LEPROUS NEURITIS

Leprous neuritis is a true bacterial infection of peripheral nerves, and nerve invasion is a major hallmark of the disease. The disease has been known since biblical times, and archeological studies of human remains have documented that leprosy did exist in that era. Recent studies based on single nucleotide polymorphisms of the bacillus have pinpointed the origins of leprosy to East Africa, with subsequent spread to Europe and Asia before being reimported into West Africa by explorers.¹ In earlier times, the disease was very common in Europe, especially in Scandinavia and England. In 1200 AD, there were some 200 “lazar” houses in the British Islands. There had been an endemic focus in the United States within 100 miles of the Gulf Coast of Texas, Louisiana, and Florida, and a smaller focus in the Midwest originating from Scandinavian immigrants. Now, there are only a few thousand cases in the United States, almost all of foreign origin.

There has been great recent progress in the control of this disease, which is now most common in underdeveloped countries. Newer methods of treatment, especially the introduction of multiple drug therapy (MDT), have resulted in a dramatic decline in active cases. There are now on the order of 300,000 active cases, whereas there were about 14 million cases 20 years ago.² Many cases are cleared from the active rolls after therapy is given, without follow-up, but the newer drugs seem to be associated with only a small percentage of resistant or relapse cases. The plan of the World Health Organization (WHO) has been to reduce the caseload to such a low level (1 case per 10,000 population) that further transmission becomes unlikely.³ This idea harkens back to the observation that leprosy disappeared from most of Europe following the loss of more than a third of the population in the wake of the Black Plague. This was attributed to a critical decline in the number of infective cases in population centers.

The history of leprosy is remarkable because of the stigma accompanying the disease in almost all cultures. The dreaded disease was considered to be a punishment of the gods for the sins of venery or egotism. This stigma is due to the chronicity of the disease, combined with the terrible disfigurement of the visible face and hands, which evoke highly negative visceral responses in the beholder.

The organism, Mycobacterium leprae, first seen in 1874 by G.H. Armauer Hansen in Norway, is the first bacterium that was associated with a human disease. M. leprae is less acid-fast than M. tuberculosis and requires the Fite modification for acid-fast staining. The ability to invade human nerves is unique, and recent studies of the bacillus have revealed that the actual site of nerve attachment and invasion is the alpha-dystroglycan moiety of Schwann cell myelin.⁴ The entire genetic sequence of the bacterium has also recently been elucidated, and demonstrates that the organism is highly specialized as an obligate intracellular human pathogen, and has lost many of the enzymatic functions that other acid-fast bacilli have maintained.⁵ These data may account for the failure to grow M. leprae on artificial media, and the difficulty to infect animals (mouse footpads and genetically susceptible armadillos). M. leprae has a highly thermosensitive growth rate: optimum cell division occurs once per 12.5 days at 27°C to 32°C. There is no growth at core body temperature, and therefore the viscera and central nervous systems are not involved in this disease. This feature limits leprosy to the skin, the anterior third of the eyes, the upper respiratory tract, and the testes. The incubation period varies from several weeks to several years. Children under 16 appear more susceptible to the disease, as are patients with certain types of immunosuppression. Although acquired immunodeficiency syndrome (AIDS) and leprosy are both very common in certain areas such as Africa, AIDS does not seem to increase the vulnerability or severity of coexistent leprosy. The disease is probably spread by infected nasal droplets (where bacteria remain viable for several days) and prolonged skin-to-skin contact.

Leprosy may manifest as a neuropathy, and a well-informed neurologist is capable of making a definitive bedside diagnosis, even in cases where the disease has been fully treated and only residual neurological deficits remain, or in the more rare patient who is trying to conceal the diagnosis. Early diagnosis is critical because one can expect to halt the progress of the neuropathy, and even obtain some degree of reversal. However, severe deficits may remain in advanced cases even after the patient is successfully treated. Cases may be misdiagnosed at medical centers in developed countries because the possibility of leprosy is not considered.

Although there is only one causative organism, the clinical picture of leprosy is wide and related to the host’s innate immune response to M. leprae. In most human populations, 90% to 95% of individuals are genetically equipped to clear the bacilli completely. When resistance is high but insufficient to entirely prevent the disease, “high resistance” tuberculoid or paucibacillary leprosy occurs. Tissue temperature has only a permissive role in shaping this clinical picture. Rather, local invasion by very few bacilli evokes a vigorous epitheloid granulomatous response, which destroys intracutaneous nerves as the lesion forms. The typical patient shows one or a very few asymmetrically dispersed, hypopigmented, anhydrotic skin lesions (Fig. 84-1). A dry patch with pain and temperature loss coinciding with the skin lesion is the diagnostic picture of paucibacillary leprosy (Fig. 84-2). The skin lesion shows central clearing and a slightly raised edge. The centers of such lesions are often clear of bacilli. For diagnosis, the skin biopsy sample should be taken at the elevated edge. Serial sections may be required to see just one or a few bacilli.

Figure 84-1 Sensory map of tuberculoid leprosy.

(From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2088, Figure 91-3.)

Figure 84-2 Skin lesion of tuberculoid leprosy.

(From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2085, Figure 91-2B.)

