Tibial nerve injuries
Jun. 04, 2022
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Cytomegalovirus is the most common cause of polyradiculopathy in AIDS. It occurs in about 2% of HIV-infected patients referred to neurologists. Expeditious diagnosis is crucial, as this disease may progress rapidly to death, but does respond to antiviral therapy when started early. The authors provide an overview of neuropathies associated with cytomegalovirus infection.
Prior to the AIDS epidemic, cytomegalovirus was rarely associated with peripheral neuropathies, but was recognized as an antecedent infection associated with Guillain-Barré syndrome (27; 10). Since the first AIDS cases were identified in the United States in 1981, several discrete neuropathic syndromes have been linked to cytomegalovirus, including lumbar radiculopathy, distal symmetrical polyneuropathy, mononeuritis multiplex (Behar and McCutchan 1987; 38; 13), and gastroparesis (54). Cytomegalovirus is one of the primary opportunistic pathogens in late stages of AIDS and affects multiple organs (40). Retinitis is the most common manifestation, affecting 10% to 20% of patients, but esophagitis, gastritis, colitis, pneumonitis, myelitis, encephalitis, and optic neuropathy also occur. Physicians should have a low threshold for entertaining this diagnosis, as many patients improve significantly with antiviral treatment.
Peripheral neuropathy is the most common neurologic complication HIV seropositive individuals. Clinical and neurophysiological evaluations reveal evidence of neuropathy in most AIDS patients (04; 49; Gastaut et all 1989; 22). In terminal AIDS pathological evidence of neuropathy is present essentially in all patients (36; 44). HIV-associated neuropathy presents as several different subtypes: (a) distal sensory polyneuropathy, (b) acute and chronic inflammatory neuropathies, (c) polyradiculopathy, (d) mononeuritis multiplex, (e) autonomic neuropathy, and (f) diffuse infiltrative lymphocytosis syndrome (56). Among AIDS patients, cytomegalovirus is associated with polyradiculopathy, mononeuritis multiplex, painful distal symmetrical polyneuropathy, and myelitis.
Cytomegalovirus is the most common cause of polyradiculopathy in AIDS (08). It occurs in about 2% of HIV infected patients referred to neurologists. Expeditious diagnosis is crucial, as this disease may be rapidly progressive, but does respond to antiviral therapy when started early.
AIDS-associated polyradiculopathy usually occurs when CD4 counts drop below 40, in the presence of other AIDS defining illnesses, and in association with cytomegalovirus, or other end-organ infection (56; 46). The absence of signs of systemic cytomegalovirus infection argues against the diagnosis. Cytomegalovirus polyradiculopathy presents as involvement of lumbar and sacral roots (34) with symptoms such as sacral or sciatic pain, saddle paresthesias, distal sensory loss, progressive ascending motor weakness and marked sphincter dysfunction. Untreated, the condition worsens rapidly to flaccid paraparesis and areflexia (06; 30). Late in the course, the arms may be involved. A pure motor presentation with weakness, muscle wasting, and fasciculations has been described (30).
In a review of 103 AIDS patients with polyradiculopathy, hyporeflexia and leg weakness were seen in 100%, urinary retention in 94%, sensory loss in 80%, paresthesias in 79%, and lumbar pain in 36%. Rare presence of extensor plantar responses or sensory levels suggests associated spinal cord involvement by cytomegalovirus. Other organs were infected by cytomegalovirus in 44% (01).
Mononeuropathy multiplex has been described in 2 settings in HIV infection (52). A limited form (1 to 2 nerves) presents in HIV-seropositive patients without AIDS and represents a variant of HIV-related chronic inflammatory demyelinating polyneuropathy (32; 18; 28). A more generalized form (greater than 2 nerves) occurs in late AIDS, is rapidly progressive, and is often associated with cachexia and fever (40). Symptoms are asymmetric and involve the arms and legs (37). Initially, 1 or 2 nerves are infected with rapid progression to multiple nerves. Sensory symptoms with painful paresthesias can precede motor weakness by weeks to months. Cytomegalovirus has also been reported as causing a multifocal neuropathy, predominantly affecting the arms (14). Said and colleagues described multifocal inflammatory and necrotic lesions in peripheral nerve biopsies in 4 patients who developed a rapid progressive multifocal neuropathy with advanced HIV infection (41). One of the patients improved with ganciclovir; the other died soon after onset of neuropathy.
