AUTHOR INFORMATION

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Authored by Florian P Thomas, MD, MA, PhD, DrMed, Associate Chief of Staff, St Louis VA Medical Center; Associate Director, Neurology Residency Program; Professor, Departments of Neurology, Molecular Virology, and Molecular Microbiology and Immunology, Saint Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, DrMed, is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, Charcot-Marie-Tooth Association, and National Multiple Sclerosis Society

Edited by Daniel H Jacobs, MD, Clinical Associate Professor, Department of Neurology, University of Florida; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCar; Consulting Staff, Barnes Jewish Hospital; Selim R Benbadis, MD, Professor of Neurology, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa General Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Florian P Thomas, MD, MA, PhD, DrMed
Editor's Email:	Daniel H Jacobs, MD

eMedicine Journal, May 3 2006, VOLUME 7, Number 5

INTRODUCTION

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Background: Multiple peripheral mononeuropathies can occur in the setting of HIV-1 disease. The presentation can be similar to multiple mononeuropathies in the non-HIV population.

Pathophysiology: These neuropathies are typically inflammatory in nature and may involve single or multiple cranial or peripheral nerves. EMG and nerve conduction studies show asymmetric multifocal involvement with axonal degeneration, and CSF will show elevated protein level and pleocytosis. They vary with the stage of HIV infection. Early multiple mononeuropathy (MM) is usually self limited. Late MM in a patient with a CD4 count <50 is usually related to CMV infection and can progress rapidly; PCR for CMV should be sent if HIV-associated MM is suspected. Anti-CMV therapy must be initiated. The practitioner should also consider complications of herpes or lymphoma when treating this disease.

Mortality/Morbidity: Mortality and morbidity are dependent on the etiology.

• The autoimmune form may undergo spontaneous remission or respond to immunomodulation, especially when the condition presents early during HIV infection.

• The cytomegalovirus (CMV)-related form may respond to ganciclovir and/or foscarnet if started expeditiously.

CLINICAL

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History: The patient describes multifocal asymmetric sensory and motor complaints in the distribution of cranial nerves, peripheral nerves, or nerve roots.

Physical:

• Physical findings include asymmetric weakness and reflex and sensory loss.



• More severe involvement suggests CMV.



• Progression may change presentation from multifocal mononeuropathies to a more generalized polyneuropathy.

Causes: A limited form (1-2 nerves) presents in HIV-seropositive patients without AIDS and may have an autoimmune origin.

A more generalized form (>2 nerves) presents in patients with AIDS. While CMV is often shown to be the cause, the occurrence of clinical CMV in AIDS has declined with the advent of highly active antiretroviral therapy several years ago.

DIFFERENTIALS

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Cervical Spondylosis: Diagnosis and Management
Diabetic Neuropathy
Median Neuropathy
Peroneal Mononeuropathy
Polyarteritis Nodosa
Radial Mononeuropathy
Traumatic Peripheral Nerve Lesions
Ulnar Neuropathy
Vasculitic Neuropathy

Other Problems to be Considered:

Cervical disk syndromes

WORKUP

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Lab Studies:

• Cerebral spinal fluid


• • Nonspecific
  
  
  
  • Mononuclear pleocytosis
  
  
  
  • Elevated protein
  
  
  
• Electromyography/nerve conduction studies


• • Reduced amplitudes of sensory nerve and compound muscle action potentials
  
  
  
  • Mildly reduced conduction velocities
  
  
  
  • Denervation
  
  
  
  • Asymmetric distribution
  
  
  
• Correlation with stage of HIV infection and CD4⁺ lymphocyte counts


• • More than 200 in patients with the limited autoimmune form
  
  
  
  • From 50-200 in patients with more widespread involvement related to autoimmunity
  
  
  
  • Less than 50 in patients with the more widespread form and evidence of CMV infection
  
  
  

Procedures:

• Nerve biopsy

TREATMENT

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Medical Care:

• Intravenous immunoglobulin (IVIG) and plasmapheresis (plasma exchange) are preferred to immunosuppression.



