Treatment and Management of Infectious, Granulomatous, and Toxic Neuromuscular Disorders

Diagnosis and Evaluation

As is the case in most neuromuscular diseases, the diagnosis of the various types of neuropathy and myopathies in HIV infection relies on a careful history and physical examination. It is important to have a basic understanding of some pertinent historical aspects of the various types of HIV-associated neuropathies. First, with the advent of cART, markers of more advanced immunosuppression, like CD4 counts, and more active infection, like viral loads, are no longer associated with HIV neuropathy and some predictors for the development of neuropathy are older age, increased height, prior exposure to antiretrovirals, substance use, hypertriglyceridemia, and diabetes ( ). This implies that a comprehensive evaluation for comorbid conditions, prior medications, or substance exposure or abuse is equally important. The HIV myopathies are less common than the neuropathies and the typical HIV myositis can occur at any stage of infection. The demyelinating polyneuropathies, and in particular the AIDP form of GBS, tend to occur at the time of seroconversion or during the early stages of HIV infection while the chronic type, CIDP, occurs more frequently in moderately advanced disease and is more common than AIDP in HIV infection ( ). Since the introduction of cART, GBS has been seen in association with IRIS ( ; ). The mononeuropathies and mononeuritis multiplex are less common and present more frequently as lesions of the facial nerve, lateral femoral cutaneous nerve of the thigh, median nerve at the wrist, or peroneal nerves. Facial neuropathies, unilateral or bilateral, are probably one of the more common presentations, again sometimes occurring during seroconversion. If the mononeuritis multiplex is present during the early stages of HIV infection, with less immunosuppression, it is associated with dysimmune processes or vasculitis, but if present with advanced immunosuppression, it can be associated with cytomegalovirus (CMV) infection ( ).

The most common symptoms with predominantly sensory neuropathies (HIV-DSP/ATN) are symmetrical distal painful dysesthesias, paresthesias, and numbness in the feet and toes that extend proximally as the neuropathy advances. Patients complain of tingling, burning, and aching pain in the toes and soles, but any nonspecific discomfort in the feet and toes should trigger the suspicion in the clinician. The distinction between viral-associated neuropathy and ATN is difficult because, clinically, they are indistinguishable and they may often coexist. Suspicion for ATN should arise if the symptoms start shortly (within weeks) after starting or increasing the dose of one of the suspect medications and if the symptoms improve or disappear after reducing the dose or discontinuing the suspect medication ( ). On the clinical examination, the most common findings are impaired distal sensation and reduced deep tendon reflexes, more prominently the Achilles tendon reflex. The latter reflex may appear normal but be relatively reduced when compared with the patellar reflex. Although patients may exhibit reduced pinprick sensation, in our experience and that of others ( ), decreased vibratory sensation at the toes is a more sensitive sign. Joint position sense is usually normal, and weakness, if present, is limited to the distal foot muscles and is mild. In addition, patients may exhibit allodynia or hyperalgesia in the distal feet.

The clinical presentation of the acute and chronic demyelinating polyneuropathies may be slightly different from the presentations seen in HIV seronegative patients. HIV patients with GBS will have a more rapid presentation and evolution than non-HIV patients ( ). HIV-infected patients with CIDP are younger and more commonly display a monophasic progressive course than non-HIV patients ( ). They are characterized by acute or progressive weakness, with or without prominent sensory symptoms, and reduced or absent reflexes. The mononeuropathies or mononeuritis multiplex cases usually present with a stepwise progression with multiple, often painful, mononeuropathies. A lumbosacral polyradiculopathy presenting as a cauda equina-like syndrome is usually seen in advanced immunosuppression with low CD4+ T-cell count. Clinically, it presents with lower back and radiating radicular pain, saddle anesthesia, and rapidly progressive weakness in the lower limbs with bladder and bowel dysfunction. It evolves in an acute or subacute fashion and is often caused by CMV or less commonly by herpes simplex virus (HSV), varicella zoster virus, syphilis, or tuberculous meningitis ( ).

Muscle involvement in HIV infection has a wide spectrum of presentations, most of which are in the inflammatory spectrum ( Table 16.2 ). T-cell-mediated inflammatory myopathies include features indicative of polymyositis (HIV-PM) and inclusion body myositis (HIV-IBM), and some authors have also described a nonspecific myositis ( ). HIV-PM is usually associated with subacute and symmetrical proximal muscle weakness, with involvement of the legs and, less often, the arms. Patients may complain of difficulty rising from a chair or climbing stairs and may indicate myalgias and decreased stamina.

Two of the variants have some distinctive clinical features: myositis associated with DILS (DILS myositis) is associated with enlargement of the salivary glands and increased peripheral CD8+ lymphocytes, and HIV-IBM, which may be clinically indistinguishable from sporadic IBM, with involvement of quadriceps and forearm muscles, except sometimes it is seen in younger patients and the creatinine kinase (CK) levels are higher ( ; ). Some studies have described overlapping features of HIV-PM and HIV-IBM initially, with evolution of HIV-PM over time to an inclusion body myositis phenotype, proven by biopsy ( ; ).