One unusual form of cytomegalovirus mononeuropathy involves the laryngeal nerve and presents as hoarseness (47). In 2 patients, hoarseness developed due to involvement of the recurrent laryngeal nerve during administration of ganciclovir for cytomegalovirus colitis. Postmortem examination of one patient showed cytomegalovirus infection throughout the body, including the recurrent laryngeal nerve. Cytomegalic cells were seen with acute and chronic inflammatory cell infiltration and edema. Another HIV seropositive patient with cytomegalovirus infection and polyradiculopathy presented with clinical and MRI evidence of cranial nerve involvement (25).
In a prospective study of 54 AIDS patients with peripheral nerve disease, which excluded patients with known exposure to neurotoxic drugs or other conditions associated with neuropathy, 38 had a distal symmetrical peripheral neuropathy; of these 25 had a painful, 13 a nonpainful neuropathy. In the group with pain 75% had temporally associated cytomegalovirus infection by antibody titers, compared to 37% in the control group with AIDS of similar severity without neuropathy. The painful neuropathy affected the legs more than the arms. Patients described severe burning or pins and needles sensation aggravated by touch and had altered touch or pin prick sensation. Symptoms progressed to maximum severity over 2 to 4 weeks and then remained stable or improved spontaneously (16). However, the association between sensory neuropathy and cytomegalovirus due to infection of and damage to the dorsal root ganglia leading to distal axonal degeneration (15; 13) remains controversial. Definitive evidence of cytomegalovirus in dorsal root ganglia is rare (43; 20). Although disseminated cytomegalovirus infection may contribute to peripheral nerve damage, possibly through an effect on endothelial cells and the microvasculature, it does not appear to be the primary cause of sensory neuropathy.
As mentioned, cytomegalovirus is linked to Guillain-Barré syndrome in the general, HIV seronegative population. Guillain-Barré syndrome is an acute inflammatory demyelinating polyradiculopathy that often follows nonspecific flu-like illnesses. In 1 study, antibody testing in Guillain-Barré syndrome patients revealed prior Campylobacter jejuni and cytomegalovirus infection in 23 and 8%, respectively (21), whereas cytomegalovirus antibodies were identified in 25% of such patients in another study (50). The disease is characterized by ascending paralysis evolving to maximum deficit over a period of about 2 to 4 weeks. Areflexia, sensory loss and dysesthesias, and autonomic dysfunction are commonly seen. Cytomegalovirus associated Guillain-Barré syndrome is associated with more prominent sensory involvement and severe disease (55; 21).
Patients who are immunosuppressed because of other disease processes or treatments are also at risk for cytomegalovirus disease. Although cytomegalovirus neuropathies are rare outside of the HIV-infected population, cytomegalovirus polyradiculopathy has been reported after bone marrow transplantation (57).
Prognosis remains poor even with immune reconstitution and antivirals against cytomegalovirus. This is, in part, due to overall health of the patient (39).
Cytomegalovirus polyradiculopathy, if untreated, is rapidly fatal (100% mortality). In one review of cytomegalovirus polyradiculitis, 16 of 31 patients received ganciclovir; 3 patients stabilized, 6 improved. Of these, most had received ganciclovir within 2 weeks of symptom onset, and polymorphonuclear pleocytosis declined after induction therapy. Patients who failed to respond showed persistent polymorphonuclear pleocytosis, positive cultures and hypoglycorrhachia (05).
In another review of 103 patients with polyradiculomyelitis, mean survival in the untreated group was 5.4 ± 1.8 weeks compared to 14.6 ± 9.4 weeks in the group treated with ganciclovir, and 7.2 ± 3.0 weeks in patients already on ganciclovir at disease onset (01). Of 56 patients with cytomegalovirus polyradiculopathy who were treated with ganciclovir, 36% improved, 25% stabilized, and 39% continued to progress (01). Patients resistant to ganciclovir may respond to foscarnet, which is effective in ganciclovir-resistant cytomegalovirus retinitis, but there is little evidence as yet for to its efficacy in cytomegalovirus polyradiculomyelitis (26).
Cytomegalovirus has been associated with, and is thought to play a causal role in, polyradiculopathy, mononeuritis multiplex, and distal symmetrical polyneuropathy in patients with end-stage AIDS.
Cytomegalovirus is a ubiquitous double stranded DNA herpes virus. It causes a characteristic cytopathologic enlargement of host cells with intranuclear and cytoplasmic inclusion bodies. Some 50% to 90% of adults are antibody positive for cytomegalovirus. The virus establishes latency in hematogenous cells. It is found in saliva, breast milk, semen, vaginal secretions, and blood (23). Virus isolation from saliva or urine in a patient with neuropathy is difficult to interpret as causative, as it may represent nonspecific reactivation or simply chronic viral secretion (23).
