Neurologic Disease in the HIV Patient

OVERVIEW: What every practitioner needs to know

Are you sure your HIV patient has neurologic disease? What should you expect to find?

Common presentations of neurologic disease in HIV patients

Symptomatic presentations by anatomical location

Clinical presentation of neurologic disease in HIV patients varies depending on the anatomical location of the problem.

Brain (chronic) – cognitive complaints are common in HIV patients. Symptoms are typically slowly progressive and associated with behavioral change (e.g. apathy or withdrawal), and motor abnormalities (e.g. slowness of movement, gait disorder). Sometimes family members are more aware of the problem than the patient and report impairment in activities of daily life.
Brain (subacute) – symptoms can be grouped into 3 main categories:
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Altered mental status without specific neurologic symptoms

Diffuse brain symptoms

Focal brain symptoms
Seizures can accompany any of these symptom complexes because both primary brain pathology and systemic conditions (e.g. alcohol withdrawal, hypoglycemia) can cause seizures. A focal seizure, i.e. one that begins in a particular part of the body, is more suggestive of primary brain pathology than a seizure that appears generalized from the beginning.
Diffuse brain symptoms are not referable to a specific localization and include headache, alteration in mental status, nuchal rigidity, photophobia and generalized seizures.
Focal brain symptoms depend on the location of the dysfunction within the brain. Examples include:

Right hemisphere: left sided weakness and numbness, loss of vision in parts of the left visual field, “neglect” of the left side of the body and objects to the left of the patient

Left hemisphere: right sided weakness and numbness, loss of vision in parts of the right visual field, difficulty speaking and understanding language

Basal ganglia: muscle rigidity, slowness of movement, tremor

Brainstem: complicated and strange combinations of neurologic symptoms (due to the close location of many functionally disparate structures), e.g. right facial numbness, left body/limb numbness, poor coordination in the left arm and leg, dysarthria, and vertigo (all at once).

Cerebellum: gait imbalance, impairment in limb coordination (patients may complain that a hand or leg is not doing what they want)
Brain (acute)- the etiology of acute brain dysfunction (e.g. altered mental status, focal neurologic deficits) in an HIV-patient is often not directly related to HIV (e.g. stroke, bacterial meningitis, intoxication/withdrawal, metabolic derangement). These syndromes are addressed elsewhere.
Spinal cord (myelopathy)- symptoms of myelopathy vary depending on the spinal cord level involved. In HIV, myelopathy typically involves the thoracic spinal cord. Patients experience slowly progressive weakness and stiffness in the lower extremities accompanied by bowel and bladder dysfunction. A “sensory level” below which sensation is diminished or absent may also occur, typically on the torso. Sometimes there are no sensory complaints. If higher levels of the spinal cord are involved patients may have similar symptoms in the arms.
Peripheral nerve- HIV-associated distal symmetric polyneuropathy (HIV-DSP) is among the most common neurologic complications of HIV. Patients may complain of one or more of the following symptoms in the feet: numbness, pain, pins and needles, tingling, hypersensitivity to touch. In more severe cases the legs and/or hands may also be involved. Patients do not usually report weakness. More rarely, HIV patients may exhibit other patterns of peripheral nerve disease (see ).
Muscle – the main symptom of muscle disease (myopathy) in HIV is proximal weakness, which may be associated with myalgia. The patient may report difficulty performing activities such as climbing stairs, arising from a low seat or holding the arms over the head. Lack of sensory abnormalities is an important clue.

Key diagnoses based on symptomatic presentation

Brain (chronic) – slowly progressive cognitive impairment will most often be due to HIV-associated neurocognitive impairment (HAND), however the differential diagnosis includes:

Brain lesions (e.g. toxoplasmosis, primary CNS lymphoma, progressive multifocal leukoencephalopathy)

Cytomegalovirus encephalitis

Neurosyphilis

Reversible causes of dementia (e.g. hypothyroidism, vitamin B12 deficiency)

Dementia related to substance abuse or head trauma

Dementia unrelated to HIV (e.g. Alzheimer’s or vascular dementia in older patients)

Brain (subacute) – sub-acute altered mental status without specific neurologic symptoms is typically due to systemic illness (as listed here). However, it is possible to have primary brain disease without specific symptoms, so the differential diagnoses listed under diffuse and focal brain symptoms should also be considered.

