Clinical Vignette

An independent 74-year-old man left a family wedding reception early because he did not feel well; he complained of mild nausea and general malaise. His daughter called the next day and when he did not answer the phone she went to his home to check on him, discovering him wandering in his backyard acutely confused. She convinced him to go to the emergency department, where he was found to be febrile with a temperature of 38.5° C (101.3° F). He soon became unresponsive to verbal stimuli, had conjugate right eye deviation, neck stiffness, and bilateral palmar grasps. He withdrew to noxious stimuli; plantar responses were flexor.

A noncontrast head computed tomography (CT) was unremarkable. Cerebrospinal fluid (CSF) examination demonstrated a WBC count of 45/mm³, predominantly lymphocytes, protein of 110 mg/dL, and a normal glucose level. Intravenous acyclovir 10 mg/kg every 8 hours was begun. A magnetic resonance image (MRI) of the brain demonstrated T2-weighted hyperintensity with edematous changes in the left insular cortex region of the inferior temporal lobe, the parahippocampal gyrus, and the hippocampus, extending into the subthalamic nucleus suggestive of herpes simplex virus (HSV) encephalitis. Electroencephalography (EEG) demonstrated periodic lateralized epileptiform discharges (PLEDs). This diagnosis was confirmed by HSV polymerase chain reaction (PCR) 4 days after symptom onset. The patient gradually improved and was treated with a 21-day course of acyclovir. After a short stay in a rehabilitation facility, he was discharged home.

Comment: This is a fine example of the rapidity with which herpes simplex encephalitis (HSE) will declare itself and the urgent need to consider the diagnosis in any acutely confused patient, initiating treatment based on clinical judgment alone without waiting for definitive diagnostic proof to become available. Unless this type of decision making takes place, the HSE will have caused irreversible cerebral damage, particularly involving the temporal lobes with their memory and language function modalities.

Etiology

A wide spectrum of viral agents may cause an infectious encephalitis. Diagnosis and management are dependent on identifying the precise causative agent. Only a few viruses are amenable to specific antiviral therapy. Therefore, prevention strategies are particularly important, especially for arthropod-borne viruses such as West Nile virus (WNV) and eastern equine encephalitis (EEE).

HSE is the most common acute encephalitis in the United States, with an annual incidence of 1 in 250,000 to 1 in 500,000. It affects all ages and both sexes equally, without significant seasonal variation. Early antiviral treatment significantly reduces mortality, but morbidity remains unacceptably high. Most cases of HSE are caused by oral herpes (herpes simplex virus [HSV] type 1); however, genital herpes (HSV-2) is more common among neonates with disseminated disease. HSE commonly develops as a recurrent infection but on occasion may occur during primary infection. Animal data verify the presence of retrograde virus transport into the brain via olfactory or trigeminal nerves. However, the human disease pathogenic pathways are not fully clarified. There is a predilection for HSE, once established, to lead to a hemorrhagic necrosis with inflammatory infiltrates and cells containing intranuclear inclusions.

Clinical Presentation

The symptoms and signs of patients with subacute or acute focal encephalitis are generally rather nonspecific, with fever, headache, and altered consciousness being the most common. Focal manifestations often include seizures, typically complex partial in character because of the temporal lobe’s predisposition to develop a herpes infection. It is common for these patients to also develop language difficulties, personality changes, hemiparesis, ataxia, cranial nerve defects, and papilledema (Fig. 49-1). The differential diagnosis includes stroke, brain tumors, other viral encephalitides, bacterial abscesses, tuberculosis, cryptococcal infections, and toxoplasmosis.

Figure 49-1 HSV Encephalitis.

Diagnosis

One of the major issues in diagnosis is for the examining clinician to put HSE into his or her diagnostic spectrum very early on in the temporal profile of the patient’s illness. If this is not applied, a major therapeutic window allowing for successful treatment is sometimes lost. One of the saddest neurologic clinical scenarios is to evaluate a patient for confusion that has been present for the past 3–5 days and wrongly attributed to medication, or minor infection such as one involving the urinary or respiratory tracts. This is particularly liable to occur in a previously mentally vital senior citizen who develops a febrile illness with acute confusion and the change in mental status is presumed to be secondary to the fever per se, secondary nonspecific metabolic or toxic effects of empirical antibiotics, a stroke, or even “sundowning.”

