered withrate of early CNS invasion

– Multiple neurological relapses after Rx
– Serological Rx failure
– Slower rate of decline of titer

Two forms
– Asymptomatic-
CSF mononuclear pleocytosis, increased protein, reactive
VDRL
 Probability of progression 20% in 10 years
– Symptomatic

Neuro syphilis…




Types:(manifestations may progress fast in HIV!)
Meningeal:onset< 1 year
– HA, nausea, vomiting, stiff neck, CN involvement
– Seizures, altered mental state
– With uveitis & iritis coexist
Meningiovascular :5-10 yrs(more common)
– Inflammation of pia & arachnoids with wide spread arterial
involvement
– Stroke syndrome-MCA in young commonest presentation
– Usually follows sub acute encephalitis syndrome (HA, vertigo,
insomnia) followed by gradually progressing vascular syndrome
Parenchymatous#:relatively rare
General paresis 20 yrs?
Personality,Affect,Reflexes,Eye(Argyll Robertson
pupils),Sensorium,Intellect&Speech
 Tabes dorsalis
25-30 yrs?
Demyelination of the posterior columns,dorsal roots & ganglia

Neuro syphilis Cont…

Dx: -Serology
 Non treponemal test-RPR & VDRL
 Treponemal test-FTA-Abs, TPHA for confirmation
-CSF: mononuclear pleocytosis >5wbc/mm3, protein >45mg/dl,+VDRL



Reactive VDRL( sensitivity~50%specific)---seen in 40% in 1ry & 2ry
FTA-Abs.(sensitive ) if non reactive excludes
-Skin biopsy-silver staining to look for organism(suspicion & -serology)
Rx:-Aqueous penicillin G(18-24mU/dIV,given as 3-4mUq4h or continuous
infusion)for 10-14days or
-PPF2.4mU/dIM+oral probenecid(500mg qid),both for 10-14days
If penicillin allergic patient –Desensitize & treat with penicillin
- Response
 Dramatic, arrests progression
 Relapse –retreatment
– Follow up
 Regardless of HIV status, patients are considered adequately treated if the
non treponemal test antibody titer declines at least four-fold over a specified
period of time(a year for early syphilis&2-3yrs a/r latent syphilis)
 CSF every 6 months

II)Parenchymal brain disorders
I-Diffuse:
IA)Condition with clear level of consciousness
a)Minor cognitive motor disorder(MCMD)
Clinical diagnosis-at least two of:-Impaired attention or coordination
-Mental slowing
-Impaired memory
-Slowed movements or incoordination
*Sxs usually subtle & often overlooked. Clear consciousness,no serious
impairment in daily living.
Course-Some continue to have only minor problems& others progress to
full dementia.*No controlled trial for treatment so far.
**Paper published in neurovirology journal(jan2007) by David
B.Clifford et.al.-a cross sectional neurological evaluation of cohort of
community dwelling Rx naïve HIV infected pts in Ethiopiafinger
tapping speed in HIV infected than HIV-ve;correlating wz viral load.
Other CNS &/or PNS performance similar with control group.
(unanticipated minor evidence of neurocognitive & PN deficit)
b)Dementia
 Defn:-combination of acquired limitation in congnitive
abilities(attn/concn.,processing,abstraction,memory,speech or visual
spatial skills) +abnormalities in motor function or in emotional or
behavioral functioning.
 AIDS dementia complex:describes the syndrome as a subcortical
dementia with a focus on changes in memory,mov’t(motor)&mood.
Epidemiology:-Incidence from 20-30%to 10-15%since ART;but
overall prevalence same.
*ART doesn’t prevent neuropsychological impairment ;it only alter type
of impairment & delay onset of dementia
Clinical course:-classic triad of sxs-Subcortical dementia(memory &
psychomotor speed impairment);depressive sxs& movement
disorder.
**Absence of higher cortical dysfuncton (aphasia, agnosia, apraxia..)
distinguish HAD from classic cortical dementia like
alzheimer’s.(*Late& severe HAD may have it)
Clinical staging of HIV encephalopathy(AIDS Dementia
Complex)
b)Dementia