Systemic infection (sepsis, pneumonia, UTI)

Intoxication or withdrawal from substances of abuse, vitamin deficiencies in substance use (particularly thiamine in alcoholics)

End organ disease (uremic or hepatic encephalopathy)

Non-convulsive status epilepticus (NCSE). Continuous or intermittent seizure activity can cause altered mental status without obvious clinical signs of seizure. NCSE can be triggered by any of the above systemic illnesses or may arise spontaneously in patients with epilepsy or structural brain disease.
Brain (subacute) -sub-acute diffuse brain symptoms may be due to:

Cryptococcal meningitis

Cytomegalovirus encephalitis

Neurosyphilis

Brain (subacute) – sub-acute focal brain symptoms may be due to:

Cerebral toxoplasmosis

Primary CNS lymphoma (PCNSL)

Progressive Multifocal Leukoencephalopathy (PML)

Toxoplasmosis and PCNSL often also cause headache because they are mass lesions, whereas PML does not because it is infiltrative. In patients with high CD4 counts, non-HIV-related etiologies such as metastatic or primary brain tumors are more likely than the conditions listed above.

Spinal cord (myelopathy)

HIV-associated vacuolar myelopathy (HIVM)

Structural compressive lesion (e.g. epidural abscess, disc herniation)

Other viral infections (HTLV-I, VZV, HSV)

Vitamin deficiency (B12 and rarely copper)

HIV, HTLV-I and vitamin deficiencies typically cause slowly progressive symptoms, whereas structural causes and viral myelitis are more acute.

Peripheral Nerve – distal symmetric polyneuropathy (DSP).See for etiologies of other patterns of peripheral nerve disease.

HIV-associated DSP

Other causes

Neurotoxic antiretrovirals (di-deoxycytidine ,stavudine, didanosine – none of these are widely used anymore)

Diabetes Mellitus

Substance abuse

Muscle

HIV-associated myopathy

Other causes

Hypothyroidism

Statin use (particularly simvastatin). Patients receiving protease inhibitors may be at higher risk.

Key physical findings based on symptomatic presentation

Brain (chronic) -a diagnosis of HIV-associated neurocognitive disorder (HAND) is best established by a comprehensive neurologic and neuropsychologic assessment. There are also very brief bedside tools, such as the HIV-dementia scale (HDS) that can be used for screening. We describe here an intermediate approach to diagnosing HAND based on its cardinal clinical features: cognitive impairment, behavioral/affective changes and motor abnormalities.

Cognitive assessment. It is important to consider what is likely to be normal for a patient population when assessing mental status. For example, in our inner city Harlem population, almost everyone knows the president, most people know the mayor, and almost no one knows the governor or vice-president. Some basic elements of the mental status examination are below:

Assessment of level of consciousness. Is the patient alert? If not, a detailed mental status examination is not useful. Rather causes of delirium should be sought (infection, metabolic derangement etc.).

Orientation. Traditionally “A&O x3” is recorded in the chart, referring to the patient’s ability to give his name, location, and the date. The meaningfulness of this notation is questionable. It is more useful to assess orientation by noting how well the patient can describe events relevant to his/her life such as medication names and dosages, or current events.

Memory and concentration.

Give the patient 3 words to remember. Ask the patient to repeat the words immediately and again in 3-5 minutes.

Test simple calculations (e.g. If you buy a carton of milk for $3.65 and you give the cashier $5.00, how much change should you get back?). Again, one must take educational level into account.

