Neuropathies can result directly from various bacterial and viral infections, as well as from an indirect or parainfectious autoimmune response to the infection (Table 17-1). Parainfectious neuropathies (e.g., Guillain–Barré syndrome associated with various infections and vasculitis associated with hepatitis) are discussed in detail in other chapters.

CLINICAL FEATURES

Leprosy is caused by the acid-fast bacteria Mycobacterium leprae. Leprosy is the most common cause of peripheral neuropathy in Southeast Asia, Africa, and South America. The main route of transmission is felt to be from person-to-person spread via nasal droplets. The bacteria is very slow growing with an incubation period that can vary between 2 and 40 years, customarily between 5 and 7 years.¹

There is a spectrum of clinical manifestations ranging from tuberculoid leprosy at one end to lepromatous leprosy on the other end of the spectrum, with borderline leprosy in between based upon the Ridley–Joplin classification (Table 17-2).^1–5 The World Health Organization (WHO) introduced a simpler classification based on the number of skin lesions to help guide treatment: multibacillary (six more skin lesions) and paucibacillary (fewer than six skin lesions) leprosy.¹ In general, lepromatous leprosy is always multibacillary, and tuberculoid leprosy is usually paucibacillary; borderline leprosy can be either multibacillary or paucibacillary. The clinical manifestations of the disease are determined by the immunological response of the host to the infection. In tuberculoid leprosy, the cell-mediated immune response is intact.^1–5 Thus, there are focal, circumscribed inflammatory responses to the bacteria within the affected areas of skin and nerves. The resulting skin lesions appear as well-defined, scattered hypopigmented patches and plaques with raised, erythematous borders (Figs. 17-1 and 17-2). Cutaneous nerves are often affected, resulting in a loss of sensation in the center of these skin lesions. Cooler regions of the body (e.g., face and limbs) are more susceptible than warmer regions such as the groin or axilla. In addition, the ulnar nerve at the medial epicondyle, the median nerve at the distal forearm, the peroneal nerve at the fibular head, the sural nerve, the greater auricular nerve, and the superficial radial nerve at the wrist are common sites of involvement and become encased with granulomas, leading to mononeuropathy or mononeuropathy multiplex. These nerves are thickened and often palpable.

In lepromatous leprosy, cell-mediated immunity is severely impaired, leading to extensive infiltration of the bacilli and hematogenous dissemination, producing confluent and symmetrical areas of rash, anesthesia, and anhidrosis.^1–5 Neuropathies tend to be more severe in the lepromatous subtype. As in the tuberculoid form, there is a predilection for the involvement of cooler regions of the body. Infiltration of the organism in the face leads to the loss of eyebrows and eyelashes and exaggeration of the natural skin folds, leading to the so-called “leonine facies.” Superficial cutaneous nerves of the ears and distal limbs are also commonly affected. A slowly progressive symmetric sensorimotor polyneuropathy gradually develops due to widespread invasion of the bacilli into the epi-, peri-, and endoneurium. Distal extremity weakness may be seen, but large fiber sensory modalities and muscle stretch reflexes are relatively spared. Involvement of nerve trunks leads to superimposed mononeuropathies, including facial neuropathy.

Neuropathies are most common in patients with borderline leprosy.^2,3,5 Patients can develop generalized symmetric sensorimotor polyneuropathies, mononeuropathies, and mononeuropathy multiplex, including multiple mononeuropathies in atypical locations, such as the brachial plexus. Borderline leprosy is associated with clinical and histological features of both the lepromatous and the tuberculoid forms of leprosy (Table 17-2 and Fig. 17-3). There is partial impairment in cellular immunity in patients with borderline leprosy, such that there is some degree of mycobacterial spread as well as an inflammatory response. The immunological state is considered unstable in patients with borderline leprosy in that the immune response and clinical manifestations can shift up and down the spectrum.

Patients with leprosy may present with isolated peripheral neuropathy without skin lesions, particularly in endemic areas.^6,7 Most cases of the so-called pure neuritic leprosy have the tuberculoid or borderline tuberculoid subtypes of the disease.

LABORATORY FEATURES

Sensory nerve conduction studies (NCS) are usually absent in the lower limb and are reduced in amplitude in the arms.^1,6,7 Motor NCS may demonstrate reduced amplitudes in affected nerves.^8,9 Motor conduction velocities are normal or slightly reduced; however, a few patients may demonstrate values less than 20 m/s in both the upper and the lower limb. Electromyography (EMG) reveals mild-to-moderate degrees of active denervation. The pattern of involvement on the EMG and NCS can be generalized as symmetric or reflective of a mononeuropathy or multiple mononeuropathies, as apparent from the clinical features. Ultrasound can demonstrate enlarged axons, particularly of the median nerve in distal forearm near the carpal tunnel and of the ulnar nerve just proximal to the medial epicondyle (Fig. 17-4).¹⁰

HISTOPATHOLOGY

Leprosy is usually diagnosed with skin lesion biopsy and using the Fite method to stain the acid-fast bacilli red (Fig. 17-3).³ The morphological index (MI) is the ratio of viable to nonviable organisms on skin smears. The bacteriological index (BI) is a logarithmically scaled measure of the density of bacilli in the dermis. Both the MI and BI have been used to measure treatment response.