For patients with suspected encephalitis, the initial diagnostic studies must include a CT scan (to rule out a mass effect) and then immediate CSF examination. CT scan results are abnormal in 50% of cases early on and usually demonstrate localized edema, low-density lesions, mass effects, contrast enhancements, or hemorrhage. MRI and EEG may be subsequently obtained for further confirmation. These usually demonstrate major temporal lobe damage (Fig. 49-2); however, a normal study does not exclude an HSE diagnosis. If such does occur, it is often wise to repeat the study within a few days, particularly if the patient continues to be confused.

Figure 49-2 Herpes Simplex Encephalitis.

CSF findings are nonspecific, often including a lymphocytic pleocytosis with a slight protein increase. Abnormal CSF findings are found in 96% of biopsy-proven HSE cases. EEG may show repetitive spiked, sharp wave discharges and slow waves localized to the involved area often as PLEDs.

The accuracy of PCR testing for HSV-DNA to detect HSV-1 and -2 in CSF compares favorably with the previous use of brain biopsy. This methodology provides excellent sensitivity and specificity (90–98%). The viral sequence for HSV may be detected months after the acute episode and may be negative in early disease phases. PCR should not be used to monitor therapy success. No standardized commercial assay is available. Brain biopsy was previously the gold standard for specificity, but it is rarely indicated now with the widespread availability of HSV PCR testing. If used, biopsy specimens are examined for both histopathologic changes and HSV antigens by immunofluorescence testing and appropriate culture techniques.

Therapy

Immediate initiation of acyclovir is indicated the moment HSE is clinically suspected. This relatively benign medication has the greatest chance of efficacy if it can be initiated very early on in the patient’s clinical course. The excellent outcome of the patient in the initial vignette in this chapter emphasizes the absolute importance for primary care and emergency medicine physicians to immediately consider HSE in individuals of any age who experience relatively acute changes in mental status. Unfortunately, if immediate therapy is not commenced at presentation, the outcome is usually poor, with minimal chance of return to independent living.

Prognosis

Before the availability of intravenous (IV) acyclovir, mortality from HSE was approximately 70%. If one is able to initiate antiviral therapy within the first 24 hours of symptom onset, the prognosis is much better for long-term outlook if the patient is fully treated for 21 days. This approach has reduced both mortality and morbidity substantially. Overall, although morbidity remains high, with 60–70% of patients having significant neurologic deficits, the mortality is now 10–20%.

On rare occasions, a patient seemingly doing well with initial therapy has a relapse. Inadequate early dosing of the acyclovir is the usual cause. Thus, initial treatment regimens must include daily doses of 30 mg/kg intravenously usually in three separate aliquots of 10 mg/kg.

Clinical Vignette

A 60-year-old New Hampshire man presented in mid-August with 2 weeks of headache followed by dizziness and unsteady gait, then nausea and vomiting. He walked his black Labrador retriever past a local pond in the woods every day, sustaining multiple mosquito bites. He had type II diabetes mellitus and history of a prior nephrectomy for renal cell carcinoma. At clinical presentation he was febrile, 38.3° C (101° F), somnolent but arousable, was vague answering questions, there were fine tremors in his hands, and muscle stretch reflexes were globally depressed.

Brain MRI revealed increased signal with mild mass effect in the left hippocampus. Spinal fluid examination demonstrated a WBC of 1,860/mm³ (81% polymorphonuclear neutrophils (PMNs), 11% lymphocytes, 8% monocytes), 26 red blood cells/mm³, protein 106 mg/dL, glucose 98 mg/dL (serum 209), and Gram stain negative. He had continued fevers with progressive gait ataxia, upper extremity weakness, and memory loss. Bacterial cultures and studies for Borrelia burgdorferi, Treponema pallidum, herpes simplex virus, and West Nile virus were negative. CSF IgM and plaque assay were positive for eastern equine encephalitis. He gradually recovered motor function over the next few months with supportive care and 1 year later he had minimal residual cognitive deficits.

Epidemiology

Eastern equine encephalitis virus is a member of the family Togaviridae, genus alphavirus, that is found in the eastern half of the United States. Eastern equine encephalitis (EEE) is a mosquito-borne viral disease. Here it causes disease in humans, horses, and some bird species. It generally takes from 3 to 10 days to develop symptoms of EEE after being bitten by an infected mosquito. An average of 5 human cases occur per year (approximately 220 confirmed cases in the United States between 1964 and 2004, most frequently in Florida, Georgia, Massachusetts, and New Jersey). EEE virus transmission is most common in and around freshwater hardwood swamps in the Atlantic and Gulf Coast states and the Great Lakes region. The main EEE virus transmission cycle is between birds and mosquitoes.