Ask the patient to interpret a proverb (e.g. sometimes people say ‘a bird in the hand is worth two in the bush.’ Have you ever heard that before? Can you tell me what it means?). This question is only fair for a native English speaker, who is familiar with the saying. In this example the “correct” response is an abstract one about value and uncertainty.

Motor impairment – weakness, increased muscle tone, brisk deep tendon reflexes, pathologic reflexes (snout, glabellar and Babinski signs), and slowed movements are associated with cognitive impairment in HIV.

Test strength in the limbs by asking the seated patient to perform the following motions against resistance: raise the elbows out to the side (like chicken wings), make tight fists with the hands, lift up the knees (one at a time), flex up the feet.

Test muscle tone by asking the patient to relax his arms and legs completely, making them as loose as possible. Move the upper limbs at the elbow and wrist joints and the lower limbs at the knee and ankle joints. The limb should move without excessive resistance.

Test the biceps deep tendon reflex by tapping the biceps tendon in the antecubital fossa with a reflex hammer and observe for flexion at the elbow. If you have no trouble eliciting this reflex and you are not a neurologist it’s brisk. Then tap the patellar tendon. If you are kicked it’s brisk.

Test for pathologic reflexes. Tap the patient’s forehead right between the eyebrows. It is normal for the patient to blink a few times and then stop. Continued blinking is abnormal and is called a glabellar sign. Tap the patient’s closed lips with your reflex hammer. Normally nothing happens. The abnormal snout reflex is present if the lips purse. Scrape the lateral foot gently and observe the response of the great toe. The abnormal Babinski sign is present if the great toe goes up when stroking the underside of the foot.

Test the speed of movements by asking the patient to tap his thumb and index finger together as rapidly as possible.

Test the gait by observing the patient walk normally and with one foot in front of the other (like a tightrope walker). Sober patients of relatively normal body habitus should be able to perform a tandem gait up until about the age of 65.

Behavioral/affective changes – The Beck Depression Inventory (BDI) is a quantitative instrument commonly used to screen for depressive symptoms. The questions below are adapted from the BDI.

Do you still feel interested in and get pleasure from the things you used to enjoy?

Do you feel bad about yourself?

Do you feel sad, discouraged, or irritable?

Have your eating or sleeping habits changed?

Brain (sub-acute), diffuse. Physical findings will vary based on the etiology. Reduced level of consciousness and nuchal rigidity are common and non-specific. The findings described below, if present, may provide a hint as to the specific etiology.

Papilledema. Blurring of the optic disc margins bilaterally is frequently seen on ophthalmoscopic examination in cryptococcal meningitis. This is due to increased intracranial pressure.

Nystagmus. Involuntary jerking eye movements can be caused by cytomegalovirus (CMV) encephalitis.

Brain (sub-acute), focal. Physical findings depend on the location of the lesion within the brain. Examples include:

Right hemisphere: left sided weakness and sensory loss, increased tone in the left arm and leg, brisk reflexes on the left, left Babinski sign, left visual field cut, “neglect” of the left side of the body and objects to the left of the patient.

Left hemisphere: right sided weakness and sensory loss, increased tone in the right arm and leg, brisk reflexes on the right, right Babinski sign, right visual field cut, aphasia.

Basal ganglia: masked facies, increased muscle tone, slowness of movement, tremor, involuntary movements.

Brainstem: complicated and strange combinations of neurologic signs (due to the close location of many functionally disparate structures), e.g. right facial numbness, left body/limb numbness, dysmetria in the left arm and leg, dysarthria, and nystagmus.

Cerebellum: wide based gait, inability to perform tandem gait, dysmetria in the arms and legs (tested by the finger-nose-finger and heel-knee-shin maneuvers).

Spinal cord (myelopathy).The physical findings described below are for a lesion at the thoracic level. Lesions at higher levels will produce analogous signs in the arms.

Lower extremity weakness

Lower extremity spasticity

Brisk deep tendon reflexes at the knees and ankles

Babinski signs

Gait abnormality. Some patients may be completely unable to walk. Others may have a “scissoring” gait, which is caused by spasticity.