An important part of establishing the diagnosis of HIV-DSP/ATN relies on the exclusion of other causes or modifying factors for neuropathy. We usually order a comprehensive metabolic panel with fasting blood sugar to check for diabetes and liver or renal impairment. We also check vitamin B ₁₂ levels, pyridoxine (vitamin B ₆ ) levels, and thiamine levels in whole blood; perform thyroid function tests; carry out lipid panel to check for hypertriglyceridemia; test for hepatitis B or C coinfection; and perform serum and urine immunofixation. Careful assessment for alcohol and substance consumption is also important given the high prevalence of their use in people with HIV and the increased risk for neuropathy ( ). For a clinical presentation of acute or subacute painful sensorimotor polyneuropathy, CD8+ cell counts to identify DILS is necessary, even in the absence of other clinical features. Nerve conduction studies (NCSs) are helpful in establishing the diagnosis of HIV-DSP/ATN and in detecting neuropathy in patients with nonspecific symptoms in the feet. The typical pattern shows a predominantly sensory axonal polyneuropathy, although the study may be normal even in the presence of pain, given the possibility of predominant involvement of small sensory fibers. An inflammatory demyelinating polyneuropathy (AIDP or CIDP) will be suspected if motor weakness is a prominent feature. NCSs and needle electromyography (EMG) are an important part in the evaluation of these patients, because they provide objective information about axonal loss and demyelination. AIDP usually occurs in patients with preserved CD4+ cell counts, but if seen in a patient with profound immunosuppression, the possibility of infection with CMV should be considered and treated accordingly ( ). In HIV-DSP, the typical features would be those of a length-dependent predominantly sensory polyneuropathy with loss of sensory axons in the distal lower extremities, resulting in reduced-amplitude sensory responses. Up to 25% of patients may have abnormal electrophysiologic findings without symptoms, and approximately 20% of patients with HIV-DSP have normal NCSs due to preferential involvement of small fibers ( ). We have also examined the value of the ratio of the superficial radial sensory amplitude to the sural sensory amplitude but have not found that this increases the detection of neuropathy.

In addition to the clinical features, laboratory studies like serum creatine kinase (CK) and aldolase, the EMG examination, and the muscle biopsy are important tools in the evaluation of a patients suspected of having HIV-associated muscle involvement. In the HIV-inflammatory myopathies (HIV-PM, HIV-IBM), the serum CK level can be markedly increased, up to 10 times the upper limit of normal (ULN), although it can also be elevated in AZT myopathy. The needle EMG typically shows increased spontaneous activity with fibrillation potentials and positive waves, as well as increased numbers of small-amplitude, short-duration polyphasic motor unit potentials, and this can be observed in the toxic and HIV-associated types. Not uncommonly, myositis and distal sensory neuropathy coexist, as both are more common in the advanced stages. A muscle biopsy can be important in differentiating toxic myopathy from the nontoxic subtypes. In zidovudine-associated myopathy, features of mitochondrial dysfunction are prominent, with numerous “ragged red” fibers, subsarcolemmal accumulation of red granular material, sparse, if any, endomysial inflammation, lipid accumulation, and paracrystalline mitochondrial inclusions on electron microscopy ( ). The typical biopsy in the patient with HIV-PM will show more prominent perimysial, endomysial, perivascular, and primary inflammation of nonnecrotic fibers, with varying degrees of necrosis, phagocytosis, and degeneration of muscle fibers ( ; ). Biopsies from patients with HIV-IBM will show primary inflammation but will also show rimmed vacuoles and amyloid deposition with Congo red staining. Immunostaining for aggregated proteins, i.e., TDP-43 and p62, and electron microscopy for inclusions can also help in differentiating from HIV-PM or other myopathies with inflammation ( ). An additional test in HIV-IBM can be the presence of antibodies against cytosolic 5’ nucleotidase (anti-CN1A ab), which is uncommon in HIV-PM ( ). In some patients, abundant nemaline (rod) bodies can be observed and may be a predominant feature without inflammation, a finding used to define the nemaline subtype of HIV-associated myopathy, HIV-SLONM. This observation has led to the suggestion that adult patients with nemaline myopathy on muscle biopsy should be tested for HIV infection. Additionally, serum and urine electrophoresis are performed since SLONM can be associated with a monoclonal gammopathy. In DILS-associated myositis, typically there is a prominent CD8+ inflammatory infiltrate, and the diagnosis can be determined by measuring CD4 and CD8 T cells in blood and determining the CD4/CD8 ratio as well as excluding other confounders such as other autoimmune or infectious diseases. The muscle biopsy can show CD8+ T cell infiltration consistent with the diagnosis. Tests should also be sent for antibodies against extractable nuclear antigens (anti-SSA, anti-SSB), cryoglobulins, human T-lymphotrophic virus type 1 (HTLV-1), and EBV. Biopsy of salivary gland is often needed for definitive diagnosis ( ).