• During a 7- to 10-day period, 4-5 plasmaphereses may be performed, as described in standard protocols. Potential complications include autonomic instability, hypercalcemia, and bleeding from depletion of clotting factors.



• Base the decision to use IVIG, plasmapheresis, or steroids on the individual patient.

MEDICATION

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The more extensive disease state, resulting from CMV, can be treated with ganciclovir and/or foscarnet if instituted early. Conversely, the limited autoimmune form can be treated with IVIG, plasmapheresis, or steroids. These treatments have proven efficacious in some studies but not in others.

Drug Category: Antivirals -- Goal is to shorten the clinical course, prevent complications, prevent the development of latency and/or subsequent recurrences, decrease transmission, and eliminate established latency. These agents usually inhibit DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase.

Drug Name	Ganciclovir (Cytovene) -- A synthetic guanine derivative active against CMV; an acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses. Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of a preferential phosphorylation of ganciclovir in virus-infected cells. In patients who experience progression of CMV retinitis while receiving maintenance treatment with either dosage form of ganciclovir, administer the reinduction regimen.
Adult Dose	5 mg/kg IV bid for 14 d Maintenance: 5 mg/kg IV qd for 5-7 d/wk 500 mg PO q4h or 1 g PO tid for life
Pediatric Dose	<3 months: Not established >3 months: Administer IV regimen as in adults
Contraindications	Documented hypersensitivity
Interactions	Concomitant administration with cytotoxic drugs (eg, dapsone, pentamidine, flucytosine, vincristine, vinblastine, Adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations) or other nucleoside analogs may have additive toxicity in replication of rapidly dividing cells (eg, bone marrow, spermatogonia, germinal layers of skin and GI mucosa); consider concomitant use of these drugs only if benefits outweigh risks; may cause generalized seizures in patients who receive ganciclovir and imipenem-cilastatin concurrently, use only when benefits outweigh risks; serum creatinine may increase following concurrent use of ganciclovir and either cyclosporine or amphotericin B In presence of probenecid, renal clearance is reduced; when didanosine is administered 2 h before or simultaneously with ganciclovir, its bioavailability may increase; conversely, the steady-state bioavailability of ganciclovir may decrease when didanosine is administered 2 h before ganciclovir but not when the 2 drugs are administered simultaneously; bioavailability of ganciclovir may decrease in presence of zidovudine; conversely, bioavailability of zidovudine is increased in the presence of ganciclovir; since both drugs can cause granulocytopenia and anemia, combination therapy at full dosing may not be possible
Pregnancy	D - Unsafe in pregnancy
Precautions	Clinical toxicity includes granulocytopenia, anemia, and thrombocytopenia; since PO ganciclovir is associated with a higher rate of CMV retinitis progression as compared to IV formulation, use only when benefits outweigh risks (eg, in advanced HIV disease); caution in patients with renal impairment, since half-life and serum concentrations may increase because of reduced renal clearance; dosages > 6 mg/kg IV can result in increased toxicity; rapid infusions also may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH of 11; phlebitis or pain may occur at the infusion site despite further dilution in IV fluids; accompany administration of ganciclovir with adequate hydration; photosensitization (photoallergy, phototoxicity) may occur and thus caution patients against UV or sunlight exposure until tolerance develops