Sensory level. The patient may be able to indicate a level below which sensation is abnormal. For a thoracic cord lesion this level will be located on the torso. The sensory level is best assessed with a sharp stimulus such as a clean pin or a broken cotton tipped applicator.

Peripheral nerve.Distal symmetric polyneuropathy will lead to the physical findings described below. See for physical findings in other patterns of peripheral nerve disease.

Decreased sensation to vibration, sharp and temperature in a distal distribution. Typically if deficits are present up to the knees, deficits will also be observable in the fingertips.

Ankle reflexes absent or diminished as compared to the knees.

Atrophy of the small muscles of the feet may be present in advanced cases.

Muscle

Proximal weakness. Test strength in the limbs by asking the seated patient to perform the following motions against resistance: raise the elbows out to the side (like chicken wings), make tight fists with the hands, lift up the knees (one at a time), flex up the feet. The proximal muscles tested by shoulder abduction and hip flexion will be weak, whereas the distal muscles tested by grip strength and foot dorsiflexion will be normal.

Muscle tenderness. Weak muscles may be tender to palpation.

Most other neurologic examination findings will be normal including: sensation, tone and reflexes.

Which individuals are of greater risk of developing neurologic complications of HIV?

At what level of CD4 count are patients at risk?

There are no hard and fast rules about what neurologic conditions can occur at what CD4 count, and most clinicians caring for HIV patients can give examples of patients who had diseases they shouldn’t have based on CD4 count alone. Accordingly the CD4 categories below are very broad and are meant as a rough guide.

Low CD4 count (e.g. less than 100-200). Below are conditions that occur almost exclusively in patients who are very immunocompromised.

Toxoplasmosis

Primary CNS lymphoma

Cytomegalovirus encephalitis

Cryptococcal meningitis

Borderline CD4 count (e.g. less than 500) -Progressive multifocal leukoencephalopathy is probably more common in patients with lower CD4 counts, but patients with less marked immunosuppression are still at risk
Any CD4 count. Below are conditions that may occur at any CD4 count.

Brain

HIV-associated neurocognitive impairment (HAND) occurs at any CD4 count but is more common in patients who have had a low CD4 nadir

Neurosyphilis

Dementia unrelated to HIV (e.g. due to hypothyroidism, vitamin B12 deficiency, substance abuse, head trauma, Alzheimer’s or vascular dementia)

Altered mental status due to systemic condition, intoxication or withdrawal from substances of abuse.

Non-convulsive status epilepticus (NCSE).

Myelopathy

Distal symmetric polyneuropathy (DSP)

Myopathy

Specific diseases that predispose patients to neurologic complications of HIV

Diabetes (predisposes to neuropathy)
Alcohol misuse (predisposes to neuropathy and dementia)
Poor nutritional status (predisposes to neuropathy and dementia)
Hepatitis C (predisposes to neuropathy if patient develops cryoglobulinemia; possible increased risk of dementia)

What laboratory studies should you order and what should you expect to find?

What laboratory studies should you order and what should you expect to find based upon the symptomatic presentation?

Slowly progressive cognitive impairment

Serum vitamin B12 levels, rapid plasma reagin (RPR) and thyroid-stimulating hormone (TSH)

Lumbar puncture (LP) is most useful in 2 scenarios:

If CD4 count is low: check CSF cell count and differential, glucose, protein, CMV PCR.

If patient is on antiretrovirals and viral load (VL) is undetectable (UD) in the blood, look for viral reservoir in CNS: check CSF cell count and differential, glucose, protein and HIV VL.

Neuroimaging (to rule out a mass lesion) and PT/PTT should be done prior to LP.

Altered mental status without specific neurologic symptoms

Comprehensive metabolic panel, CBC, blood alcohol levels, TSH, RPR, B12, urinalysis, urine toxicology.

EEG may be appropriate to r/o NCSE.

Consider LP if no other cause found. Neuroimaging (to rule out a mass lesion) and PT/PTT should be done prior to LP.