Clinical Presentation and Treatment

Most persons infected with EEE virus do not demonstrate a clearly discernible illness. In those individuals who do develop clinical illness, symptoms range from mild flu-like illness to a fulminating encephalitis eventually leading to coma and death. The mortality rate from EEE is approximately 33%, making it one of the most deadly mosquito-borne diseases in the United States.

Diagnosis

Laboratory diagnosis of EEE virus infection is based on serology, especially IgM testing of serum and CSF, and neutralizing antibody testing of acute- and convalescent-phase serum. MRI is the most sensitive imaging modality for diagnosis of EEE (Fig. 49-3). The most commonly affected areas of the central nervous system (CNS) include the basal ganglia (unilateral or asymmetric, with occasional internal capsule involvement) and thalamic nuclei. Other areas include the brain stem (often the midbrain), periventricular white matter, and cortex (most often temporally). Affected areas appear as increased signal intensity on T2-weighted images.

Figure 49-3 Eastern Equine Encephalitis.

Therapy/Prognosis

There is no specific treatment for EEE; optimal medical care includes intensive hospitalization and supportive care.

Approximately half of those persons who survive EEE will have mild to severe permanent neurologic damage, particularly involving cognitive impairment. Those older than age 50 and younger than age 15 years appear to be at greatest risk for developing severe EEE.

Etiology/Epidemiology

West Nile virus is a flavivirus usually found in Africa, West Asia, and the Middle East. The Middle Eastern strains are most closely related genetically to the St. Louis encephalitis virus found in the United States. There are many potential animal, ornithologic, and insect reservoirs including humans, horses, some other mammals, birds, and mosquitoes. The West Nile virus was not documented in the Western Hemisphere until 1999. In the temperate zones of the world, West Nile encephalitis cases occur primarily in the late summer or early autumn. In southern climates, where temperatures are milder, WNV can be transmitted year-round.

Clinical Presentation

West Nile fever is typically a mild disease characterized by flu-like symptoms that develop 3–15 days after the bite of an infected mosquito. West Nile fever usually lasts only a few days and does not seem to cause any long-term health effects. Mild fever, headache, body aches, occasional skin rash, and swollen glands are the most common symptoms.

However, there is a more severe disease spectrum that can manifest as encephalitis, meningitis, or meningoencephalitis. A poliomyelitis-like illness is also described, with an acute proximal and asymmetric flaccid paralysis, very occasionally occurring during recent outbreaks in the United States. Neurophysiologic, radiologic, and pathologic studies suggest that WNV has a proclivity to damage anterior horn cells within the spinal cord.

Diagnosis

Diagnosis is made by serologic assays of blood and CSF.

Therapy

Treatment is entirely supportive; there is no specific drug treatment or vaccine available. In the rare instances of a polio-like illness, the long-term outcome hinges on the degree and distribution of anterior horn cell damage.

Clinical Vignette

A 31-year-old mother of a 13-month-old child presented to the emergency department with headache, vertigo, diplopia, and an unsteady gait. She had been treated with antibiotics for acute sinusitis during the preceding 8 days. Her neurologic examination demonstrated a lethargic, restless, febrile woman with meningismus, photophobia, horizontal nystagmus, and slight appendicular ataxia of her right arm and leg.

Brain CT demonstrated diminished absorption bilaterally in both thalami and to a lesser degree her internal capsules, midbrain, pons, and right posterior temporal lobe. There were signs of a primary maxillary and sphenoid sinusitis. Spinal tap demonstrated a CSF with moderate increased pressure of 275 mm/CSF, a cell count of 485 white blood cells (84% neutrophils), a protein concentration of 106 mg/mL, and glucose of 66 mg/dL. Intravenous antibiotics as well as acyclovir were begun. Gram stain and culture were negative initially and on a repeat study within less than 1 day.

During the first day of admission, she developed increased obtundation and intermittently varied automatisms. Bilateral flexor posturing and intermittent left-sided extensor posturing developed during her second day of hospitalization. Dexamethasone was administered every 6 hours. EEG demonstrated bilateral 3–5-Hz activity. Repeat imaging demonstrated extension of the low-density lesions into the basal ganglia and frontal lobe operculum. Temporal lobe biopsy was negative for HSV virus. Three days after admission, all spontaneous movements ceased; her pupils became dilated, fixed, and nonreactive; she was now areflexic and did not respond to any form of sensory stimulation. EEGs were electrically silent on two occasions over the next 24 hours. She died on the fifth hospital day.