Drug Name	Foscarnet (Foscavir) -- Organic analog of inorganic pyrophosphate that inhibits replication of known herpes viruses in vitro, including CMV; exerts antiviral activity by selective inhibition at the pyrophosphate-binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases; consider viral resistance in patients with poor clinical response or persistent viral excretion during therapy.
Adult Dose	Induction: 60 mg/kg/dose IV q8h or 100 mg/kg IV q12h for 14-21 d Maintenance: 90-120 mg/kg/d as single infusion for life Patients who demonstrate excellent tolerance may benefit from initiation of maintenance treatment at 120 mg/kg/d earlier in treatment; individualize dosing according to patient's renal function
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Because of its propensity for renal impairment, avoid in combination with potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine) unless benefits outweigh risks; concomitant use with IV pentamidine may cause hypocalcemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Renal function usually declines; determine a 24-hour creatinine clearance at baseline and periodically thereafter to ensure correct dosing; discontinue if clearance drops below 0.4 mL/min/kg; hydration may reduce risk of nephrotoxicity; because of propensity to chelate divalent metal ions and alter levels of serum electrolytes, closely monitor electrolytes, including calcium and magnesium; quickly assess serum electrolyte and mineral levels of patients with symptoms of electrolyte abnormalities (perioral numbness or paresthesias, seizures); infuse foscarnet only into veins with adequate blood flow to permit rapid dilution and distribution and avoid local irritation; because of high incidence of granulocytopenia (17%) and anemia (33%), monitor blood counts regularly; do not administer by rapid or bolus IV injection; toxicity may increase from excessive plasma levels

Drug Category: Immune globulin -- Has demonstrated efficacy in treatment of autoimmune neuropathies and reduction in duration of hospitalization and need for mechanical ventilation.

Drug Name	Intravenous immune globulin (Gamimune, Gammagard, Gamunex) -- The following physiologic mechanisms may be relevant to the efficacy of IVIG: neutralization of circulating myelin antibodies through anti-idiotypic antibodies; downregulation of proinflammatory cytokines, including INF-gamma; blockade of Fc receptors on macrophages; suppression of inducer T and B cells and augmentation of suppressor T cells; blockade of the complement cascade; promotion of remyelination; 10% increase in CSF IgG.
Adult Dose	2 g/kg IV over 2-5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity, in patients with IgA deficiency and anti-IgE/IgG antibodies
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Consider checking serum IgA before IVIG and using an IgA depleted product (G-Gard-SD) if indicated; IVIG may increase serum viscosity and thromboembolic events; following adverse effects are associated with IVIG: migraine attacks; 10% increased risk of aseptic meningitis; increased risk of urticaria, pruritus or petechiae, 2-5 days postinfusion, which may last up to 1 mo; increased risk of renal tubular necrosis in older patients, patients with diabetes, volume-depleted patients, and patients with preexisting kidney disease The following changes in lab results are associated with IVIG: elevated antiviral or antibacterial antibody titers for 1 mo; 6-fold increased ESR for 2-3 wk; apparent hyponatremia

Drug Category: Glucocorticoids -- These agents modify the body's immune response to diverse stimuli. Possible mechanisms of action include stabilization of blood-nerve barrier, enhancement of nerve conduction, inhibition of synthesis and/or secretion of TNF-alpha, IL-6, IL-2, and IFN-gamma, and modulation of serum and leukocyte-bound levels of cell adhesion molecules.

Drug Name	Prednisone (Deltasone, Sterapred) -- Immunosuppressant used to suppress autoimmune effects on affected nerves.
Adult Dose	60-80 mg/d PO qam; taper slowly to qod as symptoms resolve
Pediatric Dose	4-5 mg/m2 PO qd 1-2 mg/kg PO qd; taper slowly to qod as symptoms resolve
Contraindications	Documented hypersensitivity, in patients with severe infections
Interactions	Clearance may decrease when used with estrogens; when used with digoxin, digitalis toxicity may increase secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids and may necessitate a dose increase; monitor patients for hypokalemia when administering concurrently with diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in patients with hyperthyroidism, cirrhosis, nonspecific ulcerative colitis, osteoporosis, peptic ulcer, diabetes, and myasthenia gravis; may cause hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, myalgia, acne, hirsutism, facial plethora, and glaucoma; adrenal crisis may occur if steroids are withdrawn abruptly

FOLLOW-UP

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Further Outpatient Care:

• Coordinate care with the primary care physician and an infectious disease specialist.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to promptly make the diagnosis and provide treatment, in particular of CMV-associated neuropathies, can lead to significant morbidity and death

TEST QUESTIONS

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CME Question 1: Which of the following statements concerning multiple mononeuropathies is false?