Because of the predominant involvement of small unmyelinated and myelinated fibers, the use of skin biopsies to study epidermal nerve fibers has been shown to be an important tool in the study of neuropathy in these patients. Skin biopsies are usually obtained in the lateral aspect of the distal leg and thigh. Studies examining epidermal innervation in adult HIV patients have shown that the density in epidermal nerve fibers is reduced in HIV patients compared to control subjects regardless of neuropathy status and is more reduced in patients with HIV-DSP ( ). However, in children and adolescent patients, the epidermal nerve fiber density may be paradoxically increased ( ). Additional studies have shown that reduced epidermal nerve fiber densities in asymptomatic HIV patients may be a predictive factor for the development of neuropathy within 1 year ( ). Nerve biopsies are usually not necessary for the diagnosis of neuropathy in these patients, unless the patient has an asymmetrical or multifocal pattern that may suggest a vasculitic component.

Lumbar puncture with cerebrospinal fluid examination would be necessary in the context of a demyelinating polyneuropathy or a polyradiculopathy. Both acute and chronic demyelinating polyneuropathies show increased protein levels in the cerebrospinal fluid (CSF), but unlike the non-HIV demyelinating neuropathies, this is often, but not always, associated with a mild pleocytosis ( ).

The diagnosis of the acute or subacute progressive lumbosacral polyradiculopathy will require a lumbar puncture, electrodiagnostic testing, and a contrast-enhanced magnetic resonance imaging (MRI) of the lumbosacral roots. The CSF may show a polymorphonuclear pleocytosis, with increased protein and reduced CSF glucose ( ). In these cases, polymerase chain reaction (PCR) testing of the CSF for CMV, and if negative, PCR for HSV, varicella zoster, is necessary. The EMG will confirm the clinical suspicion and demonstrate acute denervation in the paraspinal muscles, and the MRI may show enhancement of the lumbosacral roots.

Treatment and Management

The basic principles for treatment of HIV neuropathies are mainly based on preventive strategies and symptomatic or immunomodulating treatment. As with other toxic neuropathies and myopathies, removal of the offending agent is a critical and important step for improvement or reversal of symptoms. Treatment of HIV-DSP is important because the associated neuropathic pain can result in impairment, reduced quality of life, and unemployment ( ; ). In the case of ATN, however, in a phenomenon called coasting , symptoms may increase temporarily for 6 to 8 weeks after stopping the offending medication. This should not be confused with progression of the neuropathy. Also, because ATN often coexists with HIV-DSP, the symptoms may improve but may not disappear completely. The reduced incidence of HIV-DSP since the introduction of cART supports the notion that proper treatment of the HIV infection, with reduction in viral loads and increased CD4 counts and avoidance of neurotoxic antiretrovirals, can also result in improvement of the neuropathy. Early initiation of cART has been shown to reduce the incidence of DSP ( ) and the prevalence of painful symptoms in patients with symptomatic painful sensory neuropathy, and should be an integral part of treating or preventing HIV-DSP ( ). Careful follow-up by an HIV specialist is an integral part of the management of these patients.

There are no Food and Drug Administration (FDA)–approved drugs for the symptomatic treatment of HIV-DSP, and many of the medications used in the management of painful dysesthesias and paresthesias in other neuropathies such as diabetic neuropathy have been proven ineffective. These include gabapentin, pregabalin, duloxetine, amitriptyline, 5% topical lidocaine gel, 0.075% topical capsaicin cream, Peptide T, and mexiletine ( ; ). The only treatments that have proven effective in randomized controlled trials have been topical high concentration (8%) capsaicin, smoked cannabis, and recombinant human nerve growth factor ( ; ). The topical high-concentration (8%) capsaicin dermal patch is applied after pretreatment with a topical mixture of local anesthetics (EMLA cream) to limit pain and discomfort ( ). Smoked cannabis is limited to states or countries where this therapy is legal and presents the additional potential for respiratory side effects. Acupuncture/moxibustion (burning of mugwort leaf) has shown some efficacy as a nonpharmacologic therapy in a small study, but larger studies are necessary before proving this an effective ( ). Lamotrigine has been used, but published reports have shown efficacy only in a small study and in subsequent analysis in the subgroup with ATN and not in HIV-associated neuropathy as a separate entity ( ). The clinician must always also be aware of the potential interactions with the antiretroviral medications and the multitude of other medications that HIV patients must take.

Although controlled studies specific for HIV-associated acute or chronic demyelinating polyneuropathies have not been performed, it is generally accepted that response to treatment is similar to non-HIV AIDP and CIDP.

Preferred treatment options for HIV-AIDP include intravenous (IV) gamma globulin at a dose of 0.4 g/kg/day for 5 days. Plasmapheresis is an alternative, but IV immunoglobulin (IVIg) is generally more accessible and does not require special expertise. For HIV-CIDP, comparison with non-HIV-CIDP patients has shown that patients with HIV-CIDP are highly steroid responsive and many go into remission within 12 months of treatment, implying the effectiveness of a limited course of steroid treatment and negligible risk of complications due to coexistent HIV immunosuppresion ( ). One strategy that we often use is an induction dose of 60 mg of daily prednisone for approximately 8 weeks, followed by a slow tapering course and change to alternate day treatment. Other treatment alternatives would also be regular courses of IVIg or plasmapheresis.