A possible pathogenic mechanism may result from the ability of cytomegalovirus to trigger cryoglobulinemia (29).
Initial infection is generally asymptomatic. Symptomatic disease typically develops, when impaired T cell immunity leads to reactivation of latent cytomegalovirus infection. Although all human Herpes viruses can activate during HIV infection, this is most severe with cytomegalovirus. At autopsy some 50% of brains from AIDS patients show hallmarks of cytomegalovirus, ie, diffuse micronodular encephalitis and scattered microglial nodules containing cytomegalic cells or viral antigen (23).
In AIDS, direct cytomegalovirus infection of peripheral nerves occurs with infiltration by polymorphonuclear cells and necrotizing vasculitis of epineural arteries. Cytomegalovirus antigens, genome, and virions have been found within peripheral nerve and spinal ganglia of patients with polyradiculopathy, mononeuropathy multiplex, or peripheral neuropathy. Infectious targets may involve endothelial and Schwann cells, macrophages, and fibroblasts (28). Definitive evidence of cytomegalovirus in dorsal root ganglia, however, is rare (43; 20). Endothelial cell infection may result in ischemia or inflammatory damage with axonal degeneration and myelinated fiber loss (15; 07; 13). Furthermore, in patients with Guillain-Barré syndrome and antecedent cytomegalovirus (CMV) infection, Sawai and colleagues found autoantibodies against membrane-organizing extension spike protein (moesin) expressed by Schwann cells at the nodes of Ranvier (42). It connects the actin cytoskeleton to the extracellular matrix through transmembrane proteins, thus facilitating myelination. Moesin may be an immune target in the pathogenesis of cytomegalovirus-related Guillain-Barré syndrome.
Cytomegalovirus is ubiquitous, with 25% of U. S. city dwellers seropositive by the age of 2 years and 33% positive by the age of 10 years. Respiratory or salivary spread is probably most common in children; venereal transmission is most common in adolescents and adults.
Cytomegalovirus is the most commonly identified opportunistic viral pathogen in AIDS. The disease occurs in 20% of AIDS patients with CD4 counts below 100/microliter, most commonly retinitis. Only 1% of these develop polyradiculopathy (02), with mononeuritis multiplex and polyneuropathy still less common. Subclinical infection is more common, with reports demonstrating cytomegalovirus in the nervous system in as many as 50% of autopsies (02). Both the incidence and prevalence of clinical cytomegalovirus infection in AIDS have declined since the advent of highly active antiretroviral therapy several years ago (33).
In the general population, cytomegalovirus was reported to be the antecedent infection in Guillain-Barré syndrome (GBS) in 8% of cases (21), whereas a prospective study showed a GBS incidence of 0.6 to 2.2/1000 cases of primary cytomegalovirus infection versus 0.25 to 0.65/1000 cases of C jejuni infection (35).
There are no proven means of prevention as the virus is latent in the hematopoietic system in most adults. Prevention of HIV transmission and treatment of AIDS that maintains the CD4 counts greater than 100/microliter are likely to have the most impact in preventing cytomegalovirus neuropathies.
The differential diagnosis of polyradiculopathy in AIDS includes diabetic neuropathies, neurosyphilis (31), lymphomatous meningitis, cryptococcus, toxoplasmosis, or tuberculosis of the conus medullaris, lymphomatous spinal masses, Herpes simplex virus-2, Varicella zoster virus, or HIV inflammatory polyradiculitis.
In a review of 23 AIDS cases with acute lumbosacral polyradiculopathy (48), cytomegalovirus was causative in 15 cases, most of whom stabilized with ganciclovir. Two patients had metastatic systemic lymphoma. A more benign syndrome with slower progression, milder deficits, spontaneous improvement, and no evidence of cytomegalovirus infection was identified in 6 patients. Other AIDS associated diseases that must be considered include Kaposi sarcoma and toxoplasmosis, among others.
Spinal disc syndromes need to be considered in the differential diagnosis. However, in cytomegalovirus polyradiculopathy the clinical signs indicate involvement of multiple roots. Also, sphincter impairment, sacral sensory loss, and loss of the anal reflex accompany the progressive lower motor neuron weakness of the legs, which is unlike the sudden effect of central disc prolapse.