Brain (sub-acute), diffuse

Comprehensive metabolic panel, CBC, blood alcohol levels, TSH, RPR, B12, urinalysis, urine toxicology, serum cryptococcal antigen in patients with low CD4 counts.

LP (neuroimaging and PT/PTT prior to LP): check CSF cell count and differential, glucose, protein. Cryptococcal Ag, fungal culture and CMV and JCV PCR in patients with low CD4 counts. VDRL in patients with positive RPR in the blood.

Brain (sub-acute), focal

Toxoplasmosis antibodies in blood.

Spinal cord (myelopathy)

RPR, B12, HTLV I and II antibodies, Copper levels if at risk for malabsorption, Lyme Abs if exposed

HIV-associated distal symmetric polyneuropathy (HIV-DSP)

Comprehensive metabolic panel, HgbA1c, TSH, B12, serum immunofixation

Muscle

CK, anti-Jo-1, TSH. Consider ANA, RF.

Nerve conduction studies and EMG

What imaging studies will be helpful in making or excluding the diagnosis of neurologic disease in the HIV patient?

Imaging studies play an important role in the diagnosis of many of the neurologic complications of HIV. How do you decide which image to order? The main two imaging modalities used in neurology are computed tomography (CT) and magnetic resonance imaging (MRI).

In general, MRI provides much better visualization of neurologic structures and is the preferred modality. However MRI has some limitations:

they take longer (bad for the agitated or unstable patient)
they may be less available
some patients are unable to tolerate them due to claustrophobia
they are not suitable for patients with metal in their bodies (e.g. due to gunshot wounds or pacemakers).

When any of these limitations apply, CT may be preferred. CT is also preferred if the main indication is looking for blood (e.g. brain hemorrhage after trauma).

Both MRI and CT may be ordered with or without contrast. MRI and CT contrast are typically avoided in patients with renal impairment. Contrast is often indicated in HIV patients, particularly those with low CD4+ counts, because the differential diagnosis includes infectious or neoplastic diseases which are better visualized with contrast. Contrast should not be given for CT if the main indication is looking for blood because contrast and blood have a similar appearance on CT.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

When should consultation be obtained?

Neurologic consultation should be obtained for all patients with focal neurologic deficits. Although a neurologist with specific expertise in HIV is unlikely to be available in most settings, a general neurologist will be helpful to localize the lesion anatomically and work with the primary provider to develop a management plan.

What therapies should you initiate?

HIV-associated neurocognitive impairment (HAND). Antiretroviral therapy should be started if the patient is not taking it already. Consider use of CNS penetrant agents when possible, but antiviral potency and tolerance should be the primary considerations.

Antiretrovirals with a high CNS penetration: Zidovudine, Abacavir, Nevirapine

Antiretrovirals with intermediate CNS penetration: Stavudine, Lamivudine, Emtricitabine, Efavirenz, Amprenavir, Fosamprenavir, Atazanavir, Indinavir

Central nervous system (CNS) toxoplasmosis. The most common treatment is: pyrimathamine (200mg for one day, then 50-75mg per day) plus sulfadiazine (1-1.5g four times per day) plus leucovorin (10-25mg with each dose of pyrimethamine). Clindamycin can be used instead of sulfadiazine, in patients who are allergic to sulfa. Trimethoprim plus sulfamethoxazole is an acceptable alternative regimen.

Steroids may be used if there is significant mass effect, but doing so will create diagnostic uncertainty: if the patient improves it will be unclear whether the steroids or the antimicrobials were responsible; if the patient does not improve and requires brain biopsy, the pathology will be more difficult to interpret.

After 4-6 weeks of antimicrobial treatment the dose is often reduced, but secondary prophylaxis must be continued until CD4 count is stable above 200 for at least several months.

Primary CNS lymphoma. Antiretroviral therapy should be started if the patient is not taking it already. Use of CNS penetrant agents should be considered when possible. Further treatment should be provided in consultation with oncology.