Brain imaging
-CT/MRI-cerebral atrophy often
-used to eliminate other potential
diagnosis associated with poor
progrosis
 DDX-Toxo encephalitis
imaging-PML
LP -Infections 30 syphilis
TFT -Thyroid dysfunction
Test
-Nutritional deficiencies
b)Dementia
Rx:-Standard optimal HAART  cognitive
impairment.
 ART drugs with est CSF penetration are betterZDV,d4t,3TC,ABC,NVP,IDV
 Aggressive Rx of associated psychiatric
problems(such as mood,anxiety,or substance use
d/o)

c)Neuropsychiatric disorders

HIV and AIDS can produce a number of psychiatric conditions and
exacerbate many others ;some of them:
-Major depression
-Mania
-Schizophrenia
-Substance abuse or dependence
-Antisocial behavior
-Post-traumatic stress disorder (PTSD

The presence of a preexisting psychiatric disorder can increase the
risk of HIV acquisition and can also complicate HIV treatment.

Behaviors that are intimately connected with many of these
neuropsychiatric conditions actually fuel spread of HIV and thus
continuation of the HIV epidemic.
c)Neuropsychiatric disorders

Successful treatment can be achieved with even
the most difficult patients by applying a
comprehensive diagnostic formulation.
 **Each facet of this formulation strategy has the
potential to sabotage treatment for all the
remaining conditions, and, thus the treatment plan
must be comprehensive in scope in order to
address the whole person.
IB)Condition with disturbance of consciousness

Delirium
-Defn:-Development of disturbance of consciousness
with a ability to sustain,focus or shift
attention,which occurs over a short period of time.
 Is associated with -in cognition & perceptual
disturbance
- in sleep wake
cycle,psychomotor activity( or activity)&
emotional state.
- mortality,longer hospital stay,
care needed upon discharge.
Unfortunately still remains underdiagnosed.
Delirium

Careful Hx,P/E&Ix is vital to determine etiology:
-Intoxication by drugs & poisons
-Withdrawal syndrome
-Metabolic encephalopathies
-Infections(intracranial or systemic)
CMV,PML,cerebral toxo,cryptococcal meningitis,CNS
lymphoma.
-Neoplasia
-Head trauma&space occupying lesions
-Epilepsy
-Vascular disorders(cardiac& cerebrovascular)
- sensitivity reactions
-physical agents
Delirium….

DDx-mental status change in HIV pt—
>AIDS mania
>major depression
>bipolar disorder
>schizophrenia
*Delirium can usually be distinguished by its rapid onset ,
fluctuating level of consciousness& link to medical
etiology.
Rx-General issue:Orienting the patient
close & often constant observation(give safety &
reassurance to the patient)
-information to clinicians
-limit restraints
provide stable environment-private room, clock, calendar
&board that indicates location.
Delirium Rx….

Controlling symptoms
Psychologic behavior-low dose potency neuroleptic
agentshaloperidol/CPZ.
-don’t use sedating
drugs(diazepam)unless they are treating underlying
cause of delirirm

Identify & correct cause address potential
medical etiologies
Focal parenchymal brain disorders

1. Cerebral toxoplasmosis
Most common cause of 2ry CNS lesions with AIDS(ART&TE px.era )
 Late complication of HIV (CD4+Tcell<100/l),
 ? A reactivation syndrom 10x with Abs to the organism than sero –ve
Ethiopian study-Trans R Soc Tropical medicine & hygene(1998jul-Aug).170factory
workers (18-45yrs)sera tested for anti-toxo IgG –80.6%+with no sign. difference in
prevalence b/n pts infected &not infected by HIV;but ab.titers were higher in HIV+.
Previous study~74%seroprevalence from 1010 sera sample from d/t geographic regions.