The differential diagnosis of polyneuropathy in AIDS includes B12 and folate deficiency, thyroid disorders, malnutrition, paraneoplastic disorders, Herpes simplex virus ganglioneuritis, direct HIV effect, and drug toxicity.
Imaging. Early in the course of cytomegalovirus polyradiculitis, imaging studies may be normal. Investigations need to include imaging of the cauda equina by myelography or MRI. This is always required to exclude lymphoma. In cytomegalovirus polyradiculopathy, MRI may be normal or show nodular thickenings on multiple roots with leptomeningeal enhancement from the conus medullaris to the cauda equina (51; 26; 30). Myelography may show arachnoiditis or crowding of nerve roots (26). In a review of 103 patients with diagnosis of cytomegalovirus polyradiculopathy, 31% had gadolinium enhancement and 17% an abnormal myelogram (01).
Laboratory studies. Cerebrospinal fluid analysis typically reveals high protein, low glucose, and polymorphonuclear pleocytosis. A review of 103 cases of AIDS and polyradiculopathy found the following mean values: WBC 651 ± 1,053 x 10-6 (with average of 68% polymorphonuclear granulocytes); protein 2.28 ± 1.78 g/L; CSF/serum glucose ratio 0.48 ± 0.17. Cytomegalovirus can be cultured in up to 50% of CSF samples (11; 45; 03; 34; 05). Cytomegalovirus can be cultured from CSF in up to 50% (11; 45; 03; 34; 05), and it can frequently be cultured from blood. Cytomegalovirus polymerase chain reaction is most sensitive for CSF diagnosis, with a sensitivity of 92% and a specificity of 94% (01). Cytologic analysis can exclude the presence of lymphoma cells and may occasionally demonstrate cytomegalic cells (19). Repeat lumbar puncture in difficult cases can be useful even if the initial CSF is normal. Occasionally, CSF evolves over 1 to 2 weeks from normal to abnormal after the onset of neurologic signs (05).
Branched chain DNA assays may be valuable in the future, as this may allow quantitation of cytomegalovirus in the CSF. It may allow to follow treatment responses, as viral DNA levels decrease before clinical improvement) and in identifying resistance to therapy early in the disease course (12).
Neurophysiological studies. Nerve conduction studies and EMG can be helpful in the confirmation of a clinical diagnosis of cytomegalovirus radiculopathy or mononeuropathy multiplex. It can, however, be challenging because of common neuromuscular comorbidities in AIDS, such as myopathies of different etiologies (46) or distal axonopathy.
In cytomegalovirus associated mononeuropathy multiplex, nerve conduction studies and EMG show reduced amplitudes of sensory nerve and compound muscle action potentials, mildly reduced conduction velocities, and denervation, often in an asymmetric distribution. Roullet and colleagues compared electrodiagnostic findings in 14 patients with cytomegalovirus mononeuritis multiplex with recordings from 90 nerves, 5 or more per patient (40). Evidence of axonal neuropathy was found with relative sparing of some nerves. Distal nerve syndromes were most prominent, but multiple radicular involvement was seen in some patients. Lowered compound muscle action potentials were recorded in 19 nerves with normal or mildly reduced nerve conduction velocities. F-waves were absent in 6 nerves and prolonged in 10. Sensory nerve action potentials were reduced in 17 nerves with normal or only mildly reduced nerve conduction velocities.
In cytomegalovirus associated polyradiculopathy, neurophysiological differentiation from other rapidly progressive neuropathies such as Guillain-Barré syndrome is important. Typical findings include widespread denervation, prolonged or absent F-waves, and low-amplitude or unobtainable tibial or peroneal compound motor action potentials, sometimes with normal sensory nerve action potentials from the affected areas (30).
Neuropathology. Neuropathological features in cytomegalovirus radiculopathy include necrosis and acute and chronic inflammation of the ventral and dorsal nerve roots, with cytomegalic cells and cytomegalovirus immunoreactivity in Schwann and endothelial cells as well as foci of microvascular thrombosis and inflammation (34). Necrotizing radiculomyelitis and focal myelitis with anterior horn cell loss can be seen; this spinal cord involvement is the likely basis of sensory levels and extensor plantars. In one autopsy series, cytomegalovirus was found in the peripheral nervous system, usually in endothelial cells, in 26% of AIDS patients as well as in 46% of those who had lived for greater than or equal to 2 years after the AIDS-defining illness (07).
Biopsies in cases of cytomegalovirus-related mononeuropathy multiplex can reveal marked vasculitic changes and centrofascicular degeneration.