When the host has little inborn resistance to the invasion of bacilli, these become widespread and numerous, with hematogenous spread and reproduction in the cooler tissues. Thus, the skin lesions and nerve involvement are roughly symmetric. This form of leprosy is called lepromatous. The palpably enlarged nerves present in this form of leprosy narrow the differential diagnosis. The invasion of intracutaneous nerve networks is manifested by a pattern of temperature-linked sensory loss that starts in the coolest regions of the body, around the breast plate, tip of the nose, lobes and helices of the ears (Fig. 84-3). Once this temperature-linked pattern of sensory loss is discerned, the diagnosis becomes apparent.⁶ Over the years, the pattern progresses to “less cool” regions and results in very extensive sensory loss, sparing only areas over the carotid arteries, the anterior neck, armpits, inguinal folds, intergluteal folds, and the precordium (Fig. 84-4). The insulating effect of corium of the hands and feet make the tissue temperatures beneath these surfaces somewhat warmer, so that sensory loss tends to occur over the dorsa of hands and feet rather than over the soles and palms. The distribution of skin lesions is also temperature dependent, and roughly approximates the distribution of sensory loss. There are striking examples of small differences in temperature creating distinctive features on the sensory examination. Facial sensation becomes normal at the hairline because of the insulating effect of hair. For example, the old leprosy atlases depict men who followed the Samurai tradition of shaving their heads and experienced leprosy lesions in the scalp; when they let their hair grow back, there was destruction of the follicles except over the warm areas overlying the temporal arteries. The cooler hemiplegic side of a stroke victim showed more extensive sensory loss. Sensory-sparing underbelts, watchbands, and other snug garments have also been documented.

Figure 84-3 Sensory map of early lepromatous leprosy.

(From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2090, Figure 91-5.)

Figure 84-4 Sensory map of chronic lepromatous leprosy.

(From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2091, Figure 91-6.)

The major named nerves, which run closest to the surface of the body, are also affected in a predictable fashion (Fig. 84-5). Thus, the deep peroneal branch to the extensor digitorum brevis of the foot and the ulnar nerve proximal to the olecranon groove are involved early. The median nerve segment from the wrist crease to where it is covered by the forearm flexor muscle group is affected later, with further sensory loss and paralysis of median-innervated intrinsic muscles. Foot drop ensues when the peroneal nerve is affected as it circles around the head of the fibula. Multiple branches of the facial nerve are involved, particularly affecting the medial corrugators of the forehead, the small twigs to the orbicularis oculi and to the muscles composing the nasolabial folds, so as to create a highly diagnostic, patchy paralysis described by Monrad-Krohn.⁷ If one actually severed the ulnar, median, and peroneal nerves at the sites affected by leprosy, the corresponding deep tendon reflexes would remain intact. The preservation of deep tendon reflexes in the presence of significant peripheral neuropathy is yet another very helpful diagnostic feature.

Figure 84-5 The most commonly affected nerves in leprosy.

(From Sabin TD, Swift TR, Jacobson RR: Leprosy. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2089, Figure 91-4.)

Although there are many intermediate forms between these polar types of leprosy, complex interplay between the two themes—tissue temperature and natural immunity of the host—can always be discerned. These cases are labeled dimorphous, borderline, or intermediate. Modern leprosy workers tend to divide all cases into paucibacillary and multibacillary for purposes of management. Among the high-resistance dimorphous cases, there is a group called pure neural leprosy. These patients have no skin lesions but extensive nerve damage, and they can be very difficult to diagnosis, even on sophisticated neurological services. A nerve biopsy may be helpful (the sural or cutaneous branches of the radial nerve are good sites), but a fascicular biopsy at a site of clinical involvement will have the best yield. Polymerase chain reaction techniques can also help in this situation.⁸

Alterations in immune response, known as leprosy reactions, occur in some patients. In high-resistance cases, there may be a sudden increase in cell-mediated immunity causing acute inflammation of existing lesions and rapid onset of deficits in neighboring and subjacent nerves that had already been invaded by bacilli. The nerve damage will be permanent unless this situation is rapidly recognized and treated with steroids. In multibacillary patients, there is an entity called erythema nodosum leprosum. Here, the circulating immune response goes awry and produces what resembles an autoimmune disease. Features of an Arthus reaction, including consumption of complement and arteritis, are present. Although there are systemic symptoms, the brunt of the damage occurs in the area of greatest bacillary density. Except for the distribution, the erythema nodosum looks the same as in other systemic diseases. Rapid, widespread nerve pain and dysfunction results from vasculitis of the vasa nervorum. This is a situation that must also be quickly recognized. The treatment of choice is thalidomide, but steroids can be used if thalidomide is contraindicated or not available.

In addition to direct nerve invasion and leprosy reactions, there are additional causes of nerve damage. The enlarged nerves seen in leprosy are much more vulnerable to repeated trauma and compression, particularly the peroneal nerve at the fibular head, and the ulnar nerve proximal to the olecranon groove. This situation may require nerve repositioning or decompressive surgery.

Electrodiagnostic studies are nondiagnostic. In multibacillary forms of the disease, they reveal a mononeuritis multiplex.

When early diagnosis is made, most people require only antibacterial treatment. The most effective antibacterial regimen for M. leprae includes the drugs dapsone, clofazimine, rifampin, ofloxacin, and minocycline. The course of antibacterial therapy depends on whether the patient has the paucibacillary or multibacillary forms of leprosy. Paucibacillary patients receive 100 mg of dapsone daily with rifampin 600 mg monthly for 6 months. Multibacillary patients are given the same combination for 1 year, in addition to clofazimine 50 mg daily, with a monthy 300-mg dose of clofazimine. Shorter regimens used by WHO also make the patient noninfectious in a few days and have an extremely low relapse rate for both types of disease.⁹ The addition of rifampin has made the greatest difference in the antibacterial treatment of leprosy since the introduction of dapsone in 1940.

Treatment of leprosy reactions is very important because widespread neurological damage can occur in either type. When there is neuritis in paucibacillary reactions, steroids generally control the reactive process. Occasionally, high doses may be needed. With erythema nodosum leprosum reactions seen in multibacillary cases, thalidomide is the treatment of choice in a dose of 300 to 400 mg/day. The reaction generally abates in 24 to 48 hours. If thalidomide is not available, steroids can be used. Obviously, very strict precautions must be used in women of childbearing age who are administered thalidomide. Clofazimine has a role both as an antibacterial and in helping to control erythema nodosum leprosum.

Certain surgeries are available for advanced cases, such as nasal reconstruction after bony collapse of the bridge of the nose, and correction of gynecomastia secondary to destructive mycobacterial orchitis. Tendon transfer procedures are used to correct clawing of the hands and foot drop.

