Neurological complications of HIV

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Neurological complications of HIV

• Will Chegwidden, Senior Occupational Therapist
  Emma McGettigan, Senior Physiotherapist
• Infection Immunity Speciality Group
• Barts Hospital
• August 2005

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Outline of session

• Classification of HIV impairment and HIV
  neurological impairment
• Neuropathogenesis of HIV
• CNS involvement
• PNS involvement
• Issues for therapists and discussion

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Classification system

• To understand how neurological impairment occurs
  in HIV, it is helpful to use a classification
  system of how impairment occurs generally in HIV
  disease
• One way is to divide in to the following five
  categories
• Opportunistic Infections
• Malignancies
• Auto-immune and reconstitution diseases
• Constitutional disease
• Other /multi-factorial / poorly understood

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How being HIV leads to illness or impairment

• OIs Immunosupressed state renders individual
  susceptible to infections / illnesses
  opportunistic infections (most widely
  understood)
• Autoimmune diseases and reconstitution diseases
  where the immune system is overactive e.g.
  joint disease (not fully understood)
• Malignancies Some malignancies much more
  prevalent with HIV unsure why, some links to
  other viruses
• Constitutional Disease The action of HIV at
  cellular level directly causing illness
  constitutional symptoms (not fully understood)

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Disease groupings

• OIs
• Viral Infections (CMV, HSV, PML, HPV)
• Bacterial Infections (TB, MAI, Salmonella)
• Protozoal Infections (PCP, Toxoplasmosis)
• Fungal Infections (Cryptococcyl Meningitis,
  Candida)
• Malignancies (KS, CNS lymphoma, Burketts, MCD)
• Autoimmune diseases (Arthraligias, GBS)
• Constitutional Conditions (HIVE/HAD/ADC, DSPN,
  Wasting Syndromes)

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Neuropathogenesis

• Neurological impairment can occur through several
  routes
• As a result of opportunistic infections
• As a result of HIV related malignancies
• As a result of autoimmune disorders
• Directly related to the action of HIV (can be CNS
  or PNS related)
• Multifactorial / drug related / not understood

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Opportunistic infections with CNS involvement

• Cerebral toxoplasmosis
• PML
• Meningitis (Cryptococcyl meningitis, TB
  meningitis)
• Encephalitis (CMV, HSV, VZV)
• Neurosyphilis

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2. HIV related malignancies withneuro involvement

• Primary lymphoma (most common)
• Kaposis sarcoma with cerebral involvement (rare)
• Multiple lymphomas with either CNS (including
  spinal cord compression) or rarely PNS
  involvement (ie secondary CNS/PNS lymphomas)

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3. Autoimmune disorders withneuro involvement

• Guillain-Barré Syndrome (GBS)
• Inflammatory Demyelinating Polyneuropathy (IDP)

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4. Direct action of HIV

• AIDS Dementia Complex (ADC) or HIV Associated
  Dementia (HAD)
• Distal Symmetrical Polyneuropathy (DSPN)
• Mononeuritis multiplex
• Vacuolar Myolopathy
• ?Wasting Syndromes (although cardiac system now
  implicated more)

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5. Multifactorial / drug related / poorly
understood

• Neuromuscular weakness syndrome
• Role of drugs in peripheral neuropathy

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Direct action of HIV in the CNS

• HIV can easily cross the blood brain barrier
• HIV thought to chiefly target phagocytic
  macrophages, but also astrocytes, microglia and
  monocytes
• Do not affect directly affect CNS neurons or
  oligodendrocytes

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Theories of how HIV crosses the blood brain
barrier

• Different theories including
• Infected monocytes and lymphocytes traffic across
  the BBB as part of their normal immune
  surveillance role
• Blood brain barrier weakened by this process
  leading to increased trafficking
• Monocytes differentiate in to microglia and
  macrophages

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Theories of how HIV crosses the blood brain
barrier

• Also theory that meningeal macrophages infiltrate
  the CNS through the CSF compartment
• May also be a combination of these processes
• Neurotoxic viral proteins released in to CNS by
  HIV infected cells resulting in neuronal injury
  / death

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Direct action of HIV in the PNS

• Thought that HIV cells can lead to axonal
  degeneration (resulting in DSPNs)
• Thought that HIV can lead to inflammation /
  demylination (resulting in inflammatory
  demyelinating neuropathies)

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Principles of HIV Neurology

• Time Locking Neurological compliocations are
  directly related to the duration of HIV disease,
  degree of advancement of HIV disease
• Parallel Tracking Existence of muliple
  pathologies in different parts of the nervous
  system (cerebral, spinal cord, peripheral nerves)
• Layering multiple complications in one part of
  the nervous system
• Unmasking previously compensated deficits may
  be unmasked by occurrence of an additional insult

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Presentations

• Vary wildly
• Often multiple pathologies on different courses
• Often hard to diagnose, especially if already
  treated empirically
• May not be HIV related!