Approach to the patient with lumbosacral polyradiculopathy and AIDS
I. MRI and myelogram to exclude mass lesions
II. CSF analysis
A. If white blood cells > 50 and >40% polymorphonuclear granulocytes (or if polymerase chain reaction is positive for cytomegalovirus)
B. If CSF is not suggestive of infection, but progression of weakness is rapid, proceed to empiric cytomegalovirus treatment
C. If CSF is not suggestive and weakness is not rapidly progressive, monitor exam daily. If exam is worsening, consider empiric cytomegalovirus treatment.
D. Repeat lymphocyte proliferation if there is no evidence of cytomegalovirus, but no other etiology is evident.
III. Empiric treatment
A. Ganciclovir is the first line of treatment
B. If already on ganciclovir, start foscarnet (alone, or in addition to, ganciclovir)
Approach to the patient with peripheral neuropathy and HIV infection
I. Nerve conduction studies and EMG
A. Distal symmetrical polyneuropathy: evaluate for secondary causes, attempt correction, provide symptomatic treatment
B. Inflammatory demyelinating polyneuropathy: assess level of immunosuppression.
1. If immunosuppression is not advanced: immunotherapy
2. If immunosuppression is advanced: CSF analysis
a. Evidence of cytomegalovirus: anticytomegalovirus therapy
b. No evidence of cytomegalovirus: nerve biopsy (consider anticytomegalovirus therapy if biopsy is negative)
C. Mononeuropathy multiplex: if disease is extensive or with severe immunosuppression:
1. CSF analysis:
a. Evidence of cytomegalovirus: to anticytomegalovirus therapy
b. No evidence of cytomegalovirus: nerve biopsy (consider anticytomegalovirus therapy if biopsy is negative)
D. Progressive polyradiculopathy: CSF analysis:
1. polymorphonuclear granulocyte predominance: anticytomegalovirus therapy
2. mononuclear cell predominance: CSF cytology
a. cytology suggestive of lymphoma: bone marrow biopsy, then radiation and chemotherapy if indicated
b. cytology not suggestive of lymphoma: consider neurosyphilis
Therapy is urgent in all AIDS patients with cytomegalovirus-associated neurologic diseases and should be initiated immediately and empirically in patients with advanced HIV infection, rapidly progressive polyradiculopathy, and polymorphonuclear CSF pleocytosis. It must be continued indefinitely, even if no improvement is apparent (26). Ganciclovir 5 mg/kg IV every 12 hours or 2.5 mg/kg every 8 hours for 10 to 14 days is given for induction, followed by 5 mg/kg IV per day, 5 days per week for maintenance (30). CSF improvement with conversion to a lymphocytic predominance and reduced pleocytosis usually indicates a therapeutic response (05).
Foscarnet alone, or in addition to ganciclovir, should be tried in ganciclovir-resistant patients or those already on ganciclovir at the time of onset of polyradiculomyelitis. Ganciclovir resistance is suspected in patients with persistent pleocytosis on serial CSF analysis; branched-chain DNA assays may also be of value in identifying resistance to treatment. Foscarnet is prescribed at 60 mg/kg every 8 hours or 100 mg/kg q12h for 14 to 21 days, adjusted for renal function, followed by foscarnet 90 mg/kg per day.
Acyclovir is not used for cytomegalovirus polyradiculitis, as ganciclovir is approximately 26 times more potent against cytomegalovirus (09).
Valganciclovir is a prodrug of ganciclovir with equal oral and intravenous efficacy in cytomegalovirus retinitis. It is promising as an oral drug for cytomegalovirus polyradiculitis (09). Valganciclovir is used for cytomegalovirus prophylaxis, but at 900 mg daily, has a 10% to 40% risk of leucopenia, whereas 450 mg/day showed equal efficacy and fewer side effects (24)
Cidofovir has been used with some success in cytomegalovirus retinitis, but there is little evidence for efficacy in neurologic disease (33).
Pavan Tummala MD MS
Dr. Tummala of Saint Louis University has no relevant financial relationships to disclose.See Profile
Niranjan N Singh MD
Dr. Singh of the University of Missouri, Columbia received honorariums from AbbVie for speaking engagements.See Profile
Florian P Thomas MD MA PhD MS
Dr. Thomas of Hackensack University Medical Center, Hackensack Meridian School of Medicine, received an honorarium from Pharnext for consulting work.See Profile
Louis H Weimer MD
Dr. Weimer of Columbia University has received consulting fees from Roche.See Profile
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