C/P:Acute/ fulminant OR Insidious ( several weeks)
-Patient typically present with headache.
-One study –115case review:headache,confusion,fever(55, 52, and 47% respectively)
-Focal neurologic deficits & seizure are also common
-Dull affect-global encephalitis
-More profound mental status(confusion,lethargy,coma)+N,VICP

Dx:-Clinical
-Serology (+ >97% for IgG), if –ve likelihood of toxo is < 10%
-Radiological
-Brain biopsy-definitive Dx(due to risk indications..)
DX of Cerebral toxoplasmosis

Neuro imaging (CT/MRI):
Multiple/single, ring enhancement,
surrounding edema
– Seen in almost all-except diffuse form
– False negative-10%
– Multiple in 2/3, ring enhancing-90%
– Size < 2cm
– Site: Parietal/frontal lobes, thalamus ,
BG, Brainstem, Corticomedulary
junction, Pituitary gl
DDX:PCNSL,Tb/fungal/bact.abscesses
 CSF: +/- mild mononuclear pleocytosis
and elevated protein. DNA amplification.
Tachyzoites (on cytocentrifuged CSF
samples stained with Giemsa)
 SPECT /PET : in distinguishing
toxoplasmosis or other infections from
CNS lymphoma.
DX of Cerebral toxoplasmosis

A presumptive diagnosis of Toxo can
be made if the patient has
1. CD4 <100/µL & Sero +ve for T.
gondii IgG Ab
2. Not on effective prophylaxis for
toxoplasma
3. Brain imaging demonstrates a
typical radiographic appearance (eg,
multiple ring-enhancing lesions/
“eccentric target sign”)
– If these 3 criteria are present, a 90
% probability that Dx is toxo.
Brain biopsy is indicated if :
-all 3 of the above criteria not met with strong
clinical suspicion.
- patient doesn’t respond (clinical or radiogr.)
to empiric Rx
Treatment of Toxo
Toxoplasmic encephalitis generally responds promptly to treatment.
 Lack of either clinical or radiographic improvement within 10 to 14
days of empiric therapy for toxoplasmosis should raise the possibility
of an alternative diagnosis
 First line therapy
2choces-1- Pyrimethamine(200mg-L/75C) + sulfadiazine(6-8g/d -4d/d)
2-Pyrimethmine+Clindamycine
*All pyrimethamine regimens should include folinic acid to prevent
drug-induced hematologic toxicity (10 to 25 mg/day PO).
 Alternatives: 1. Pyrimethamine+ Azithromycin
2. Pyrimethamine+ Atovaquine
3.Sulfadiazine+ Atovaquone
* TMP-SMX-study showed no statistically significant difference with
standard Rx.Has side effect profile & can be used as effective
alternative Rx regimen esp. in resource poor settings.
 Relapses: common (typical 6wks Rx then dose maintenance Rx
is needed!!)
 Steroid:- radiographic evidence of midline shift, ICP or clinical
deterioration within the first 48 hours of Rx.

Treatment of Toxo

1ry prophylaxis: CD4 <100/mm3 & +ve toxo IgG Ab

Secondary prophylaxis may be d/c with CD4>200/l for 6mths.

Monitoring of therapy :
– Clinical evaluation. :Clinical improvement usually precedes
radiographic improvement. Thus, a careful daily neurologic
exam. during first 2 wks of treatment.
– Serial brain imaging/Radiographic reassessment : should be
deferred for 2-3 wks
unless no clinical improvement in 1st wk or has shown any
worsening.
– Rx advrse effects
No value to serial assessment of IgG toxoplasma antibody titers.
2. Primary CNS lymphoma
– AIDS defining malignancy (KS, Cervical Ca, NHL)
– ~20% cases of lymphoma in HIV
– Usually associated with EBV infection,no age predilection.
– Median CD4 ~ 50/ul: at later stage and poorer prognosis than
systemic lymphoma
– Presentation:
 Slowly progressing-weeks
 Cognitive impairment
 Head ache, confusion, Constitutional symptoms (fever,
nights sweats, and weight loss) > 80%.
 Focal deficit: CN findings, hemiparesis, aphasia, head
ache &/or seizure
 Duration <3 months
Dx,Rx&Px of PCNSL