The management of insensitivity to pain is one of the more challenging aspects of the disease. When there is extensive loss of pain sense in actively used extremities, the patient suffers loss of the digits in a process known as absorption. Without intervention, the patient inevitably accumulates many small wounds and burns. Since these injuries are not painful, they tend to be neglected and this permits infection of deeper tissues. Over a period of years, multiple bouts of mild osteomyelitis result in shrunken, deformed, and eventually useless hands and feet. While these deformities are considered characteristic of leprosy, they also occur in hereditary sensory neuropathy, diabetic neuropathy, and syringomyelia, all situations where there is loss of pain sensation in limbs that can still be actively used. Treatment focuses on educating the patient to the dangers of loss of pain sensation, treating every wound assiduously with splinting, avoidance of infection, prevention of repetitive injury to the same area, and monitoring the hands and feet for signs of tissue stress (heat, redness, callus, and ecchymoses). Special footwear with molded insoles to spread pressure evenly over the sole of the foot is very effective in preventing “trophic” ulcers. Occupational therapists can identify dangerous activities in the home or workplace, where special devices may be used to prevent painless but dangerous injuries. Loss of sweating in the hands and feet results in cracking of the skin, which serves as another portal of entry for infection. This problem can be solved by daily soaking of the hands and feet, followed by application of a cream to seal in the moisture.

The patient with early leprosy may be easy to treat by eradication of the bacilli, but an advanced case may require a team approach, including physical therapist, occupational therapist, shoemaker, vocational therapist, reconstructive surgeon, and psychosocial rehabilitation specialist.

HUMAN IMMUNODEFICIENCY VIRUS

Human immunodeficiency virus (HIV) is associated with diverse peripheral nervous system complications (Table 84-1). The specific type of peripheral nervous system syndrome is dictated by the severity of the HIV infection, as determined by CD4⁺ cell counts.¹⁰ Prospective studies indicate that the incidence of symptomatic peripheral nervous system complications due to HIV is around 3%, and complications are more common in more advanced cases.¹¹ If peripheral nervous system complications are assessed by clinical symptoms and electrophysiological tests, the incidence in prospective studies is much higher, at least 30%, and advanced HIV infection again poses a higher risk. Assessing the epidemiology of HIV-related peripheral nervous system complications is confounded by the fact that several common antiretroviral drugs used to treat HIV are themselves toxic to peripheral nerves.

TABLE 84-1 Peripheral Nervous System Complications From Human Immunodeficiency Virus Infection

HIV seroconversion may be accompanied by an acute peripheral nervous system process, most commonly unilateral but also bilateral facial nerve palsies.¹² Guillain-Barré syndrome is known to occur at the time of HIV seroconversion, and Guillain-Barré syndrome may be the presenting feature of HIV infection. The Guillain-Barré syndrome associated with HIV is clinically and electrophysiologically identical to non-HIV Guillain-Barré syndrome,¹³ and is characterized by acute flaccid paralysis with diminution or loss of reflexes. However, instead of the albuminocytological dissociation of typical Guillain-Barré syndrome, the cerebrospinal fluid in HIV-associated Guillain-Barré syndrome often shows a pleocytosis. HIV serology may be initially negative for several weeks following seroconversion. If clinical suspicion for HIV is high, HIV viral load can be used for the diagnosis in the acute setting. The therapeutic approach and therapeutic response is similar in HIV-associated Guillain-Barré syndrome and in idiopathic Guillain-Barré syndrome.

The peripheral nervous system complications of early HIV infection, with CD4 cell counts above 500 cells/μL, are similar to the complications of HIV seroconversion, and are dominated by facial nerve palsies and Guillain-Barré syndrome. However, these peripheral nervous system processes are seen in a small minority of HIV patients.¹⁰

In moderately advanced HIV infection, with CD4 cell counts between 200 and 500 cells/μL, peripheral nervous system complications are due to immune dysregulation.¹⁰ Chronic inflammatory demyelinating polyneuropathy (CIDP) is known to occur in HIV, and, like Guillain-Barré syndrome, CIDP in HIV is clinically and electrophysiologically identical to non-HIV CIDP. Again, a mild mononuclear cerebrospinal fluid pleocytosis is often seen. Pathologically, CIDP in both HIV and non-HIV forms is characterized by macrophage-mediated demyelination. Although there are no therapeutic trials with HIV-infected CIDP patients, it is believed that they respond to treatment like non-HIV CIDP patients.¹⁴ Corticosteroids, plasmapheresis, and intravenous immunoglobulin are the usual therapies for CIDP. When immunosuppressant treatment is utilized, prophylaxis against opportunistic infections is warranted.¹⁰

Mononeuritis multiplex caused by vasculitis is known to occur with HIV infection of all severities, but especially in moderately advanced cases. The clinical syndrome is characterized by a progressive accumulation of individual nerve lesions, leading to multifocal sensory and motor derangement, with electrophysiological evidence of multifocal axonal neuropathies. Axonal degeneration is the most common pathological finding on nerve biopsy, with perivascular or endoneurial inflammatory infiltration. Although the etiology of mononeuritis multiplex in HIV is unknown, it may be due to the deposition of HIV-related antigen and antibody immune complexes in perineural vessels. Treatment with immunotherapy should be reserved for patients with disabling deficits, as all therapies have the potential of worsening the underlying immunodeficiency, and milder cases are known to improve spontaneously. When the degree of immunodeficiency from HIV is profound (CD4⁺ cell count less than 100) and mononeuritis multiplex is present, the suspicion of cytomegalovirus infection should be high, and these cases should be treated aggressively with ganciclovir, foscarnet, or both.¹⁵ Cytomegalovirus infection is discussed in further detail later.