Progressive polyradiculopathy is now rarely encountered since the introduction of cART. Treatment is based on anti-CMV therapy and the initiation or optimization of highly active antiretroviral therapy (HAART). The current therapies available are ganciclovir, valganciclovir, foscarnet, cidofovir, and fomivirsen. If CMV infection is suspected, the initial recommendations are for IV infusions of ganciclovir or foscarnet, twice daily as induction therapy, followed by IV maintenance therapy. In patients with severe disease, the use of two medications concomitantly is indicated ( ). Patients may worsen during the first 2 weeks of therapy, but this does not indicate treatment failure ( ). Monitoring of CSF pleocytosis may be used as a marker of response to therapy. Maintenance therapy may be stopped once the CD4 counts have remained above 200 cells/μL and the viral loads have been reasonably suppressed for several months ( ).

Because of their relative rarity, there are no controlled studies of treatment for the HIV-associated myopathies. Treatment recommendations are based on anecdotal experience and from small case series and isolated case reports. The basic assumption for the nontoxic myopathies is that the manifestations are related to immune-mediated mechanisms associated with immune dysregulation in HIV infection. Based on this, investigators have used standard immunosuppressants with overall positive results ( ; ; ). HIV myositis can be treated with a short course of prednisone at a dose anywhere from 40 to 60 mg/day, as well as IVIg at dose of 2 g/kg given over 5 days. This should be given in conjunction with antiretroviral therapy to ensure adequate viral suppression. In HIV-associated nemaline rod myopathy (HIV-SLONM), steroids, IVIg, and plasmapheresis have also been used, with some success in a few cases ( ; ; ).

In the case of AZT-myopathy, discontinuing or reducing the dose of zidovudine and substituting with a nonmyotoxic antiretroviral agent usually results in improvement. The rapidity and degree of improvement depend on the severity of the myopathy at the time of discontinuation, but strength is usually improved within 4 to 6 weeks ( ; ). If strength does not improve, the possibility of a coexisting inflammatory component should be considered and a trial of steroids or IVIg may be of benefit.

Diagnosis and Evaluation

The diagnosis of WNV infection should be suspected in any patient with onset of asymmetric paralysis in the context of a febrile illness, and more so if there are features of meningitis or meningoencephalitis. The diagnosis can be made by the detection of WNV-specific immunoglobulin M (IgM) from serum or CSF preferably between 8 and 21 days after onset; before 8 days, WNV-IgM may not be detected ( Table 16.3 ). Because WNV-specific IgM may be detected in serum for up to 3 years, and in CSF at 3 to 6 months after the acute illness, a positive result may reflect past infection ( ). In cases where doubt exists, to confirm recent WNV infection, it is usually required that a four-fold or higher increase in acute and convalescent antibody titers 2 to 3 weeks apart be detected. Because there can be cross-reaction with antibodies against other flaviviruses, determination of neutralizing antibody titers (plaque reduction neutralization test) is usually required when only serum specimens are available ( ; ). Alternatively, PCR of CSF for viral RNA can be performed, although the sensitivity is lower. Other ancillary studies include CSF analysis, MRI, and EMG/NCS. CSF analysis in WNV is notable for a modest pleocytosis (<500 cells/mm ³ ), with initial and often prolonged (>48 hours) predominance of polymorphonuclear neutrophils, changing later to a lymphocytic predominance, which is unusual for viral meningoencephalitides. The CSF protein is increased but the CSF glucose remains normal ( ). This pleocytosis differentiates WNV-AFP from GBS. The MRI is most often unremarkable, although in patients with WNV encephalitis, abnormally increased signal can be observed on T2-weighted, diffusion-weighted, and fluid-attenuated inversion recovery images in cerebral white matter, in the deep gray matter nuclei such as thalamus and basal ganglia, and in the brain stem. In patients with AFP, there can also be increased signal in the anterior horns of the spinal cord in the T2-weighted images, an important finding indicating focal involvement of the motor neurons ( ; ). EMG and NCS are an important component in the assessment of suspected WNV-AFP. These most often show decreased compound muscle action potential (CMAP) amplitudes with preserved motor conduction velocities and normal sensory NCSs. This picture is in the context of widespread denervation in weak limbs and paraspinal muscles, consistent with an anterior horn cell disorder ( ).

Treatment and Management

There is no specific antiviral treatment for infection with WNV at the present time, so a lot of the efforts have focused on prevention; information campaigns educating the public about protection measures during outdoor activities in the high-risk season and the development of potential vaccines. Patients with documented WNV infection and risk factors for worse outcomes, the elderly, or the immunosuppressed should be hospitalized for observation and detection of progression to neuroinvasive disease. Support treatment includes management of fever, hydration, pain control for headache, and management of nausea and vomiting. In patients with encephalitis, management of seizures and increased intracranial pressure may be required. Since some patients develop signs of dysautonomia (labile blood pressure, dysrhythmias, gastrointestinal symptoms) ( ), this should be monitored and managed. Patients with WNV-AFP who develop early dysarthria and dysphagia may be at increased risk for respiratory failure and should be monitored accordingly ( ). Based on the experience with polio virus poliomyelitis, aggressive physical activity during the acute febrile illness, or initial 48 to 72 hours of weakness, should be avoided ( ). With respect to specific therapies, most reports at present are anecdotal, and clinical trials have shown no efficacy or inconclusive results due to difficulties in recruiting an appropriate sample size. A study of anti-WNV antibodies using an IVIg preparation made with pooled blood from donors with high titers of anti-WNV antibodies (Omr-IgG-am, Omrix Biopharmaceuticals) and compared to United States–produced IVIg was inconclusive because of difficulties enrolling an appropriate number of patients. Additional anecdotal reports or open-label studies have shown no effectiveness for ribavirin and interferon α. Some investigators have proposed a role for high-dose steroids, based on a few cases and anecdotal reports in patients with particular clinical features, but this remains to be proved ( ; ).