Dx: Neuroimaging (MRI/CT)
– Lesion: size 3-5 cm, limited number: 1-3
– 40% multifocal , some degree of ring
–
–
–

enhancement –nodular or patchy (less
pronounced than toxo)
Location: cortex, corpus callosum,
periventricular
<10% posterior fossa
CSF cytology not helpful
PCR for EBV-(specif 100%, sensit 90%)
Biopsy Definitive Dx
Rx:
– Radiation, steroid: some relief
– HAART increases survival > 15 months

Prognosis: Poor - median survival < 1 year
– Survival is 1-3 mths from time of
presentation in untreated patients
– the outcome is not substantially improved
by therapy, with reported median
survivals of up to 3.5 months
3. Progressive Multifocal Leukoencephalopathy

Etiology: JC virus(Human polyoma virus), reactivation of prior
infection (70% of adult population: Ab to JC virus)

Late manif of AIDS ; in ~4% of pts with AIDS

A demyelinating lesion of sub cortical white matter (Cerebral
hemisphere predilection to parieto-occipital area) , cerebellum , BG,
thalamus, brainstem & spinal cord

Lesions are usually bilateral, asymmetric, & localized preferentially to
periventricular areas & subcortical white matter .

C/P:
– Typical patient:-Protracted course +/- Change in mental
state,Multifocal deficit: hemiparesis, aphasia, sensory deficit
– Ataxia & visual field defect ,aphasia,& sensory deficit may occur
Dx of PML

Dx
– CSF: Normal or non specific
PCR for JC :- specific ,if
+ve decrease need for
biopsy
CT : patchy or confluent
hypodense lesions of white
matter
MRI: multiple non
enhancing white matter
lesion (predilection for
occipital or parietal lobes).
Brain biopsy-giant astrocytes
& altered oligodendrocytes
nuclei contains viral
inclusions & myelin loss
DDx: HIV encephalopathy
and CMV encephalitis

–
–
–
–
PML Rx, Px...
*No specific Rx
– HAART –Regression of lesion and
-Prolonged survival > 2.5 years
– Trial: no clear benefit by cidofovir, IFN ,
topoisomerase inhibitor, cytosine arabinoside
 Prognosis
– Median survival in HIV pts + PML ~2.6 months
– In patients on HAART 1year survival has
increased from10%50%
– Paradoxical worsening has been seen with
initiation of HAART as IRIS
– Spontaneous remission -8%
– Favorable out come
 Baseline CD4 > 100/ul
 Maintenance of Viral load < 500 copies/ml (
baseline doesn’t have independent predictive
value of survival)
 **One of the few OIs that continues to occur with
some frequency despite widespread use of HAART:
4-Stroke in HIV
-Ischemic and hemorrhagic –clinical in 4%, autopsy report 34%.
-Sxs-sudden in onset unlike other focal deficits.
Ischemic
Hemorrhagic




Bacterial endocard
Non bacterial
thrombotic
Infectious vasculitis(VZV, Tb, syphilis, crypto,
angioinvassive fungi-asperg
& mucor)


Granulomatous angitis
Procoagulant state



Thrombocytopenia
Coagulopathy-CLD,DIC
PCNSL, KSa, toxo
Drugs- cocaine,
amphetamin

TTP
5. Brain abscess (bacterial)

Hematogenous spread
(Staphylococcus, Streptococcus,
Salmonella, Aspergillus,
Nocardia, Rhodococcus, Listeria)
 Associated with evidence of
disseminated infection
 Predilection to MCA territory
(posterior frontal & parietal
lobe), junction of white-gray
 Present as ICSOL than infectious
– 11-12 days some times stay
months
– HA, fever, focal deficit < 50%
CT: Multiple hypo dense
lesions, ring enhancement
-Gm stain & culture –micro.dx
– Blood Culture positive~10%,
ESR & WBC increases
Brain abscess