Diffuse infiltrative lymphocytosis syndrome is characterized by CD8⁺ cell infiltration of visceral organs, resulting in enlarged salivary glands and sicca syndrome.¹⁶ Peripheral nerves can be infiltrated, resulting in polyneuropathy. This is usually a painful distal symmetric sensory polyneuropathy, which develops subacutely over weeks. Electrophysiological studies reflect an axonal process. Nerve biopsy reveals diffuse CD8⁺ cell infiltration of the epineurium and endoneurium. Highly active antiretroviral therapy is effective in diffuse infiltrative lymphocytosis syndrome.¹⁷

Several recent case reports have described motor neuron disease in the setting of HIV infection, with the potential for clinical improvement after the initiation of highly active retroviral therapy.^18,19 These cases are of great interest because they may help us understand the basic mechanisms of motor neuron diseases in general.

Approximately one third of patients with AIDS will develop a clinically significant distal symmetric polyneuropathy (DSP).²⁰ DSP is the most common peripheral nervous system complication of HIV infection, and is present on autopsy in nearly all patients who die from AIDS.²¹ Risk factors for the development of DSP include elevated HIV viral load, low CD4⁺ cell counts, and exposure to neurotoxic antiretroviral medications.

The clinical phenotype of DSP is that of a distal, predominately sensory polyneuropathy. Pain is often present, generally burning in quality, and allodynia may make ambulation difficult. Neurological examination reveals distal loss of pain, temperature, and vibratory senses. Ankle jerks are diminished or abolished in most cases. When ankle jerks are intact, a purely small-fiber neuropathy or a superimposed myelopathy should be considered. Weakness of the distal lower extremities, when present, is mild and is seen only in long-standing cases of DSP. Commonly, DSP is asymptomatic or symptoms are mild enough to be ignored by the patient.

Electrophysiological testing in DSP is consistent with a sensory-predominant axonal polyneuropathy. Sural sensory responses are small in amplitude or absent. When DSP is severe, the sensory responses from the hands may be abnormal. Motor nerve abnormalities are generally mild. Notably, when DSP involves purely small-fiber sensory nerves, routine nerve conduction studies and electromyography are normal.

Nerve biopsies are not routinely performed in DSP. When obtained, nerve biopsies show distal axonal degeneration, affecting both unmyelinated and myelinated axons.²¹ Perivascular mononuclear infiltrates may be present.

The pathogenesis of DSP in HIV infection is not known. As direct neuronal infection is not believed to occur, recent research has focused on indirect mechanisms. Attention has been directed toward the HIV-1 envelope protein gp120. Current hypotheses propose indirect neurotoxicity from gp120 via chemokine receptors on Schwann cells and neurons.¹⁴

As with other painful neuropathies, treatment is largely symptomatic. There is some evidence that highly active antiretroviral therapy may mildly improve DSP.^22,23 Symptomatic treatments have been based on drugs used in other painful sensory neuropathies (especially diabetic polyneuropathy), including amitriptyline, gabapentin, and lamotrigine. There is no evidence to suggest that any one of these agents is specifically effective in the DSP of HIV. Narcotics may be needed in refractory cases. As with all other aspects of HIV management, careful attention to drug-drug interactions is important when choosing a symptomatic therapy.

Several nucleoside analogue reverse transcriptase inhibitors are known to cause a toxic polyneuropathy, and this has been a frequent confounder in the study of DSP. The so-called “d-drugs”—ddC (dideoxycytidine), ddI (didanosine), and d4T (stavudine)—are all known to cause a dose-dependent toxic polyneuropathy.²⁴ The clinical syndrome is identical to DSP, and usually develops after several months of treatment with a d-drug. Distal numbness and painful dysesthesias develop, and exam reveals distal sensory abnormalities with diminished or abolished ankle jerks. Electrophysiological studies demonstrate a distal sensory-predominant axonal polyneuropathy. Serum lactate levels may help in determining if a painful sensory polyneuropathy is drug-related or due to the HIV infection itself.²⁵ Offending drugs should be stopped in all patients with DSP. “Coasting” may occur, whereby the patient’s symptoms continue or worsen for 6 to 8 weeks after removal of the toxic drug.¹⁰

Due to similar modes of transmission, co-infections with syphilis, hepatitis C, and human T-lymphotropic virus type 1 (HTLV-1) should be considered in the evaluation of peripheral nervous system syndromes in the HIV-infected patient, as they may act as confounders.¹⁰

CYTOMEGALOVIRUS

Cytomegalovirus is a common herpesvirus that causes serious peripheral nervous system syndromes in immunosuppressed patients, such as organ transplant recipients or patients with advanced HIV infection. In immunocompetent patients, cytomegalovirus infection can be asymptomatic or result in a mononucleosis-like illness. After infection, cytomegalovirus becomes latent, and may emerge again in the setting of immunosuppression. In the peripheral nervous system, cytomegalovirus is known to cause a polyradiculopathy and mononeuritis multiplex.

Cytomegalovirus lumbosacral polyradiculopathy is a severe infectious cauda equina syndrome that affects patients with severe immunosuppression, usually patients with HIV and CD4 counts less than 50 cells/μL. The clinical presentation consists of a rapidly progressive flaccid areflexic paraparesis with urinary retention.²⁶ Weakness of the lower extremities progresses over days and may be asymmetrical. Although there may be complaints of numbness, particularly in the perianal region, objective sensory findings are uncommon. Rarely, the syndrome manifests as a polyradiculomyelitis, with a thoracic spinal level and Babinski responses. The prognosis of patients with cytomegalovirus lumbosacral polyradiculopathy is very poor, even with optimal therapy, and the condition is uniformly fatal if left untreated.²⁶