The information available about the long-term outcome of infection with WNV suggests that there is a wide range of residual symptoms and deficits and that these, in general, do not necessarily correlate with the severity of the initial infection ( ; , ). Patients with WNF and WNV meningitis have a more favorable outcome than those with encephalitis or AFP. Many patients report residual functional and cognitive changes such as difficulty with concentration and memory, suggestive of a subcortical type dysfunction, which impacts their ability to return to work ( ; , ). However, some patients, particularly if in good health prior to the illness, still recover to their premorbid level of functioning. Patients with WNV-AFP appear to have the worse long-term outcome, with more prominent morbidity and mortality rates. As a group, worse outcome and increased mortality rates are seen in patients who develop respiratory failure, have more extensive weakness due to loss of motor neurons, and are older. Mortality rates in patients with more severe involvement and in particular those with respiratory failure can range from 6% to 25%. Some studies have shown limited or absent recovery in very weak limbs, as one would expect with severe loss of motor neurons. In general, the outcome data to this date have shown that there is a spectrum of functional outcomes and that recovery is highly variable and that intensive support and effective rehabilitation strategies at the appropriate time, after hospital discharge, can result in good functional recovery ( ; , ).

Diagnosis and Evaluation

It has been stated that in the COVID-19 pandemic, any patient who presents with an acute paralytic illness should be tested for SARS-CoV-2 infection ( ). The concomitant presence of anosmia, ageusia, lymphopenia, or thrombocytopenia should prompt immediate suspicion for the diagnosis in patients presenting with neuromuscular symptoms. Diagnostic tests for COVID-19–associated neuromuscular symptoms are no different from those routinely used for diseases of the muscle, neuromuscular transmission, or peripheral nerve. Given the concern of potential contagion, telemedicine and teleconsultations have become the preferred method of routine follow-up of patients with known and stable neuromuscular diseases. In-person visits are being limited to new patients who have not been examined with concerns of a potentially complicated neuromuscular condition with serious complications and those in which appropriate evaluation and diagnosis will be crucial for treatment and management decisions. Emphasis is made in evaluating only patients with acute presentations or with life-threatening symptoms or rapid progression without an established diagnosis.

The American Association of Neuromuscular and Electrodiagnostic Medicine has also published guidelines for the performance of electrodiagnostic studies during the COVID-19 pandemic, emphasizing prescreening, coordinated scheduling, the critical need for the study and potential for changing management, and the use of protective equipment ( ).

Treatment and Management

Management of neuromuscular patients in the COVID must take into account the preexisting respiratory and cardiac involvement and their immunocompetence status. Patients with neuromuscular disorders are at increased risk for complications due to the impaired respiratory capacity, as well as preexisting cardiomyopathy. Those on immunosuppressants are also at increased risk, in spite of the fact that some have suggested that the use of some immunotherapeutic drugs may decrease the exaggerated immune reaction caused by SARS-CoV-2 and be beneficial to patients ( ).

Published guidelines and recommendations for patients with neuromuscular diseases in the COVID-19 era agree on avoiding unnecessary hospital or outpatient visits and procedures, and considering teleconsultation strategies. Particular consideration should be given for increased risks of infections during hospital visits for necessary treatment, such as intrathecal nusinersen, and from complications of therapies such as those that may predisposed to arrhythmias as well as those that may worsen respiratory dysfunction. Patients with disorders of neuromuscular transmission may be at risk of deterioration by using drugs that may affect neuromuscular transmission. Guidance for care of these patients during COVID-19 infection has been published and should be considered by those caring for these patients ( ; ; ).