The host’s immune response to the bacilli determines the histopathology (Table 17-2).^1–5 Nerve biopsies can also be diagnostic, particularly when there are no apparent skin lesions. The tuberculoid form is characterized by granulomas formed by macrophages and T lymphocytes (CD4 T lymphocytes greater than CD8). Caseatiing granulomas may or may not be present. Importantly, bacilli are not seen. In contrast, with lepromatous leprosy, large number of infiltrating bacilli, CD8 greater than CD4 lymphocytes, and organism-laden, foamy macrophages with minimal granulomatous infiltration are evident (Fig. 17-5A). The bacilli are best appreciated using the Fite stain, where they can be seen as red staining rods in clusters within the endoneurium, within macrophages, or within Schwann cells (Fig. 17-5B). On electron microscopy, the bacilli appear as dense osmiophilic rods surrounded by a clear halo (Figs. 17-5C and D). Borderline leprosy can have histological features of both tuberculoid and lepromatous leprosy.

PATHOGENESIS

The clinical and pathological spectrum of the disease is dependent on the host’s immune response to M. leprae and reflects the relative balance between the Th1 and Th2 response (Table 17-2).^1–5 The tuberculoid form defines one end of the spectrum, in which the CD4 T cells predominate. These CD4 T cells produce interleukin-2 and gamma-interferon which in turn lead to activation of macrophages. On the other extreme, the lepromatous form is dominated by CD8 cells, which produce interleukin-4, interleukin-5, and interleukin-10, thereby downregulating cell-mediated immunity and inhibiting macrophages. The borderline subtypes exhibit immune responses spanning the spectrum between the tuberculoid and lepromatous forms.

TREATMENT

Patients are treated with multiple drugs: dapsone, rifampicin, and clofazimine depending on the form of leprosy they have (Table 17-2).^1–4 The current WHO recommendations for adults with multibacillary leprosy are as follows: rifampicin (600 mg once a month), dapsone (100 mg daily), and clofazimine (300 mg once a month and 50 mg daily) for 1 to 2 years.¹¹ For adults with paucibacillary leprosy, the WHO recommends rifampicin (600 mg once a month) and dapsone (100 mg daily) for 6 months.¹¹ For adults with single skin lesion paucibacillary leprosy the recommended WHO regimen is a single dose of rifampicin: 600 mg, ofloxacin: 400 mg, and minocycline: 100 mg. Proven relapses are re-treated with multidrug regimen.

The WHO recommendations are controversial as there have been no clinical trials to support their efficacy and the relapse rate of multibacillary leprosy is high. Thus, some advocate for more aggressive treatment based in part on Ridley–Joplin classification: tuberculoid leprosy to be treated with dapsone 100 mg daily for 5 years and lepromatous leprosy to be treated with rifampin 600 mg daily for 3 years and dapsone 100 mg daily for life.¹

Patients should be instructed on the side effects of these medications before starting treatment. Rifampicin may make the urine turn a slightly reddish color for a few hours after its intake. Clofazimine causes brownish-black discoloration and dryness of skin. However, this disappears within few months after stopping treatment. The main side effect of dapsone is allergic reaction, causing itchy skin rashes and exfoliative dermatitis. Patients known to be allergic to drugs containing sulfa should not be given dapsone.

Treatment is sometimes complicated by the so-called reversal reaction, particularly in borderline leprosy.^1–3 The reversal reaction can occur at any time during treatment and develops because of a shift to the tuberculoid end of the spectrum, as the result of an increase in cellular immunity during treatment. The cellular response is upregulated as evidenced by an increased release of tumor necrosis factor-alpha, gamma-interferon, and interleukin-2 with new granuloma formation. This can result in an exacerbation of the skin lesions and the neuropathy. High-dose corticosteroids blunt this adverse reaction and is often used prophylactically in high-risk patients (i.e., those with borderline leprosy) at treatment onset.

Erythema nodosum leprosum is another adverse reaction that usually occurs during treatment of patients with lepromatous leprosy.^1–3,12 Multiple erythematous, sometimes painful, subcutaneous nodules appear, and may be associated with worsening of the neuropathy. Erythema nodosum leprosum probably results from slow degradation of bacilli and release of new antigens. Subsequently, antigen–antibody complexes form and complement is activated in affected tissue. Erythema nodosum leprosum is commonly treated with corticosteroids, clofazimine, or thalidomide.