Progressive multifocal leukoencephalopathy. Antiretroviral therapy should be started if the patient is not taking it already. Use of CNS penetrant agents should be considered when possible. PML may worsen after starting ART (Immune reconstitution syndrome or IRIS), but long time survival is improved, and there is no other proven treatment for PML. Some clinicians believe that mirtazepine may slow progression.

Neurologic complications of CMV. Three weeks of ganciclovir (5mg/kg intravenously twice daily) and foscarnet (60mg/kg every 8h or 90mg/kg every 12h) is recommended followed by oral valganciclovir until immune reconstitution is achieved.

Neurosyphilis. The recommended treatment for neurosyphilis is aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion, for 10–14 days.

Non-convulsive status epilepticus (NCSE). This is potentially a neurologic emergency and should be managed by a neurologist. A common treatment is lorazepam 2mg IVP followed by phenytoin 1000mg IV over 20 minutes. Phenytoin is not usually used after the acute period because of interactions with antiretrovirals.

Cryptococcal meningitis. Amphotericin B (0.7–1mg/kg/d) plus flucytosine (100mg/kg/d) for 2 weeks is recommended, followed by fluconazole (400mg/d) for a minimum of 10 weeks, followed by fluconazole 200mg/d as secondary prophylaxis.

HIV-associated vacuolar myelopathy. There is no proven treatment. A trial of IVIg (.4g/kg/day for 5 days) may be given, based on encouraging open label data.

Structural myelopathy due to a compressive lesion. This is a neurosurgical emergency. Dexamethasone 10mg IV can be given while awaiting emergent decompression.

HIV-associated distal symmetrical polyneuropathy (DSP). There are no neuroregenerative therapies. Treatment is focused on alleviating neuropathic pain, which can be difficult. Finding the best regimen is often a process of trial and error and sometimes more than one agent is necessary. Common treatments for neuropathic pain follow:

Gabapentin is often used as a first treatment because of its affordability, lack of interactions with antiretrovirals, few side effects, and wide dosing range. A common dose is 300mg qhs titrated up to tid over 1 week. One may escalate to 1600-2400mg/d in divided doses.

Pregabalin is very similar to gabapentin. If gabapentin is providing partial benefit, sometimes a switch to pregabalin improves symptom control. A common dose is 75mg bid, increasing to 300mg bid as needed and tolerated.

Duloxetine is a serotonin–norepinephrine reuptake inhibitor (SNRI). It is a good choice in patients with co-morbid depression or with more generalized body pains. Duloxetine is relatively contraindicated in patients with cirrhosis and should be used in caution with those co-infected with Hepatitis C. A typical starting dose is 30 mg daily increasing to 60 mg after 1 week. Patients may experience nausea when starting duloxetine but this is usually transient.

Amitriptyline and nortriptyline are tricyclic antidepressants (TCAs). They are sedating and are a good choice for patients with insomnia and for those whose symptoms are worse at night. A typical starting dose is 10-25mg at night. TCAs must be used with caution in the elderly and cognitively impaired because they may cause confusion.

CNS complications of herpes simplex virus (HSV) or varicella–zoster virus (VZV). Treatment is similar to HSV encephalitis: acyclovir 10mg/kg IV every 8 hours for 10-14 days followed by oral suppressive therapy.
HIV-associated myopathy is treated similarly to polymyositis in HIV-uninfected individuals with either IVIg (4g/kg/day for 5 days, approximately every 6 weeks as needed) or prednisone (e.g. 60mg daily to start and tapered to lowest dose as possible).

What empiric therapy should I initiate while diagnostic testing continues?

Most of the above conditions are not acute in presentation and so empiric therapy is not necessary or appropriate.

What other therapeutic modalities are helpful?

Physical therapy is often an important part of recovery from a neurologic insult, particularly when there is significant weakness in one or more limbs. In disorders of the central nervous system, such as myelopathy or progressive multifocal leukoencephalopathy (PML), there may be spasticity in the limbs that can be ameliorated with muscle relaxants or botulinum toxin.