Diagnosis and Evaluation

The diagnosis of Lyme neuroborreliosis is initially and foremost a clinical diagnosis, based on a precise history, a careful physical examination, and supportive laboratory tests ( Table 16.3 ). The history will be important to establish the appropriate geographic location, the seasonal preference, and the typical systemic and neurologic manifestations. In North America, the majority of Lyme disease cases occur in the Northeast, mid-Atlantic, and upper Midwest regions of the United States ( ). The infection is also prevalent in middle Europe and Scandinavia, and it occurs in Russia, China, and Japan. Thus, it will be critical to determine if the patient resides or has traveled to an area where the disease is endemic. The seasonal aspect should be explored: Most infections occur from spring to autumn and are unlikely to happen during the winter months, when the tick is not active. Although most patients will not recall a tick bite, in a large proportion of patients it will be possible to establish the recent occurrence of a skin rash. This rash, the hallmark of Lyme disease in the United States, is a slowly expanding erythematous annular lesion, resembling a bull’s-eye or a target, known as erythema migrans , occurring within a few days to the first few weeks after infection. The lesion is described as being at least 5 cm in diameter, and in the United States it could be multifocal. It is an early manifestation of the infection and in the context of systemic symptoms, such as fever, arthralgias, headache, chills, and malaise, would be strongly indicative of recent infection with Borrelia (stage 2). In Europe, erythema migrans is less common and more indolent, with milder systemic manifestations. European patients may present later in the course of the disease with another dermatologic manifestation, acrodermatitis chronica atrophica ( ). After the development of the erythema migrans, between 3% and 15% of patients with untreated Lyme borreliosis will develop neurologic symptoms, neuroborreliosis, which can result from central or peripheral nervous system involvement. The clinical consensus divides the infection into an acute localized stage (erythema migrans) and a disseminated stage, further divided into early and late phases ( ; ). The most common early presentation in the United States is a lymphocytic meningitis, with headache and mild meningismus, often with involvement of one or more of the cranial nerves, within a few weeks to a few months following the initial infection or the erythema migrans. The other major presentation, which is more common in Europe, is a painful radiculitis (Garin-Bujadoux-Bannwarth syndrome) with a lymphocytic pleocytosis on CSF analysis. Cranial neuropathies are the most common focal neuropathies and can be observed in 40% to 70% of patients with early neuroborreliosis. The most common cranial neuropathy is a facial (seventh cranial nerve) neuropathy, which accounts for about 70% to 80% of all cases ( , ). The facial neuropathy is most commonly unilateral but can be bilateral in one third of the cases, as in sarcoidosis and GBS. Although it is usually accompanied by meningeal inflammation, half of the patients with facial neuropathy may not have a lymphocytic pleocytosis, indicating that the nerve can be involved distal to the subarachnoid space. Other cranial neuropathies that have been described are neuropathies of the third (oculomotor), sixth (abducens), and eighth (vestibuloauditory) cranial nerves ( ).

The earliest neurologic manifestations typically occur within a few weeks of erythema migrans. The painful radiculitis can present in up to 80% of patients with European neuroborreliosis. This is an acute painful radiculitis, worse at night, with painful dysesthesias, often described as lancinating in a dermatomal distribution ( ; ). The radiculitis can be in the cervical, thoracic, or lumbosacral distribution, may or not be associated with meningeal inflammation, and can be focal or multifocal and asymmetrical. Within days or weeks after the onset of the painful dysesthesias, patients may develop motor weakness in the affected root distribution, which if thoracoabdominal may be associated with abdominal protrusion. Rarely, the radiculitis has been associated with spinal cord inflammation around the same segment, resulting in long tract signs, a sensory level, and sphincter abnormalities below the level of the involved segment. Brachial and lumbosacral plexopathies, mononeuritis multiplex, and a confluent mild distal axonal polyneuropathy have also been described, although they are less common. Patients with untreated Lyme disease may present with a mild indolent chronic distal axonal polyneuropathy or polyradiculoneuropathy months to years after onset of disease ( ; ). This is characterized primarily by symmetrical nonpainful paresthesias in a distal lower limb distribution or asymmetrical radicular pain. The most common finding is multimodal sensory loss, but only 60% of the patients will have objective abnormalities in the neurologic examination. Contrary to acute radiculoneuritis, this finding is not associated with cranial neuropathy, and a lymphocytic pleocytosis on CSF is usually absent. This neuropathy is usually mild and often requires electrophysiologic studies for detection. In European patients, chronic Lyme polyneuropathy is usually associated with acrodermatitis chronica atrophica. The neuropathy preferentially affects the limb with the chronic skin changes and appears to be more painful and to affect motor fibers more commonly than the North American variety.

Laboratory diagnosis for neuroborreliosis relies on the detection of anti- Borrelia antibodies because the spirochete, if present in blood or CSF, is only present in low numbers and for a short time, it is difficult to isolate and culture, and the yield of PCR in CSF is low. In early localized stage (stage 1) disease, with a single erythema migrans lesion and local lymphadenopathy, serologic testing is not recommended, because it will be too early for antibody production ( ). Thus, if the patient has the characteristic erythema migrans lesion, treatment should be instituted in spite of the negative serologic test. Convalescent serum samples 2 weeks after the onset of symptoms may help confirm the diagnosis, although patients treated very early may never develop antibodies. For early disseminated disease (stage 2) with lymphocytic meningitis, facial nerve paralysis or radiculoneuropathy, or late Lyme disease (stage 3, Lyme arthritis), current recommendations are for the use of a two-tier (two-step) approach, checking for Borrelia -specific antibodies using IgM and IgG enzyme-linked immunosorbent assay (ELISA), and if the ELISA is positive, followed by Western blotting ( ; ). Western blots should not be performed in patients with a negative ELISA. Newer ELISAs that use recombinant proteins, and in particular against the C6 peptide, have shown comparable or higher sensitivity but higher specificity during early infection ( ). Based on these new enzyme immunoassays, the CDC has updated its recommendations and now includes a two- tier format using two sequential enzyme immunoassays as an alternative to serologic diagnosis of Lyme disease ( ).