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Conditions

• Now going to present the most commonly seen
  conditions at BLT
• Would be good to share all our experience on
  prevalence, experience of treating and
  progression of disease
• We can collate and feed back to therapists who
  arent able to attend, especially those outside
  of London

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HIV and CNS involvement
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Cerebral Toxoplasmosis

• Most common CNS impairment seen in HIV
• Is a reactivation of a latent protozoal infection
• Can also affect myocardium, lung skeletal muscle
• Generally presents as multiple enhancing lesions
  with perifocal oedema in the basal ganglia and
  grey-white matter interface of the cerebral
  hemispheres, although can be in any part of brain

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Toxoplasmosis
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Toxoplasmosis

• Common signs and symptoms
• Headache, fever
• Confusion
• Lethargy
• Seizure (may be initial clinical manifestation)
• Focal neurologic signs (50-60 of HIV-infected
  cases)
• Usually hemiparesis or visual field defects
• Treatment
• Antio-toxo drugs Sulfadiazine, pyrimethamine,
  clindamycin, pyrimethamine, folinic acid

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Toxoplasmosis

• Usually responds well to treatment
• Usually the worse the initial presentation, the
  longer the recovery may have some long term
  residual deficits
• Can sometimes have multiple small lesions which
  present with quite specific / unusual sensory /
  motor / cognitive symptoms

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Toxoplasmosis

• Therapy usually treat what you assess
  relearning gait / UL movement through normal
  movement approach cognitive rehab use of
  functional activity etc.
• Need to be aware of visual field deficits
• Great to work with as generally will recover
• ?Impact of early intervention usually recover
  quickly at first may be more important where
  tone / positioning is an issue

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PML Progressive Multifocal Leukoencephalopathy

• Used to be more common and was nearly always
  fatal now not seen that often
• Is a reactivation of a latent JC virus (due to
  immunosuppression) often seen more in more
  severely immunocompromised people
• Appears as patchy white matter on scans, often
  bilateral, asymmetrical scalloped lesions in
  sub-cortical white matter, often in parietal lobe
• Usually gradual onset

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PML Progressive Multifocal Leukoencephalopathy

• Common presenting symptoms and signs
• Hemiparesis
• Gait abnormality
• Speech disturbances
• Cognitive dysfunction
• Dysarthria
• Ataxia
• Sensory loss
• Vertigo
• Visual impairment

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PML Progressive Multifocal Leukoencephalopathy

• No specific PML treatment aim is to improve
  immune health therefore usually treatment is with
  ARVs (although cidofovir sometimes used)
• Still often fatal survivors tend to have
  residual dysfunction in some or all of the
  presenting deficit areas

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PML Progressive Multifocal Leukoencephalopathy

• Therapy approach is again to treat what you find
  in more advanced disease may need to look at
  positioning to discourage poor movement or even
  prevent contracture or looking at managing
  advanced dementia / behaviour
• If patient does survive may require some
  compensation on discharge e.g. supervision,
  wheelchairs etc.

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Cryptococcyl meningitis, TB meningitis

• Both quite common presentations
• Crypto caused by fungal infection
• TB may also cause focal lesions as well as the
  menigitis
• Both may or may not have other systemic illness
  associated e.g. Cryptococcosis, TB lung, spine,
  miliary TB

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Cryptococcyl meningitis, TB meningitis

• Symptoms
• Headache (without focal signs)
• Fever
• Altered mental status
• Nausea and/or vomiting
• May have some focal deficits, cranial nerve
  features
• Therapy input may be around focal deficits /
  cranial nerve involvement patients also
  typically become deconditioned and lack balance
  as they recover so often benefit from general
  functional / activity tolerance approach