Other infections with focal
lesionscausing brain
abscess –
- tuberculose abscess
– Syphilitic gumma
– Neurocysticercosis
– Reactivated
trypanosomiasis
Rx-Directed towards the
identified cause/empirical
-Surgical +Medical mgt.
-Prophylactic anticonvulsant
–for risk patient
-Steroids shouldn’t be routine
F/up-wz imaging
Algorithm for the management of HIV-infected patients with CNS mass
lesions
SEIZURE

+/- due to OIs,
neoplasms, HIVE
 *Threshold often lower
than NL owing to f
electrolyte abn.
 +/- a presenting c/sx
 Anticonvulsant in all
HIV + Sz unless a
rapidly correctable
cause is found
Disease
HIVE
Cerebral
Toxo
Crypt.
Meningiti
s
PCNSL
% 1st
Sz
24-47
% Pt with
Sz
7-50
28
15-40
13
8
4
15-30
PML
1
cause
23
Others:No
CNS
TB, Aseptic
meningitis
III)SPINAL CORD DISEASES
A.Myelopathy



20% of pts with AIDS
90% of HIV myelopathy have some evidence of dementia
*Study published in East Africa Journal of Med.Jan 1995,by
Dr.Guta Z.evaluated 130 pts admitted(Dec1990-Dec.1993)
with lesion localized to spinal cord at BLH. This accounted
for 18% of all neurologic admission to this dept.then.
-Commonest presentationparaparesis/plegia(77%),Quadriparesis/plegia (23%),sensory
level,sphinicter dysfunction&bed sores(70%,54%,14%resp.)
-Leading cause-Tb spondylitis(26.9%),2nd commonest HIV-1
myelopathy(16.1%).
-Restmetastatic cord compression,tropical spastic
paraparesis,progressive non-compressive
myelopathy,Cx.spondylosis,10cord tumors,TV myelytis
Myelopathy…

Three main types in AIDS:
1-*Vacuolar myelopathy
2-Pure sensory ataxia: involves distal columns
3-Paresthesias & dsysesthesias of lower extremities:
sensory
1)Vacuolar myelopathy
Common cause of spinal cord dysfunction
 Pathological abnormality-25-55%(autopsy):
– ~ to subacute combined degeneration of the cord
 Coexist with HAD and DSP in late stage
 Characterized by :
-Vacuolar changes in dorsolateral thoracic cord
-Myelin sheathPreserves axons
-Release of cytokines or abnormal B12 utilization
Vacuolar myelopathy…
-Presentation:
-Sub acute onset-months
-Gait dstces, leg weakness, spasticity,
ataxia,DTR, extensor plantar response
-Impaired proprioception-vibration &
position
-Sphincter dysfunction following
deterioration of gait
-Spares the arm
-Sensory level and back pain- unusual
 Ix: MRI: Unremarkable / cord atrophy
 Rx - Supportive mainly
- HAART: don’t respond well to ART
in contrast to cognitive problems in ADC
B. CMV Polyradiculo myelopathy



Spinal cord and peripheral nerve
Late in HIV course
Fulminant in onset + rapid progression over wks
– lower extremity & sacral paresthesias,
– dlty walking with ascending leg weakness, areflexia,
– ascending sensory loss(+/- affect thoracic & cervical roots),
– urinary retention
 Associated back and radicular pain
 Cauda equina syndrome presentation
 Dx:
– MRI-cord swelling, intramedullary enhancement
– CSF:
 Neutrophil pleocytosis (in encephalitis - mononuclear)
 PCR for DNA
Rx of CMV Polyradiculo myelopathy
– Ganciclovir/ foscarnet for 3-6 wks: prompt initiation to minimize
degree of permanent neurologic damage
– Maintenance for life long
 Response : rapid improvement ( 2-3 wks)
Minimizes permanent damage
– Combination: in previously treated for CMV
C. OTHER DISEASES INVOLVING SC IN HIV
-HAM (HTLV-I Associated Myelopathy)
-Neuro syphilis
-Infections with HSV/VZV
-TB
-Lymphoma
-B12 deficiency
-Focal d/ses affecting brain also +/- cause focal myelopathy
IV)PERIPHERAL NEUROPATHY