What other manifestations of disease could arise that are causing neurologic disease in the HIV patient?

Sometimes HIV patients with a neurologic condition who are improving on treatment including antiretrovirals, suddenly worsen. In this scenario the immune reconstitution inflammatory syndrome (IRIS) should be considered. MRI imaging in IRIS shows new enhancement at the site of the old lesion and examination of the CD4+ count over time shows a rapid rise. IRIS is treated with corticosteroids.

How should I monitor the HIV patient with neurologic disease?

Serial clinical neurologic examinations are the most important tool for monitoring the patient with neurologic complications of HIV. The clinical examination will determine the need for further monitoring with diagnostic studies. Often patients with meningitis will require repeat LP to document response to therapy. In the case of cryptococcal meningitis, repeat LP is also helpful to relieve intracranial pressure in the patient with continued headaches or poor mental status. Typically patients with focal mass lesions will require repeat MRI after treatment to ensure resolution of the lesion.

Does neurologic disease in the HIV patient influence the use of specific antiretroviral therapy?

Neuro-AIDS conditions involving the CNS, in particular HIV-associated neurocognitive disorder, may benefit from an antiretroviral regimen that is CNS penetrant, although controlled data are being collected in a study. Examples of such antiretrovirals are listed below:

Antiretrovirals with a high CNS penetration: Zidovudine, Abacavir, Nevirapine
Antiretrovirals with intermediate CNS penetration: Stavudine, Lamivudine, Emtricitabine, Efavirenz, Amprenavir, Fosamprenavir, Atazanavir, Indinavir

Add what-if scenarios here:

What if a patient with a mass lesion in the brain fails to respond to treatment for toxoplasmosis? If the CD4 count is low, primary central nervous system lymphoma (PCNSL) is suspected. Thallium Single photon emission computed tomography (SPECT) or positron emission tomography (PET) should be performed and, if safe, a lumbar puncture for EBV PCR and cytology. If a diagnosis still cannot be made, imaging of the body (e.g. CT chest/abdomen/pelvis) should be considered to look for a systemic lesion that could be the origin of the brain lesion (e.g. lung cancer, pulmonary TB). If none of the above is helpful a brain biopsy may be necessary.

What other clinical manifestations may help me to diagnose and manage neurologic disease in the HIV patient?

What are less common symptoms that may arise in HIV patients with neurologic disease?

HIV-associated distal symmetric polyneuropathy (HIV-DSP) is among the most common neurologic complications of HIV. More rarely, HIV patients may exhibit other patterns of peripheral nerve disease. Two important patterns to recognize are cauda equina syndrome and focal neuropathies.

Cauda equina syndrome is characterized by weakness and numbness in the lower extremities accompanied by bowel and bladder dysfunction. Although these symptoms are similar to those caused by myelopathy, there is no muscle stiffness in cauda equina syndrome and sensory complaints may be more pronounced than in myelopathy.

Focal neuropathies present with weakness, numbness and often pain in the distribution of a particular nerve. In some cases multiple nerves may be involved. The location of the symptoms that a patient experiences depends on the nerves involved. Major nerves and symptoms that could be caused by their involvement are listed below:

Facial nerve: unilateral facial weakness without numbness, may be accompanied by sensitivity to noise and decreased taste on the same side
Median nerve: hand weakness, numbness in the thumb, pointer and middle fingers
Ulnar nerve: hand weakness, numbness in the pinky
Radial nerve: wrist drop, numbness in the back of the hand
Peroneal nerve: foot drop or weak ankle, numbness in the lateral calf
Sciatic nerve: flail foot, numbness in the lateral calf and sole of the foot
Femoral nerve: thigh weakness, numbness in the anterior thigh and medial calf

What are the differential diagnoses?

Cauda equina syndrome

CMV

Structural lesion

HSV-2

Lymphoma

Focal and multifocal neuropathies. The differential diagnosis for focal neuropathies varies depending on the number and distribution of nerves involved.