A history of marked sexual promiscuity became available during her hospitalization. CSF culture was eventually positive for HIV although no serum or CSF antibodies to HIV were defined; all other cultures for various microbes were negative. Pathologically, there was an encephalopathic demyelinating process affecting cerebral white matter, the thalamus, and brain stem with acute neuronal damage. There was no associated vasculitis.

Comment: This case, seen at Lahey in the mid-1980s, added further support to the proposal that HIV is a primary neurotropic virus. Our experience emphasized the importance of considering HIV in the differential diagnosis of any acute encephalitis even if the patient is HIV antibody negative. Here the initial antibody negativity supported the concept that this patient’s encephalitis represented the primary phase of her HIV. Today when one wishes to consider an acute HIV infection in the setting of a negative HIV antibody one now has available an HIV viral load study. This will be positive, despite a negative HIV antibody study, if the patient has an active HIV infection. Thus, one will not need to depend on a viral culture to make the diagnosis as occurred with this patient. Such was not available at the time we evaluated this person.

Primary Neurologic HIV Infection (PNHI)

Acute aseptic meningitis is the most common neurologic disorder to develop among individuals presenting with primary HIV infection (PNHI) (Fig. 49-4). Such patients present with headache, meningismus and sometimes myalgias, and arthralgias. As per the above vignette, on rare occasions, a meningoencephalitis, an encephalopathy, an acute disseminated encephalomyelitis, a myelopathy, a meningoradiculitis, and a peripheral neuropathy, particularly a Guillain–Barré syndrome may be seen as the presenting clinical picture of HIV. Other systemic symptoms and signs seen with acute HIV infection include fever, night sweats, weight loss, rash, fatigue, lymphadenopathy, oral ulcers, thrush, pharyngitis, gastrointestinal upset, and genital ulcers. As HIV antibody testing may be negative in PNHI, laboratory clues to the presence of seroconversion include leucopenia, thrombocytopenia, and elevated transaminases. In such cases, determination of serum HIV viral load may yield a positive result. A repeat HIV antibody study is often positive if the patient survives the initial neurologic illness. The primary infectious encephalitic forms have a significant morbidity and mortality perhaps as high as 50%. Its importance in adolescents is illustrated by the finding that in the United States, HIV is the seventh leading cause of death among patients aged 15–24 years. Once seroconversion occurs, AIDS patients are at risk for a host of neurologic complications.

Figure 49-4 Primary HIV Infection of the Nervous System.

HIV Dementia

AIDS dementia complex (ADC) is the most important “primary” neurologic complication of HIV infection. It is almost universal for HIV-1 infection to occur within the cerebrospinal fluid when AIDS is previously unrecognized and thus untreated. This was quite common early on in the AIDS epidemic prior to the availability of specific highly active antiretroviral therapy (HAART) protocols. These individuals presented with a varied dementia that was particularly characterized by early- to mid-adult-age changes in mental function. Such patients often were noted to have a relatively rapid to subacute change in personality with prominent apathy, inattention, inability to form new memory, and language dysfunction. ADC individuals were unable to carry out the basic requirements of normal activities of daily living. Although a number of AIDS patients develop a variety of opportunistic brain infections, as per Chapter 51, at autopsy many proved to have a primary subacute demyelinating process with some mild cellular response, particularly characterized by clusters of foamy macrophages, microglial nodules, and multinucleated giant cells.

Once effective, combinations of HAART became available in the mid-1990s, the prevalence of ADC declined dramatically. Because the brain is a viral sanctuary, further therapeutic effort to deal with long-term HIV effect is of importance. The prevalence of HIV-associated neurocognitive disorders (HANDs) is high even in long-standing aviremic HIV-positive patients. However, from the practical viewpoint, HANDs does not usually have any daily functional repercussions. It is of concern, however, that as people with HIV live longer, the frequency of HIV-related neurologic impairment may be rising once again despite successful administration of life-prolonging HAART. There is little evidence that HAART per se leads to primary CNS toxicity. The benefits and risks of HAART in the preservation or enhancement of neurocognitive function in well, HIV-infected patients with more than 500 CD4+ cells/µL are unknown. Abnormal brain MRIs typified by both white matter (demyelination) and gray matter (atrophy) may be demonstrated in seemingly clinically asymptomatic persons living with HIV.

HIV Primary CNS Angiitis

Central nervous system vascular involvement may develop in HIV infection. This is usually a result of associated opportunistic infections including bacterial, viral (Epstein–Barr virus, CMV, hepatitis B), fungal, or parasitic organisms. Very rarely, neoplastic disease, or toxic drug abuse may provide the mechanism for CNS angiitis in this setting. At autopsy, in some studies, perhaps a quarter of HIV-infected patients have cerebral infarcts.