Complicates all stages
 Morbidity & mortality
 Symptomatic disease in 10-15% in AIDS
I-Polyneuropathies: DSPN, NRTI toxic neuropathies
(Zalcitabine, ddI, d4T), IDP
II-Focal Neuropathies: CMV
 Five major types
– DSP
– AIDP
– CIDP
– CMV associated
– Toxic neuropathy (nucleoside associated)
A). Distal Symmetrical Polyneuropathy


Most common of peripheral neuropathy in HIV
In 2/3 of AIDS (electro physiologic evidence of peripheral
nerve d/s)
 Affects axons, predominantly sensory, distal
 *Usually in late stage , +/- onset at higher CD4 than ADC
 Progresses over months to years
 Cause unknown-proposed mechanism:
– Cytokine up regulation
– Dorsal ganglia toxicity of HIV Ag
– Chronic multi-system illness
+/- Direct consequence of HIV or S/E of dideoxynucleoside
Rx
DSP….

C/P: sensory sxs exceed sensory & motor
dysfunction
– Paresthesias, hyperesthesia, numbness in feet:
(+/- ascend to ankles or beyond)
– P/E: stocking-type sensory loss to pinprick, To
& touch sensation , loss of ankle reflexes
– Symmetrical involvement, disrupting sleep
– Walking impaired b/c of pain
– Motor changes are mild& usually limited to
weakness of intrinsic foot muscle (Spares
motor function & proprioception)
– Hands spared (early)
DSP Cont...

Dx: clinical , NCS
– Exclude DDx -alcohol, drugs (dapsone &
metronidazole), other causes (LFT, B12 and folate levels,
TSH, FBG, BUN and Cr, SPE,and immunoelectrophoresis,
RPR)

Rx:
Potential Intervention: – D/C neurotoxic medics:eg-ddi,d4t,NVP
– ART: variable response (doesn’t dramatically reverse the
condition unlike in case of ADC)
Symptomatic approach: (Pain management)is main Rx-anticonvulsants (gabapentine,carbamazepine),
-tricyclic antidepressants,
-topical analgesics,
- anti-inflammatories( NSAID,tramadol), and
-opioids for recalcitrant symptoms.
B). Demyelinating Polyradiculoneuropathy (GBS,
CIDP)


Less common. Early in HIV course
Autoimmune
*Similar manifestation with non HIV
Develops during seroconversion

Dx: CSF:-protein ~193mg/dl


- lymphocyte pleocytosis (10-50)
-Peripheral n. biopsy: perivascular
infiltrate suggesting autoimmune ae.

Rx:Similar to non HIV
– IVIg preferable than plasmapharesis: variable success
– Glucocorticoids for CIDP: should be reserved for severe cases
refractory to other measures (b/c of immunosuppressive
effects)
C). Toxic neuropathy ( nucleoside analogue):
Zalcitabine, ddI, d4T


Due to effect on mitochondrial metabolism
Painful sensory polyneuropathy; resembles DSP
– Evolves over wks
 Feel as if walking on ice
 Risk increases by preexisting DSP
 Rx:
– Withdraw the drug*Stopping the offending agent (ddI,
d4T, zalcitabine) –regression of symptoms over several
months
– Changing the dose
– Response is good if acted early < 2 wks, takes 12 wks
– Sxic Rx if doesn’t resolve with d/c of drug
D). Mononeuritis multiplex (MM)