In severely immunosuppressed patients who present with the above syndrome, cerebrospinal fluid examination is of critical importance, typically showing a polymorphonuclear pleocytosis of 50 to 1000 cells/mm³, usually with elevated protein and low glucose.^26,27 However, if cerebrospinal fluid does not demonstrate the expected polymorphonuclear pleocytosis, polymerase chain reaction is required for definitive diagnosis.²⁸ While cytomegalovirus can be cultured from cerebrospinal fluid, polymerase chain reaction of cerebrospinal fluid is more sensitive, and will be positive in more than 90% of patients with cytomegalovirus lumbosacral polyradiculopathy. In immunosuppressed patients with the clinical syndrome and cerebrospinal fluid profile of cytomegalovirus lumbosacral polyradiculopathy, empiric treatment should begin before a definitive diagnosis of cytomegalovirus in cerebrospinal fluid is obtained, as test results are often delayed. If needed, evidence of cytomegalovirus infection should be sought in another organ system.²⁹

As with any patient presenting with a cauda equina syndrome, magnetic resonance imaging (MRI) should be obtained. MRI in cytomegalovirus lumbosacral polyradiculopathy may reveal thickened nerve roots and enhancement with gadolinium contrast.³⁰

Electrodiagnostic studies generally reveal a polyradicular pattern, where motor responses are absent or reduced in amplitude, although sensory responses are normal. Motor unit recruitment is reduced on needle electromyography in weak muscles, and there is evidence of denervation (assuming that enough time has elapsed for wallerian degeneration to occur). Reduction or absence of sensory responses may reflect an underlying distal symmetrical polyneuropathy or may reflect direct damage by cytomegalovirus to the dorsal root ganglion.

Treatment of cytomegalovirus lumbosacral polyradiculopathy involves intravenous administration of ganciclovir, foscarnet, or both.³¹ The major dose-related medication side effects are neutropenia with ganciclovir and nephrotoxicity with foscarnet. In HIV patients, antiretroviral therapy should be optimized.

In the evaluation of suspected cytomegalovirus lumbosacral polyradiculopathy in a patient with advanced HIV, cerebrospinal fluid should be screened for both cytology and syphilis serology.¹⁴ This is because lymphomatous meningitis and syphilis can mimic the presentation and cerebrospinal fluid profile of cytomegalovirus polyradiculopathy.¹⁰

Cytomegalovirus can present as a mononeuritis multiplex in HIV patients with CD4⁺ counts less than 50 cells/μL.¹⁵ Symptoms begin as sensory complaints in the distribution of a named nerve, and progress to asymmetrical weakness. Electrophysiological studies demonstrate a multifocal axonal process. Cerebrospinal fluid pleocytosis is present only in a minority of patients, but cytomegalovirus polymerase chain reaction is positive in at least 90% of patients. The prognosis for cytomegalovirus mononeuritis multiplex is better than that of cytomegalovirus polyradiculopathy, as most patients improve after treatment with ganciclovir or foscarnet.

LYME DISEASE

Approximately 15% of patients infected with Borrelia burgdorferi, the spirochete that causes Lyme disease, will have neurological manifestations, and these often affect the peripheral nervous system.

The broad group of spirochetes that cause Lyme disease is known as Borrelia burgdorferi sensu lato. This group is further subdivided into Borrelia burgdorferi sensu stricto, which is found in the United States, and B. burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, which are found in Europe. These spirochetes are transmitted by the bites of Ixodes ticks. These ticks feed from the spring into the fall, and their feeding pattern mirrors the chronology of new cases of Lyme disease. If an Ixodes tick attaches to a human host and feeds for longer than 24 hours, the host may be injected with B. burgdorferi spirochetes.

Lyme borreliosis has a restricted geographic area in the United States. The vast majority of cases are found on the eastern seaboard between Maryland and New Hampshire, and in the Midwest, including Wisconsin and Minnesota. Fewer cases were reported from the American west coast. In Europe, cases occur in central and western Europe, including Denmark, Sweden, Germany, Austria, Switzerland, and France.

Lyme disease is a multisystem illness, which initially affects the skin and then causes neurological, cardiac, and rheumatological symptoms.

The pathognomonic finding in Lyme borreliosis is erythema migrans, the characteristic rash. Erythema migrans starts as a small erythematous macule or papule at the site of the tick bite, which expands in size over days or weeks. As the rash expands, the border of the lesion remains erythematous while the center clears, leading to a characteristic “bull’s eye” appearance. The rash may be accompanied by fever or malaise. Days to weeks after the primary infection, multifocal erythema migrans may occur in the setting of spirochetal dissemination via the blood-stream (Fig. 84-6). It is at this point that the spirochetes may spread to multiple organ systems, causing a systemic illness with fever, malaise, headache, myalgias and arthralgias. Erythema migrans is neither pruritic nor painful, and thus may be ignored or unnoticed by patients. However, as this skin finding is pathognomonic of the disease, a history of prior rashes should be vigorously sought in cases of suspected Lyme disease, as 80% of Lyme patients have this finding in early infection.³²

Figure 84-6 Disseminated erythema migrans approximately 1 month after tick bite.

(From Said G: Lyme disease. In: Dyck PJ, Thomas PK, eds: Peripheral Neuropathy. Philadelphia: Elsevier Saunders. 2005, p 2111, Figure 92-1.)

Several weeks or months after the initial exposure to the borrelia spirochete, approximately 15% of untreated patients will develop neurological complications. The classic triad of neurological Lyme disease includes cranial neuropathy, painful radiculopathy, and lymphocytic meningitis. Although these symptoms are generally self-limited, they do improve more rapidly with appropriate antibiotic therapy. The peripheral nervous system complications of Lyme disease are numerous, and a high degree of suspicion should be maintained when evaluating patients who reside in endemic areas and who present with an appropriate syndrome in the warmer months.

Cranial neuropathies are very common in neurological Lyme disease, affecting approximately one half of patients. These generally have a cranial neuropathy, typically seen within the first few months of the infection. Lyme infection has been associated with neuropathy of every cranial nerve except the olfactory nerve, although facial nerve palsy is by far the most common. The third, fifth, sixth and eighth cranial nerves are also commonly affected. In one third of patients with facial palsy, the syndrome is bilateral. In patients presenting with bilateral facial palsies, serious consideration should always be given to the diagnosis of Lyme disease, as the differential diagnosis for this presentation is very limited.