HIV Myelopathy

Occasionally a primary vacuolar and inflammatory myelopathy is the presenting feature of AIDS. Its predisposition for the dorsal lateral spinal cord mimics the distribution and thus the clinical spectrum of B₁₂ or copper deficiency syndromes (Chapter 45). There is no effective treatment for HIV-associated myelopathy. The introduction of HAART has made little difference to its natural history. Spinal cord pathology reveals vacuolization and inflammation.

HIV Peripheral Neuropathy

There are other HIV-related syndromes, primarily various polyneuropathies that mimic motor neuron disease. These include chronic inflammatory polyradiculoneuropathy, a multifocal motor neuropathy with anti-GM1 antibodies, or a primary axonal motor polyradiculoneuropathy.

The most common HIV-related polyneuropathy is a distal symmetric primary sensory polyneuropathy (DSP). This occurs in more than one third of infected patients but may occur in twice as many if asymptomatic patients are also considered. DSP patients develop slowly progressive symmetric numbness and burning sensations in their feet. The pathophysiologic mechanism underlying the development of HIV-associated DSP is not known. Possibilities include cytokine/HIV protein neurotoxicity or primary mitochondrial damage. In addition, several of the early nucleoside reverse transcriptase inhibitor (NRTI) drugs (zalcitabine [ddC], didanosine [ddI], and stavudine [d4T]) have been shown to produce a toxic neuropathy that resembles HIV peripheral neuropathy clinically and electrically. This neuropathy has been postulated to be due to mitochondrial toxicity of these agents, may be additive to HIC neuropathy, and has led these agents to be replaced by newer NRTIs in modern HAART regimens.

HIV Myopathy

Some AIDS patients develop proximal weakness and rarely rhabdomyolysis. Clinically these patients sometimes appear to have an inflammatory myopathy; some of these individuals may occasionally respond to corticosteroid therapy. At other times the HIV virus has been primarily implicated as the cause of this myopathy. One of the original therapies, zidovudine, was also thought to be primarily myotoxic although it is difficult to separate this from a primary viral mechanism.

Etiology and epidemiology

Shingles is the most common neurologic disease. In America, it is estimated that 15% of our population will experience shingles during their lifetime. An aging population, increasing prevalence of immunosuppressed hosts from myriad causes, and widespread adoption of varicella vaccination in children are causing these rates to rise. Advancing age is the most significant risk factor for acute herpes zoster reactivation and development of the chronic neuropathic pain of postherpetic neuralgia (PHN).

The growing use of varicella vaccine reduces the rates of chickenpox in children. As a consequence, fewer adults have experienced viral exposure. Waning varicella-specific immunity in older adults leads to higher rates of shingles. The precise breach of immune surveillance that allows for varicella reactivation remains unknown. Although most cases affect healthy adults, 10% of all patients with lymphoma will develop shingles. In addition to treatment of acute symptoms, further diagnostic evaluation for an underlying carcinoma or lymphoma needs to be considered. Other patients at high risk for herpes zoster include organ-transplant recipients and those receiving corticosteroid therapy. Immunocompromised persons can experience recurrent, multifocal, protracted bouts of acute neuralgia.

Pathophysiology

Focal reactivation of latent varicella-zoster virus (VZV) in sensory ganglia causes the distinctive rash known as shingles. This occurs in 2 discrete stages. VZV causes varicella (chickenpox) primarily during childhood. Once this disorder clears, this virus becomes inactive and remains latent within the peripheral nervous system sensory ganglia. Here it persists in the host for many years, with the potential to be reactivated later in life. Reactivation is associated with a declining, virus-specific, cell-mediated immune response. If this dormant virus does regain virulence it typically presents as shingles. In immunocompetent hosts, this is generally an isolated event although with an increasingly aging population some individuals may have more than one episode.

The dorsal root ganglion is the primary site of infection. The virus spreads transaxonally to the skin. Cellular-level examination reveals hemorrhagic inflammation extending from the sensory ganglion to its projections in the nerve, skin, and adjacent soft tissue. Virions also spread centrally into the spinal cord, causing an occult focal myelitis in the anterior horn cells. The damage may also ascend into the CNS at the level of the dorsal columns and brainstem.