Facial neuropathy: Bell’s palsy, Ramsay-Hunt syndrome, Lyme disease

Mononeuropathy: Compression or entrapment.

Multifocal:

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is usually an autoimmune disorder

Mononeuropathy Multiplex can autoimmune or due to:

CMV

Vasculitis

Cryoglobulinemia (usually in the setting of Hepatitis C co-infection)

When should these diagnoses be sought?

These diagnoses should be sought if the following physical findings are present:

Cauda Equina Syndrome

Lower extremity weakness

Decreased or “flaccid” lower extremity tone

Poor rectal tone

Decreased of absent deep tendon reflexes at the knees and ankles

Gait abnormality. Some patients may be completely unable to walk depending on the degree of weakness.

Decreased sensation. Poor sensation will be noted in the involved dermatomes. For example, a lesion involving all the nerve roots at or below the level of L1 would cause sensory deficit from about hip level down.

Muscle atrophy in chronic cases.

Focal and multifocal neuropathies have a variable clinical examination which depends on the nerves involved. In chronic inflammatory demyelinating polyneuropathy (CIDP) the findings (weakness, numbness, decreased reflexes) tend to be symmetric and more confluent, involving both the proximal and distal limbs. Mononeuropathy multiplex tends to evidence more severe deficits, but in a more restricted, frequently asymmetric distribution. Table I provides examples of deficits caused by lesions of particular nerves.

What diagnostic tests should be obtained to make these diagnoses?

Cauda Equina Syndrome

MRI of the lumbosacral spine (LS) spine with and without contrast

Lumbar puncture (LP) for CSF cell count and differential, glucose, protein, CMV PCR (if CD4 count is low). Consider also EBV PCR/cytology if nerve roots abnormal in appearance on MRI or HSV2/VZV PCR.

Nerve conduction studies and electromyogram (EMG).

Facial neuropathy

MRI of brain, RPR and Serum Lyme Abs if exposure

Other mononeuropathy

Comprehensive metabolic panel, HgbA1c, TSH, B12, serum immunofixation

Nerve conduction studies and EMG.

Multiple mononeuropathies

Comprehensive metabolic panel, HgbA1c, TSH, B12, serum immunofixation, Also consider vasculitis workup (ANA, RF, ESR, c and p-ANCA, Hepatitis C abs, cryoglobulins, complement levels) if systemic signs.

Lumbar puncture (LP) for CSF cell count and differential, glucose, protein, CMV PCR (if CD4 count is low).

Nerve conduction studies and EMG.

How should these diseases be treated?

Bell’s palsy. Current guidelines recommend treatment with a short course of oral steroids (such as a prednisolone dose pack). The addition of an oral antiviral (e.g. valacyclovir 1000 mg bid for 7-10 days) is probably prudent in the HIV-positive patient.
Mononeuropathy due to compression or entrapment. Physical protection of the nerve is indicated, e.g. neutral wrist splints for carpal tunnel syndrome. Referral to neurology for further management.
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). CIDP is usually treated with IVIg as the first line (4g/kg IV daily for 5 days). Prednisone is also effective but should be used with caution in immunosuppressed patients.
Neurologic complications of CMV. Ganciclovir (5mg/kg intravenously twice daily), consider addition of foscarnet (60mg/kg every 8 h or 90mg/kg every 12h).

When can I manage these complications as an outpatient, and when should I hospitalize my patient?

Patients with progressive neurologic symptoms should be hospitalized to expedite evaluation and avoid irreversible damage.

How can diseases that cause the symptoms be prevented?

Maintenance of good immune function with antiretroviral therapy is the most important preventative measure. Secondary prophylaxis with oral valganciclovir is important for patients who have had neurologic complications of CMV and do not have adequate immune reconstitution.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Letendre, SL, McCutchan, JA, Childers, ME. “Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders”. Ann Neurol. vol. 56. 2004. pp. 416-423.

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