Painful radiculoneuritis is the other classic peripheral nervous system syndrome of Lyme disease. The syndrome is characterized by the acute presentation of severe radiating dermatomal pain. The affected dermatome may involve limb or trunk. After several weeks from the onset of pain, dermatomal weakness, hyporeflexia, and sensory loss develop. This syndrome can mimic a typical compressive radiculopathy. Thus, when evaluation of radiculopathy does not reveal a compressive etiology, Lyme borreliosis should be considered in patients from endemic areas. The radiculoneuritis of Lyme disease may be electrophysiologically indistinguishable from a compressive radiculopathy as well.³³

Patients with chronic Lyme infection may also develop a radiculoneuropathy. This syndrome is typically milder than the acute radiculoneuritis, and is characterized primarily by distal paresthesias or radicular pain. Sensory signs with preserved motor function characterize this syndrome.

The diagnosis of neurological Lyme disease is based on the combination of an appropriate neurological syndrome in a patient with exposure to an appropriate endemic area during the spring, summer or early autumn months. Involvement of other organ systems is very supportive of the diagnosis. The presence of erythema migrans or a history consistent with this rash is the most specific clue. The presence of unexplained cardiac conduction abnormality or asymmetrical oligoarticular arthritis is also highly suggestive of Lyme disease.

Although lymphocytic meningitis is considered a hallmark syndrome in neurological Lyme disease, it is often asymptomatic or minimally symptomatic. Symptoms and signs of frank meningitis are unusual. In peripheral nervous system syndromes due to Lyme disease, cerebrospinal fluid may or may not be abnormal: therefore, normal cerebrospinal fluid does not exclude the diagnosis. However, the finding of a lymphocytic pleocytosis with elevated protein and normal glucose in a patient with a syndrome consistent with Lyme disease is strongly supportive of the diagnosis.

Laboratory diagnosis of Lyme disease rests on demonstration of an antibody response to the spirochete. Culture of the organism from blood and cerebrospinal fluid has been disappointing. Multiple laboratory techniques have been devised in an attempt to improve upon the laboratory diagnosis of Lyme disease. The multitude of laboratory approaches (many of which have not undergone rigorous scientific review) has led governmental agencies in the United States, Canada, and Europe to publish guidelines for the use and interpretation of appropriate serological tests.³⁴

However, there are limitations to the diagnostic approach with serological tests. First, it takes several weeks after infection for an individual patient to produce sufficient antibodies to be measured. Thus, patients presenting with an acute neurological syndrome shortly after infection with Borrelia burgdorferi may have negative serological testing. Repeat testing after several weeks should then be abnormal. Second, in endemic areas many patients will have detectable Lyme antibodies, and this laboratory abnormality may or may not have any relevance to the current presenting complaint. Similarly, detectable antibodies may persist after successful treatment. This should not be considered treatment failure and does not warrant exposing patients to unduly long treatment due to persistent serological abnormalities. Third, Lyme serologies may be abnormal in patients with an underlying systemic inflammatory disorder, leading to false positive serological results.

To minimize the above problems, and to maximize the diagnostic accuracy of serological testing, current recommendations in the United States are that the initial screening test for Lyme disease be an enzyme-linked immunosorbent assay (ELISA). If the ELISA is borderline-positive or positive, a Western blot should be obtained. Criteria have been published for the laboratory interpretation of Western blot analysis, based on high specificity.³⁵ It is not recommended that Western blots be given diagnostic significance when the ELISA is normal. Polymerase chain reaction testing is not recommended for routine diagnosis.

In the cerebrospinal fluid of infected patients it is possible to demonstrate antibodies against the Lyme spirochete. Paired serum and spinal fluids samples are helpful to compare the relative quantity of antibodies that are being produced intrathecally to the small amount of Lyme antibody that diffuses into the cerebrospinal fluid from peripheral blood.

The prognosis for appropriately treated Lyme disease is excellent. Early Lyme disease, where the only manifestations are dermatological, is appropriately treated with doxycycline 100 mg by mouth twice a day or amoxicillin 500 mg by mouth three times a day for 14 to 21 days. Some experts advocate also treating the cranial nerve syndromes of Lyme disease with oral antibiotics, unless a lymphocytic meningitis is present, in which case intravenous therapy is recommended. Intravenous therapy is indicated for all Lyme infections with radiculitis or meningitis. Intravenous therapy generally consists of ceftriaxone 2 g daily intravenously for 14 to 28 days.³⁶

The underlying pathology in peripheral nervous system syndromes due to Lyme disease has yet to be defined. There are many reports of lymphocytic inflammatory infiltrates of nerves, without a true vasculitis. Overall, the pathology suggests a multifocal axonal process, consistent with the clinical and electrophysiological observations that Lyme disease causes a mononeuritis multiplex. There is no evidence of direct infection of Borrelia burgdorferi in peripheral nerves.

HERPES SIMPLEX VIRUS

Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) are DNA viruses that remain latent in the ganglion cells of neurons. Both reactivate periodically and cause painful vesicular ulcerations. Both are also associated with syndromes involving the peripheral nervous system.

HSV-1 resides in cranial nerve ganglia, generally the trigeminal ganglia, in a latent state and reactivates periodically, causing painful oral and labial ulcerations. The vast majority of adults are infected with HSV-1.

There is experimental evidence that HSV-1 may be a cause of Bell’s palsy, based on the detection HSV-1 DNA in endoneurial fluid of patients. This observation has lead to the widespread use of oral antiherpetic agents in idiopathic facial nerve palsy. Although data from controlled trials have not demonstrated a robust effect of oral antiherpetic agents in Bell’s palsy, in general these agents are well tolerated and safe.