A: It usually progresses in an asymmetric fashion.
B: This condition can be caused by autoimmunity or cytomegalovirus (CMV) infection.
C: Drug toxicity or nutritional deficiencies usually cause this condition.
D: It can present during the early or late stages of HIV infection.
E: It can respond to antiviral therapy.

The correct answer is C: Multiple mononeuropathies can present during early or late HIV infection, the latter situation often caused by CMV infection. The asymmetric progression is characteristic. While recovery can occur with immunomodulatory treatment when caused by autoimmunity, the prognosis is worse when CMV causes the condition, often despite appropriate antiviral treatment.

CME Question 2: A 55-year-old HIV-seropositive man presents with a 6-week history of progressive patchy weakness and dysesthesias in his arms and legs. Examination reveals asymmetric weakness, sensory loss, and hyporeflexia. Which of the following is the most likely diagnosis?

A: Guillain-Barré syndrome or acute inflammatory demyelinating polyradiculoneuropathy
B: Distal painful sensorimotor neuropathy
C: Polyradiculomyelopathy
D: Chronic inflammatory demyelinating polyradiculoneuropathy
E: Multiple mononeuropathies

The correct answer is E: The rate of progression and asymmetric features suggest multiple mononeuropathies as the correct diagnosis.

Pearl Question 1 (T/F): HIV-1–associated multiple mononeuropathies occur only at the time of seroconversion.

The correct answer is False: This condition typically is not associated with seroconversion. A less severe autoimmune form of multiple mononeuropathies with a better prognosis occurs before patients develop AIDS-defining conditions. A more extensive form caused by cytomegalovirus is associated with low CD4⁺ cell counts.

Pearl Question 2 (T/F): The characteristic clinical features of HIV-1–associated multiple mononeuropathies resemble those of a length-dependent polyneuropathy.

The correct answer is False: The characteristic clinical features are progressive and asymmetric development with sensory, motor, and reflex involvement.

Pearl Question 3 (T/F): Therapeutic options for the autoimmune form of multiple mononeuropathies that presents early in the HIV-1 clinical course are limited to symptomatic treatment of pain.

The correct answer is False: The preferred treatment option is standard immunomodulatory therapy as in acute inflammatory demyelinating polyradiculoneuropathy (eg, intravenous immunoglobulin, plasmapheresis).

Pearl Question 4 (T/F): No treatment will alter the course of multiple mononeuropathies due to cytomegalovirus that occur late in the HIV-1 clinical course.

The correct answer is False: The preferred treatment option is expeditious treatment with foscarnet and/or ganciclovir.

BIBLIOGRAPHY

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• De Gans J, Portegies P: Neurological complications of infection with human immunodeficiency virus type 1. A review of literature and 241 cases. Clin Neurol Neurosurg 1989; 91: 199-219[Medline].
• Gendelman HE, Lipton SA, Epstein L: The Neurology of AIDS. New York: Chapman & Hall; 1998.
• Luciano C, Pardo C, McArthur J: Recent developments in the HIV neuropathies. Current Opinion in Neurology 2003; 16: 403-409.
• Mancall E ed., Lippincott Williams & Wilkins: Neuromuscular disorders in HIV-1 infection. Continuum 2000; 6 number 5 Part A: 73-79.
• Maschke M, Kastrup O, Diener HC: CNS manifestations of cytomegalovirus infections: diagnosis and treatment. CNS Drugs 2002; 16: 303-315[Medline].
• Said G, Saimont AG, Lacroix C: Neurological Complications of HIV and AIDS. Philadelphia, PA: WB Saunders; 1998.
• Simpson DM, Olney RK: Peripheral neuropathies associated with human immunodeficiency virus infection. Neurol Clin 1992 Aug; 10(3): 685-711[Medline].
• Whitley RJ, Jacobson MA, Friedberg DN, et al: Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA. Arch Intern Med 1998 May 11; 158(9): 957-69[Medline].

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