With suspected involvement of the CNS, testing for intrathecal production of Lyme-specific antibodies is important in establishing the diagnosis. The demonstration of anti- Borrelia antibodies in serum or CSF alone does not constitute evidence of neuroborreliosis, because they may originate by passive transfer from blood, and many individuals from endemic areas have positive IgG and IgM antibodies in the absence of borreliosis or neuroborreliosis. To establish the presence of intrathecal synthesis of anti- Borrelia antibodies, and the diagnosis of neuroborreliosis, the use of an antibody index comparing proportions of CSF to serum antibodies has been recommended ( ; ). The index is defined as the ratio of B. burgdorferi –specific IgG in the CSF to B. burgdorferi –specific IgG in serum, in relation to the total IgG in CSF and total IgG in serum. In a group of established cases of neuroborreliosis, the index had a diagnostic sensitivity of 75% with a specificity of 97%. A limitation of this assessment is the fact that it has a low sensitivity early in the disease, and an elevated CSF-to-serum ratio can persist for years after treatment ( ). In addition, patients with pure peripheral nerve syndromes may not have an increased intrathecal production of antibody. More recently, the CSF concentration of CXCL-13, a B-cell attracting chemokine, has been proposed as a potential test for neuroborreliosis ( ; ).

Lumbar puncture for CSF analysis provides additional evidence of CNS involvement with meningeal inflammation. This typically shows a mild or moderate lymphocytic pleocytosis with a mildly increased protein concentration and normal glucose levels ( ; ). An increased IgG index and oligoclonal bands can also be observed. These findings could help differentiate other conditions with similar symptoms but without meningeal inflammation and may suggest the diagnosis of neuroborreliosis in patients with facial nerve palsies or painful radiculitis. As previously mentioned, some patients with strictly peripheral nervous system involvement may not have an associated pleocytosis or meningeal inflammation ( ).

EMG and NCS will help establish a radicular pattern of involvement and the presence of a mononeuritis multiplex or axonal polyneuropathy. Among the findings described in studies, there can be reduced-amplitude motor and sensory responses with preserved conduction velocities, consistent with an axonal polyneuropathy, and denervation in limb muscles extending to the paraspinal muscles consistent with a radicular lesion ( ; ; ). These findings may coexist.

MRI findings are not specific for neuroborreliosis, and its role may be more to exclude alternative diagnoses or to establish parenchymal CNS involvement. MRI of peripheral neuroborreliosis may provide indirect confirmatory evidence of inflammation by showing enhancement of cranial nerves in patients with cranial neuropathies or enhancement of lumbosacral roots in patients with lumbosacral radiculitis (Bannwarth syndrome) ( ).

Treatment and Management

Patients with Lyme neuroborreliosis should be treated as soon as diagnosed to prevent potential dissemination and sequelae. Current recommended regimens appear to be highly effective. An evidence-based review published by the American Academy of Neurology has shown that parenteral regimens with ceftriaxone and oral regimens with doxycycline are highly effective in both adult and pediatric neuroborreliosis ( ). Alternative parenteral choices can be cefotaxime or penicillin. Oral doxycycline has been shown to be as effective as parenteral ceftriaxone and has been used in Europe with success ( ). Doxycycline (100 mg orally twice daily in adults and in children 2.2 mg/kg twice daily to a maximum of 100 mg per dose) is considered the preferred choice for uncomplicated cases with facial neuropathies or radiculitis. Published studies have used treatment courses of 10 to 28 days, although the current recommendations are for a 14-day course; there appears to be no significant difference in the outcome. Oral doxycycline can be used for facial nerve palsy, even in the context of abnormal CSF findings (pleocytosis), and for radiculoneuritis or uncomplicated Lyme meningitis. Doxycycline is contraindicated in children younger than 8 years and in pregnant women. In these cases, amoxicillin or cefuroxime axetil are considered alternate choices. In the context of CNS parenchymal involvement (encephalitis or encephalomyelitis, which is rare), IV treatment is recommended. Recommended regimens include (1) ceftriaxone 2 g IV once daily in adults, and in children, 50 to 75 mg/kg IV once daily to a maximum of 2 g; (2) cefotaxime 2 g IV every 8 hours in adults, and in children, 150 to 200 mg/kg IV in three divided doses per day to a maximum of 6 g per day; and (3) penicillin G, 18 to 24 million units per day IV divided in six doses, and in children, 200,000 to 400,000 units/kg per day divided in six doses to a maximum of 18 to 24 million units per day. The duration of treatment will vary with severity; a 14-day course appears adequate in patients with uncomplicated disease, or up to 21 to 28 days in more complicated cases.

No benefit has been shown for prolonged treatment with antibiotics beyond 4 weeks or for the treatment of “post-treatment Lyme disease syndrome” and so it is not recommended ( ; ). Clinicians should be aware that improvement after antibiotic therapy is slow and continues after completion of therapy. This pattern should not be confused with failure of treatment, which would be suspected only if new deficits or symptoms arise. Treatment failures with ceftriaxone and doxycycline may be seen, and alternative antibiotics may be considered in those instances. Nonsteroidal anti-inflammatory agents may be helpful for treating the myalgias, arthralgias, and headache associated with the systemic disease ( ). The use of steroids as part of the treatment, in particular for facial neuropathy, has not been shown to be either beneficial or detrimental and at the present time is not recommended.