HSV-2 resides in a latent state in lumbosacral ganglia, and reactivates periodically to cause genital herpes. This syndrome is characterized by painful genital ulcers, which in some cases have been associated with recurrent radiculopathy. HSV-2 can be detected in the cerebrospinal fluid of such patients by polymerase chain reaction.

VARICELLA ZOSTER VIRUS

Varicella zoster virus (VZV), the causative agent of chickenpox, is a human herpesvirus that becomes latent in ganglia throughout the nervous system. The majority of adults have latent VZV in cranial nerve, dorsal root, or autonomic nervous system ganglia. The reactivation of VZV produces herpes zoster, also known as shingles.

Herpes zoster is characterized by severe burning pain in a dermatomal distribution, followed by a vesicular rash, which ultimately crusts. The development of herpes zoster reflects a deficiency in cell-mediated immunity. Although cases are seen in patients with underlying malignancies, HIV, or immunosuppression due to transplant status, the most common cause is a natural decline in cell-mediated immunity due to age. Zoster becomes fairly common after age 60 and the risk of outbreak is directly proportional to advancing age.

Herpes zoster may affect any dermatome or cranial nerve with the exception of the first cranial nerve. Thoracic dermatomal involvement is the most common, followed by involvement of the trigeminal nerve. Involvement of the ophthalmic branch of the trigeminal nerve can result in corneal lesions, and should prompt ophthalmological consultation. The combination of unilateral facial weakness and herpetic vesicles in the ear is known as the Ramsey-Hunt syndrome. When herpes zoster affects either cervical or lumbosacral dermatomes, there is approximately a 5% chance of motor involvement. The weakness that follows the typical herpes zoster rash has a myotomal pattern that reflects the dermatomal pattern of the rash. Sphincteric difficulties can be associated with sacral herpes zoster.

Oral antiherpetic agents are efficacious in speeding the recovery from herpes zoster. One week’s treatment with valacyclovir 1000 mg three times a day, famciclovir 500 mg twice a day, or acyclovir 800 mg five times a day all appear equally effective. However, the dosing of valacyclovir and famciclovir is more convenient than the dosing of acyclovir. Narcotic pain control may be required for patients with herpes zoster.

Postherpetic neuralgia is defined as pain in the dermatomal distribution of the prior herpes zoster rash persisting 6 weeks after the appearance of the rash. This syndrome can be a significant source of pain in the elderly population. Commonly used medications for neuropathic pain, including gabapentin, amitriptyline, and carbamazepine, may provide some relief. As these medications are often used in the elderly, they should be started at small doses and titrated up cautiously over time, with close attention to side effects. Topical lidocaine patches may be effective for pain control and are benign from a systemic point of view.

Zoster sine herpete is a syndrome identical to postherpetic neuralgia, with burning dermatomal pain. However, there is no antecedent rash. There are cases where VZV DNA has been detected in the cerebrospinal fluid of such patients using polymerase chain reaction.³⁷ Resolution of chronic pain has occurred with high-dose acyclovir at ten to fifteen mg per kilogram intravenously every 8 hours for 2 weeks.

HEPATITIS C VIRUS

Infection with the hepatitis C virus, especially in the presence of cryoglobulinemia, is known to cause disease of the peripheral nervous system. Cryoglobulinemia is a condition in which serum contains proteins that reversibly precipitate at low temperatures. Infection with the hepatitis C virus is one of the most common causes of cryoglobulinemia. Although disease of peripheral nerve may be present in hepatitis C-infected patients without cryoglobulinemia, it is much more common for peripheral nervous system disease to be seen in its presence. At least one third of patients with cryoglobulinemia from hepatitis C will have a disorder of peripheral nerve.

The most common neuropathy associated with hepatitis C is a distal symmetrical sensory polyneuropathy, which may be associated with purpura of the skin. Electrophysiologically and pathologically, the neuropathy is axonal. The pathological mechanism appears to be ischemia due to vasculitis of vaso nervorum.³⁸

Hepatitis C is also associated with a more severe mononeuritis multiplex. This may be seen either with or without cryoglobulinemia. Large nerve trunks are infarcted, leading to severe sensory and motor deficits. The erythrocyte sedimentation rate is generally elevated. This pattern may be seen in the setting of multisystem involvement, with the patient exhibiting cutaneous purpura, arthralgias, glomulonephritis, and lymphadenopathy. Pathologically, there is a vasculitis of medium-sized vessels.

The optimal treatment of peripheral nervous system syndromes in the setting of hepatitis C is not known. Immunosuppression, either with corticosteroids or cytotoxic agents, has been attempted, as has immunomodulation with plasma exchange. Interferon α, in an attempt to treat the underlying viral infection, has also been tried. The efficacy of the above therapies for peripheral nervous system disease is uncertain, and these treatments have been associated with worsening of the overall clinical syndrome.³⁹

HUMAN T-LYMPHOTROPIC VIRUS TYPE 1

HTLV-1 is a common cause of endemic spastic paraparesis in tropical areas. Although generally overshadowed by signs and symptoms referable to the central nervous system, a distal symmetric sensory polyneuropathy has been described in isolation.⁴⁰ The optimal treatment for this infection is not yet defined.

DIPHTHERIA

In the past, diphtheria was a common childhood infection. Diphtheric infection occurs in the upper respiratory tract or in skin. In developed countries, vaccination with diphtheria toxoid has made this infection very rare. However, the immunity conferred by immunizations is progressively lost with advancing age. Thus, an outbreak of diphtheria may occur in an area where vaccines are widely available.