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Cryptococcyl meningitis, TB meningitis

• Crypto treated with IV amphotericin / fluconazole
• TB treated with standard TB therapy
• Both generally respond reasonably well crypto
  quite often relapses a few times before treated
  successfully
• Either sometimes may require a shunt top
  effectively manage the raised ICP

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CMV Encephalitis (and others)

• CMV cytomegalovirus
• Quite common CMV encephalitis is a reactivation
  of latent CMV infection - features cell death in
  meninges and peri-ventricular area
• Often associated with a CMV retinitis
• Rapidly progressing responds well to treatment
  if caught in time otherwise responds poorly

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CMV Encephalitis (and others)

• Treatment is usually IV ganciclovir,
  valganciclovir, foscarnet, cidofovir these
  drugs can be quite toxic
• Presentations vary, however usually involve
  confusion, headache, delirium
• Can have focal neurology, cranial nerve deficits

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CMV Encephalitis (and others)

• Therapy approach again is treat what presents
  often complicated by permanent visual field loss
• Other encephalitis presentations include HSV
  (Herpes Simplex Virus) and VZV (Varicellar Zoster
  Virus)

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Primary CNS Lymphoma

• 1000-4000 times more common in HIV population
  than in immunocompetent population
• Doesnt correlate with low CD4 counts
• Pathogenesis not fully understood but known to be
  linked to the Epstein-Barr Virus
• Thought that long term low level immune system
  damage may be contributing factor

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Primary CNS Lymphoma

• Is generally non-Hodgkins B-cell type with high
  mitotic rate tumours usually double in size in
  14 days. (can also be a Burkitt or more rarely a
  Primary Effusion Lymphoma)
• Can be multifocal (50) and appear in uncommon
  locations with greater frequency than in non-HIV
  population
• Studies have average survival rates from
  diagnosis between 3 and 24 months
• May be treated actively or palliatively with
  radiotherapy (usually palliative) or high dose
  methotrexate (chemo)

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Primary CNS Lymphoma

• Disagreement between researchers whether
  discontinuing or continuing ARVs throughout
  treatment is most beneficial
• Therapy input is usually initially around advice
  / treatment to help maintain function /
  independence and planning for deterioration /
  palliative approach

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HIV EncephalopathyHIVE / ADC / HAD

• Number of terms used overlappingly to describe
  poorly understood syndromes of long term
  infiltration of HIV into the CNS
• Names include
• HIV-1-associated dementia complex (HAD)
• AIDS Dementia Complex (ADC)
• HIV encephalitis / HIV Encephalopathy (HIVE)
• multinucleated giant-cell encephalitis

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HIV EncephalopathyHIVE / ADC / HAD

• Can be seen in early disease but more common
  later
• Severe form less common since the introduction of
  HAART
• Many long term diagnosed however do report mild
  cognitive problems e.g. memory problems, and show
  some general brain atrophy on scans
• On scans often higher concentrations changes in
  the basal ganglia - ?due to numbers of microglia
  in the brain thought to be why high rates of
  extra-pyramidal signs / symptoms seen

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HIV EncephalopathyHIVE / ADC / HAD

• Symptoms generally develop over weeks to months
  in the following domains
• Cognition
• Decreased concentration
• Forgetfulness, particularly daily or recent
  events
• Slowing of thought processes
• Global dementia
• Psychomotor slowing verbal responses delayed,
  near or absolute mutism, vacant stare
• Unawareness of illness, disinhibition
• Confusion, disorientation
• Organic psychosis

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• Motor function
• Unsteady gait
• Clumsiness
• Tremor
• Leg weakness (legs more than arms)
• Loss of coordination, impaired handwriting
• Behaviour
• Social withdrawal
• Apathy
• Personality change
• Agitation
• Hallucinations
• Other
• Headaches
• Generalized seizures
• Ataxia

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HIV EncephalopathyHIVE / ADC / HAD

• Treatment is via reducing viral load and viral
  activity in the CNS, therefore treatment is
  primarily HAART
• Need to consider ARVs with best CNS penetration
  e.g. zidovudine (AZT), abacavir, nevirapine
• Difficult to measure drug levels as not known
  whether CSF drug levels always correlate with
  cerebral levels (not practical to brain biopsy!)