Diagnosis and Evaluation

Early diagnosis is critical because lack or delayed treatment of neuropathy in leprosy will lead to irreversible atrophy and weakness, profound sensory loss, and anesthesia, with damage and mutilation from repeated injuries and trauma. The diagnosis can be made by demonstrating organisms in skin or nerve biopsy ( Fig. 16.1 ) and the presence of serologic markers such as phenolic glycolipid-1 and polymerase chain reaction in tissue.

Nerve biopsy of an affected sensory cutaneous nerve is an important diagnostic tool, in particular in patients without skin lesions with pure neuritic leprosy. The biopsy findings vary between the different subtypes of leprosy. In tuberculoid leprosy, the nerve biopsy shows marked nerve destruction, with abundant inflammatory infiltrates in the epineurium, endoneurium, and perineurium, with prominent granuloma formation, differential fascicular loss of axons with involved fascicles adjacent to normal ones, and with few or no organisms seen. In lepromatous leprosy, there is axonal loss, more prominent of unmyelinated fibers, with variable degrees of inflammation, presence of foamy cells (macrophages and Schwann cells), and numerous bacilli ( ; ). There can be discrepancy between the classification based on clinical features and the histologic classification based on nerve biopsy, leading some authors to recommend including the nerve biopsy findings in the classification and selection of therapy ( ).

NCSs are more sensitive at detecting peripheral nerve involvement than the clinical examination. Among the electrodiagnostic tests, sensory NCSs and, in particular, sensory amplitudes and sensory conduction velocities, as well as warm perception thresholds, are among the earliest abnormalities observed and are the most sensitive measures, even in the subclinical stages ( ; ). Motor nerve conductions can also be abnormal, even before clinical signs are apparent. Based on the frequency of involvement, NCSs should be performed in the ulnar, median, and superficial radial nerve in the upper limbs and the peroneal, posterior tibial, and sural nerves in the lower limbs. The trigeminal and facial nerves should also be tested. Nerve ultrasound presents another complementary strategy to detect nerve abnormalities such as abnormal thickening and asymmetry in patients with leprosy. In some instances, it can show abnormalities when neurophysiological parameters are still normal and can provide evidence of worsening of the neuropathy after treatment.

Treatment and Management

Management of leprosy neuropathy involves managing the neurologic and physical deficits resulting from the nerve damage. Management of decreased sensation in hands and feet requires prevention of injuries, frequent evaluation for painless lesions and immediate treatment. Patients should be instructed to inspect the areas at risk on a daily basis, including the soles with the help of a mirror. Special footwear for prevention of plantar ulcers can be used. Gloves should be used for tasks that may result in skin damage. Assessment for incomplete eye closure and corneal exposure requires protective measures and may require corrective surgery.

Delayed treatment or no treatment of leprosy neuropathy is a major cause of disability, deformity, morbidity, and social isolation in these patients. Treatment of leprosy and leprosy neuropathy involves both antibacterial therapy and strategies to limit inflammatory reactions. Current antibacterial treatment involves multidrug therapy (MDT) to prevent resistance and varies between patients with paucibacillary or multibacillary disease. The first-line medications include dapsone, rifampin, and clofazimine for lepromatous disease. These medications are effective against both infectious agents, M. leprae and M. lepromatosis . Treatment recommendations, primarily duration of treatment, differ between the National Hansen’s Disease Program (NHDP) and the World Health Organization. The NHDP current treatment recommendation for tuberculoid leprosy (paucibacillary disease) consists of 12 months of rifampicin (600 mg/day) and daily dapsone (100 mg). For lepromatous (multibacillary) leprosy, a recommended treatment is clofazimine (50 mg/day), added to dapsone and rifampicin and given for 24 months. Clofazimine is available in the United States only by registering as an investigator under the NHDP investigational new drug application ( www.hrsa.gov/hansens-disease ). Patients are rendered noninfectious within 72 hours of treatment.

Treatment of leprosy may result in inflammatory reactions termed type 1 and type 2 (reversal) reactions . These immunologically mediated reactions may result in increased nerve damage and increased disability. With type 1 reactions, patients may observe enlargement of a preexisting skin lesion or the development of acute, painful nerve palsies. This reaction requires immediate treatment with prednisone at initial doses of 40 to 60 mg (1 mg/kg) lasting for 4 to 6 months and a higher dose if there is no improvement within 48 hours. Patients who have not responded to steroids after 6 weeks may be referred for surgical decompression (neurolysis). Patients with multiple or large lesions on the face may benefit from prophylactic steroids for 4 months at the start of MDT. Methotrexate and cyclosporine have been proposed as alternatives or second-line treatments for type 1 reactions. Type 2 reactions (erythema nodosum leprosum) are mostly seen in lepromatous leprosy and will present with painful erythematous papules and systemic symptoms such as fever, uveitis, fatigue, and lymphadenopathy. They will also require prompt intervention with steroids at high doses and often with repeated treatments. Prednisone (40 to 60 mg/day) should be started promptly to avoid permanent nerve damage, and quickly tapered over a 2-week period? Thalidomide has also been recommended for the management of type 2 reactions, although this therapy may be complicated by the development of drug-induced neuropathy and must be used with caution. Only prescribers under a US FDA restricted distribution program (Risk Evaluation and Management Program) are allowed to prescribe thalidomide.