Autoimmune: Necrotizing arteritis of peripheral nerves
Cxed by Multifocal, asymmetrical lesions
Occurs in all stages:
Early HIV infection: Immunologic
-Inflammation (benign &limited MM): Responds to
steroids or self limited
 Advanced immunosuppression(Late CD4 < 50/ul) :
-OIs
-Necrotizing vasculitis due to direct HIV
infection/immune-mediated phenomenon.
-Associated infections: CMV commonly, HBV, HCV,
VZV
CMV: Responds to Ganciclovir.
E). Mononeuropathies






uncommon , can involve either cranial
or peripheral nerves.
C/P : acc.to the specific nerve involved.
Wrist or foot drop, facial paralysis,
sensorineural hearing loss, and
diaphragmatic paralysis have all been
reported.
Etiologies: infection, immunologic
disease, and compression.
Acute HIV infection associated with
bilat facial palsies in setting of CSF
pleocytosis.
Late-stage AIDS, facial palsy is more
commonly due to VZV or meningeal
lymphomatosis.
Compressive neuropathies b/c
cachexia/external compression from
tumors, as KS. Commonly median,
ulnar, and peroneal nerves.
F). Autonomic dysfunction



Continuum- early to later stages of HIV infection.
76 to 84 % have > 1 abnormality, irrespective of CD4 count
+/- involv. central or peripheral autonomic pathways.Sxs~to
non-HIV pt.
 Pathogenesis: HIV or a virus-host interaction in early stage
+/- medications: TMP/SMX, vincristine, & pentamidine
H). Other Peripheral Neuropathies in HIV//
-Herpes zoster radiculitis : ipsilateral foot drop.
-Sensory ganglioneuritis -acute or subacute multimodality
sensory loss.
-Motor neuron disease syndrome — an illness very similar
to MND with subacute onset of muscle atrophy, weakness,
& fasciculations.
-Brachial plexopathy
V)MYOPATHY

Causes:
– HIV myopathy
– Toxic myopathy-ZDV/ NRTI
– AIDS cachexia (wasting syndrome)
– Infectious- toxo
– Other muscle disorders: rhabdomyolysis, NHL,
myasthenia gravis, nemaline (rod) myopathy
 Severity : range
Asxic increase in CK – more severe subacute syndrome Xed
by proximal ms weakness & myalgias
Both inflammatory and noninflammatory pathologic
processes: myofiber necrosis with inflammatory cells,
nemaline rod bodies, cytoplasmic bodies, mitochondrial
abnormalities.
1. POLYMYOSITIS

Occurs- at initial infection ,dysimmune or as IRS

Presentation: Proximal weakness, myalgia (less common)

HIV induces fibers to express MHC-I(CD 8 T cells & muscle cells) :
triggers cell mediated fiber injury

Dx:
– Muscle enzymes (CK)- 10x
– EMG : myopathic motor unit; Typical of inflammatory myopathy
– Biopsy: -


Rx: Prednisolone- motor recovery & pain relief
Prognosis: better than idiopathic PM
DDx: NRTI myopathy
Biopsy of Polymyositis…
-Fiber
degeneration
& size
variability
-Endomysial
infiltrates
2. NRTI (Zidovudine) myopathy

Mitochondrial disorders : interfere with the function of
mitochondrial polymerases
 Usually affects Pts who have taken for > 6 months
 Dose dependent
 Insidious onset of proximal muscle weakness, myalgia
 Reversible ff d/c of the drug



Dx:
– Creatinine kinase N or increases upto 10x
– Biopsy:
 Mitochondrial dysfunction (excessive or abn.
mitochondria)
 No inflammatory pattern-red ragged fibers (hallmark)
Rx:
– Withdrawal or dose reduction
DDx: Idiopathic PM and HIV myopathy
References

Uptodate-15.1
 Harrison’s textbook of medicine-16th edition
 HIV,Christina M.Marra,Infectious diseases
in Neurology
 Internet Sources
Thank You