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HIV EncephalopathyHIVE / ADC / HAD

• Therapy input more akin to treating someone with
  dementia early treatment may be looking at
  memory strategies later stages may require
  behavioural management and reality orientation /
  validation
• Severe HIVE may require 24 hour supervision

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Vacuolar Myopathy

• Holes in spinal cord
• Clinical Features onset over weeks-months of
• Bilateral lower extremity stiffness and weakness
  with variable sensory disturbances
• Gait unsteadiness
• Bladder and erectile dysfunction
• Hyperreflexia and Babinski signs
• Spastic paraparesis with no definite sensory
  involvement
• Loss of proprioception and vibration sense
• Thought to be secondary to overactive immune
  system producing excessive cytokines, or some
  poorly understood metabolic imbalance may be
  related to HTLV-I and HTLV-II

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HIV and PNS Involvement
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DSPN Distal Symmetrical Sensory Polyneuropathy

• Occurs in many HIV patients with varying
  severity
• Poorly understood aetiology but could be related
  to malnutrition and resultant wasting of
  peripheral nerves, or could be neurotoxic effect
  of cytokines
• Can also be secondary to NRTI use e.g. AZT

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DSPN

• Often occurs in a glove and stocking distribution
  but there is great variance in self report
• Can range from mild parasthesia / numbness / pins
  and needles through to severe hypersensitivities,
  or dysesthesias (burning, stabbing pain)
• Can lead to poor upper limb coordination or
  mildly impaired mobility / clumsiness,
  attributable to reduced sensory feedback

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DSPN

• Can progress to actual muscle weakness,
  particularly foot intrinsics (result of long term
  de-inervation)
• Sometimes use EMG studies to diagnose
• Often treated with quite high dose analgesics
  which can interact with other medications or have
  lifestyle implications
• Can be very disabling

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DSPN

• Therapy input can be looking at
• Psychogenic management of pain e.g. relaxation
• Task planning how to avoid parts of tasks that
  elicit pain
• Safety aspects e.g. temperature sensation,
  retraining to be aware of feet catching on stairs
• Padded / built up equipment to reduce / alter
  sensory input to help mange pain, or provide more
  gross proprioceptive feedback

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Inflammatory Demyelinating Polyneuropathy (IDP)

• IDP, and its more severe cousin Gullain- Barre
  Syndrome sometimes occur acutely in otherwise
  well HIV patients, or in HIV patients with
  advanced disease.
• Seems to be some sort of auto-immune response
  that attacks the myelins sheath mechanism is
  poorly understood
• Treated with IVIg

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(Ascending) Neuromuscular Weakness Syndrome

• Presents as rapidly progressing sensorimotor
  neuropathy, can lead to respiratory failure
• Thought to be related to NRTI use

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Mononeuritis Multiplex

• Can present as multifocal sensory and/or motor
  abnormalities and is due to asymmetrical
  involvement of individual peripheral and cranial
  nerves may be a mixed neuropathy (motor,
  sensory, autonomic)
• Thought to be diectly related to action of HIV
• Poorly understood

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Issues for therapists
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Deciding on treatment approaches and techniques

• Not knowing what you are treating
• Unsure prognoses
• Multiple pathologies in one patient with
  differing courses
• Rehab versus compensation
• Evidence base
• Consent for treatment
• Flexibility

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Related issues that impact

• Stigma and confidentiality
• Impact of asylum and immigration
• Co-morbid drug use and other social issues
• Referring on to other facilities
• Placing young physically or cognitively impaired
  adults ?care in the community
• Infection control

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Solutions existing

• Strong MDT
• Therapists input to diagnosis vital
• Close working with partner agencies, e.g.
  community neurorehab teams, Queens Square,
  RNRUs
• HRBI Unit at Mildmay
• PT and OT HIV special interest groups
• Huge research opportunities
• Working with African and emerging populations
• The internet

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Brainstorm time

• What other experiences have people to share?
• What are the biggest challenges?
• What ideas for inpatient rehabilitation
  facilities and community rehabilitation do people
  have?
• Would people be interested in research?

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References / resources

• The National AIDS Manual information on
  presentations, illnesses and treatments
• www.hivinsite.com
• www.clinicaloptions.com
• www.nam.org.uk
• www.i-base.org.uk
• www.avert.org.uk
• www.unaids.com