Infection with Corynebacterium diphtheriae can result in a distinct, delayed polyneuropathy. Days to weeks after the local diphtheria infection, numbness of the pharynx and bulbar weakness develop. Paralysis of the soft palate and inability of the pupils to accommodate are particularly suggestive of diphtheria. Diaphragmatic paralysis may also occur, requiring ventilatory support. Diphtheritic polyneuropathy typically has a biphasic course.⁴¹ After bulbar symptoms have been present for several weeks, motor and sensory symptoms appear in limbs, leading to a flaccid paralysis. The limb symptoms of diphtheria may persist for many months, and may recover incompletely. There may also be dysautonomia that is not explained by the myocarditis.⁴²

Electrophysiologically and pathologically, the polyneuropathy of diphtheria infection is demyelinating. Diphtheria secretes a toxin, which is avidly bound by Schwann cells, leading to destruction of myelin. The distinct biphasic course is believed to reflect the local effects of the toxin from pharyngeal infection in the bulbar phase of illness, followed by the disseminated effects of the toxin when the limbs are involved.

It is unclear whether administration of diphtheria antitoxin provides any clinical benefit when given after 2 or 3 days of infection. Penicillin can be used to treat the acute infection. Corticosteroids are not effective in preventing diphtheritic polyneuropathy.⁴³

GUILLAIN-BARRÉ SYNDROME

Although Guillain-Barré syndrome and its variants are not infective neuropathies per se, they have long been considered postinfectious autoimmune processes. Experimental evidence confirms the long-held view that immune attack on shared epitopes between the infective agent and peripheral nerve results in the acute polyneuropathy.

Guillain-Barré syndrome refers to an acute polyneuropathy resulting in flaccid paralysis. Some authors use the terms “Guillain-Barré syndrome” and “acute inflammatory demyelinating polyradiculoneuropathy” (AIDP) equivalently but further subdivide Guillain-Barré syndrome into several variants. Other authors prefer to refer to these groups of disorders as “Guillain-Barré syndromes,” which include AIDP, acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and acute ataxia and ophthalmoparesis (Fisher syndrome).

The prototypical presentation of AIDP is acute onset of paresthesias in the distal upper and lower extremities in an otherwise afebrile and systemically well patient. Over hours to days, weakness develops, often in a non-length-dependent pattern. The absence of tendon reflexes is so common that the presence of normal reflexes argues against the diagnosis. Facial weakness and dysphagia are also common. About a third of patients will have ventilatory failure requiring intubation. AIDP can progress very rapidly, making admission to the hospital very wise in suspected cases, so that close monitoring of respiratory status can be maintained. The spectrum of motor deficits ranges from trivial to profound. Most patients reach their clinical nadir by the third week of illness.

The axonal forms are also characterized by an evolving acute flaccid paralysis. What distinguishes AMAN from AMSAN is the presence or absence of sensory abnormalities on clinical examination and electrodiagnostic testing. Electrodiagnostic testing is usually needed to distinguish the axonal forms of Guillain-Barré syndrome from AIDP.

The Fisher syndrome is characterized by the acute onset of ataxia, ophthalmoparesis, and areflexia. Some cases progress to involve limb weakness.

The critical diagnostic procedures include electrodiagnostic testing and examination of cerebrospinal fluid. In AIDP, electrodiagnostic testing may reveal obvious signs of an acquired demyelinating polyneuropathy. However, in early AIDP electrodiagnostic testing is often nonspecifically and nondiagnostically abnormal, usually suggesting a process involving the more proximal aspects of nerve or nerve root, or simply an acute non-length dependent neurogenic process. Time may be needed to allow a clear differentiation between the demyelinating and axonal forms of Guillain-Barré syndrome. Conversely, in extremely severe cases with electrically inexcitable nerves, it may be impossible to determine whether the neuropathy is demyelinating or axonal.

The classic cerebrospinal fluid finding in Guillain-Barré syndrome is albuminocytological dissociation—that is, increased protein concentration without pleocytosis. However, increased protein is not demonstrated in all cases of Guillain-Barré syndrome, especially early in the illness. When pleocytosis is present and the electrophysiology is demyelinating, HIV and Lyme disease should be considered. When pleocytosis is present and the electrophysiology is axonal and purely motor, a poliomyelitis syndrome should be considered. Although in the past the polio virus was the main cause of poliomyelitis, other viruses can also cause this phenotype, including the emerging pathogen West Nile virus.⁴⁴

Supportive care is the most important aspect in the management of Guillain-Barré syndrome. Respiratory mechanics must be monitored serially, and intubation established if the vital capacity falls below 15 mL/kg, or if vital capacity declines rapidly. Swallowing dysfunction should be expected, and tube feedings started if there is any suspicion of dysphagia. Prophylaxis against deep venous thrombosis is mandatory. Dysautonomia may be present, requiring monitoring of cardiac telemetry and frequent blood pressure measurements. The syndrome of inappropriate secretion of antidiuretic hormone is frequent.

Immunomodulation via plasmapheresis and intravenous immunoglobulin have both been shown to hasten recovery in AIDP. Neither modality is clearly superior to the other, and the decision for treatment is often based on availability and the likelihood of adverse events. Both modalities are generally safe, albeit expensive. The primary risks of plasmapheresis are related to the placement and maintenance of the large-bore pheresis catheter, and include pneumothorax, sepsis, and bacterial endocarditis. Risks of intravenous immunoglobulin include arterial thrombotic events, renal failure, and aseptic meningitis.

The working hypothesis on the pathogenesis of the Guillain-Barré syndromes has been the concept of molecular mimicry. Several weeks after a systemic infection, epitopes of peripheral nerve shared with the infective agent are attacked, leading to the clinical syndrome. Most attention has been focused on Campylobacter jejuni, Mycoplasma pneumonia, and the herpesviruses, including cytomegalovirus, as the most common infective triggers. Because the Guillain-Barré syndrome occurs in the postinfective state, there is usually no clinical need to determine the antecedent infective agent or to use antibiotic or antiviral therapies. Evidence suggests that the genetic polymorphism of the infective agent determines the clinical phenotype of the Guillain-Barré syndrome. For example, the genetic polymorphism of Campylobacter jejuni correlates with the clinical variant of Guillain-Barré syndrome.⁴⁵