A recent review looked at 13 studies involving 445 participants treated for erythema nodosum leprosum with corticosteroids, clofazimine, thalidomide, and other agents (i.e., pentoxifylline, indomethacin, and levamisole).¹² The quality of the trials was generally poor and results could not be pooled due to the treatments being so heterogeneous. That said, clofazimine treatment was felt to be superior to prednisolone and thalidomide.¹²

Prevention of leprosy is of primary importance. It is recommended that children exposed to leprosy in the household be prophylactically treated with rifampin daily for 6 months.^2,3 Various vaccinations are available, including BCG, killed leprae, and chemically modified organisms.

CLINICAL FEATURES

Lyme disease is caused by infection with Borrelia burgdorferi, a spirochete, transmitted by ticks. The deer tick, Ixodes dammini, is responsible for the disease in most cases. Ticks acquire the spirochetes by feeding on an infected host (e.g., deer) and then transmit the spirochetes to the next host (e.g., humans) at a later feed. It takes approximately 12–24 hours of tick attachment to transfer the spirochetes.

There are three recognized stages of Lyme disease: (1) early infection with localized erythema migrans, (2) disseminated infection, and (3) late-stage infection. The localized response occurs within 1 month of a tick bite. It consists of an erythematous circular region centered around the area of the original tick bite. The erythematous area gradually expands and the center of the lesion becoming clear creating a bull’s eye appearance. The rash resolves spontaneously after approximately a month. Importantly, not all patients with Lyme disease develop erythema migrans. The second stage of the illness is marked by dissemination of the spirochetes throughout the body. Patients develop systemic symptoms including fever, chills, localized adenopathy, fatigue, myalgias, headache, neck and back pain, and additional skin lesions about the body. Cardiac involvement may lead to pericarditis and heart block. Inflammatory arthritis of large and small joints may also occur.

Neurological complications may develop during the second and third stages of infection (Table 17-3).^13–22 Facial neuropathy is the most common neurological manifestation of Lyme disease and is bilateral in about half of cases, which is rare for idiopathic Bell palsy. Involvement of nerves is frequently asymmetric. Patients with Lyme disease may also manifest with multiple mononeuropathies or, more commonly in our experience, with radiculopathy or polyradiculopathy. Although often considered in the differential diagnosis of GBS, it usually does not resemble cases of GBS given the asymmetric nature and electrophysiological features (see below). Rarely, affected patients develop an inflammatory myopathy as opposed to neuropathy.²²

The late stage of infection is characterized by further destructive inflammatory changes in the joints. The distal extremities develop a bluish discoloration of the skin (acrodermatitis chronica atrophicans). Spirochetes may be readily cultured from biopsies of these sites. Approximately 50% of patients have numbness, paresthesia, weakness, and cramps in the distal extremities, and proprioception and vibration are reduced as are muscle stretch reflexes.

LABORATORY FEATURES

Examination of the cerebrospinal fluid (CSF) should demonstrate lymphocytic pleocytosis and increased protein in patients with polyradiculitis, cranial neuropathies, and central nervous system involvement. Immunofluorescent or enzyme-linked immunosorbent assay may detect antibodies directed against the spirochete in the serum and CSF. False-positive reactions are not uncommon and, therefore, Western blot analysis should be performed to confirm a positive enzyme-linked immunosorbent assay.

Electrodiagnostic studies are suggestive of a primary axonopathy. In a patient with a mononeuropathy or multiple mononeuropathies, NCS typically reveal reduced compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes.^13,17–22 Those with facial nerve palsies have reduced facial nerve CMAPs and abnormal blink reflexes.¹⁵ The electrophysiological abnormalities are often asymmetric.^23,24 Needle EMG reveals increased insertional and spontaneous activity in the form of fibrillation potentials and positive sharp waves and decreased recruitment of neurogenic-appearing motor unit action potentials (MUAPs). Patients presenting with a radiculopathy may have normal motor and sensory NCS, but the EMG is abnormal as above.

HISTOPATHOLOGY

Nerve biopsies are not typically performed in patients with Lyme disease and symptoms of neuropathy, but can reveal perivascular infiltration of plasma cells and lymphocytes around small endoneurial, perineurial, and epineurial blood vessels without clear necrotizing vasculitis. Axonal degeneration and secondary demyelination can be seen.

PATHOGENESIS

Peripheral nerve involvement may be the result of an indirect immunological response and/or some form of vasculopathy.

TREATMENT

Recommended treatment of facial nerve palsies in adults is the combination of amoxicillin 500 mg p.o. q.i.d. plus probenecid 500 mg q.i.d. for 2–4 weeks. Patients who are allergic to penicillin can be treated with doxycycline 100 mg p.o. b.i.d. for 2–4 weeks. Children less than 4 years of age can be treated with amoxicillin 20–40 mg/kg/d in four divided doses for 2–4 weeks. If allergic to penicillin, children can be treated with erythromycin 30 mg/kg/d in four divided doses for 2–4 weeks.