Clinical Presentation

The clinical onset is often heralded by a few days of relatively severe localized pain or nonspecific discomfort in the affected area. The acute pain of shingles is characterized by burning discomfort associated with volleys of a severe lancinating sensation. At times, this is so uncomfortable that it may mimic an acute to subacute intra-abdominal or intrathoracic disorder such as an acute peptic ulcer or even a myocardial infarction. Nociceptive pain from soft tissue inflammation and itching may also be associated. Rarely, VZV produces pain without a rash (zoster sin herpete).

The eruption is unilateral and typically does not cross the midline. It overlaps adjacent dermatomes in 20% of cases. A vesicular skin rash, within a dermatomal distribution, forms the clinical signature of VZV reactivation in the dorsal root ganglion. Although any spinal segment or cranial nerve may be involved, the lower thoracic roots and the ophthalmic sensory ganglia are most commonly affected and thus a zoster rash is found frequently in these levels. Vesicles usually appear 72–96 hours later (Fig. 49-5). The lesions have an erythematous base with a tight, clear bubble that becomes opaque and crusts after 5–10 days.

Figure 49-5 Herpes Zoster.

Persistence of neuropathic symptoms beyond 3 months fulfills diagnostic criteria for PHN. This chronic, devastating neuropathic pain of PHN, rather than the nociceptive pain, is the most common significant consequence of shingles. Patients experiencing neuropathic pain report the paradox of numbness and pain in the same region. Affected regions also commonly manifest motor and autonomic deficits. Age, rash severity, intensity of acute pain, and associated neurologic abnormalities are all risk factors for PHN. In most instances, PHN resolves within 6 months after the initial rash.

Ophthalmic herpes zoster with involvement of the first division of the trigeminal nerve is the most common cranial nerve affected. If the rash involves the tip of the nose, it is likely that ophthalmic herpes zoster is present (Fig. 49-1). All patients with ophthalmic shingles require formal evaluation with a slit lamp and fluorescein study to assess any zoster dendrites and subsequent risk of corneal scarring. Surveillance is warranted because iritis and retinal necrosis may have delayed onset. Patients with this site of herpes zoster involvement are uniquely predisposed to developing a stroke from large vessel carotid vasculitis ipsilateral to the ophthalmic division involvement.

Ramsay Hunt syndrome occurs when herpes zoster affects the geniculate ganglion and subsequently the facial nerve. This syndrome is usually associated with vesicles in the external ear; at times these are easily overlooked. This lesion sometimes eventuates in tinnitus, vertigo, and deafness.

Very uncommonly, patients whose zoster is characterized by radicular involvement of either the arm or leg may have concomitant loss of motor function. Rarely, severe spinal cord involvement may produce an acute meningoencephalitis mimicking a bacterial process with many polymorphonuclear leucocytes, with a variable prognosis. The telltale shingles rash may be delayed in onset for a few days.

Diagnosis

The rash in itself is all that is necessary to make the diagnosis. It is the delayed onset of the rash that leads to early diagnostic confusion. At times, the rash is rather subtle, with just a few vesicles developing. It may be easily missed, particularly in hirsute males unless one carefully searches for its presence.

Treatment

Acute patient care combines treatment of the underlying viral infection, host inflammatory response, and accompanying neuropathic pain. Once the diagnosis of shingles is confirmed, early institution of appropriate antiviral therapy will have important ramifications for the risk of chronic pain symptoms. Formal assessment of pain quality and intensity is critical to analgesic decision making, especially in elderly patients who tend to minimize pain symptoms. Multiple validated verbal, numeric, and visual scales may be used to gauge pain intensity throughout the illness course.

Antiviral medications are the mainstay of acute herpes zoster treatment and need to be administered within 72 hours after rash onset. Acyclovir (800 mg 5 times daily for 1–1.5 weeks) is the treatment of choice for immunocompetent hosts. When treating an immunocompromised host, acyclovir needs to be administered intravenously to prevent generalized zoster rash dissemination. This medication accelerates cutaneous healing, shortens the duration of viral shedding, and reduces the risk of ophthalmic complications.

The effect of medications such as acyclovir on chronic pain is less clear. The potential benefit of combined treatment with corticosteroids is controversial with regard to cutaneous healing and alleviation of acute pain. To reduce the risk of bacterial superinfection, cutaneous lesions need to be kept clean and dry. Oral opioids are first-line therapy and have clearly proven efficacy in reducing neuropathic pain intensity in acute and chronic stages. Opioids are used in combination with a tricyclic drug (e.g., nortriptyline or gabapentin). Early use of low-dose tricyclic antidepressants (amitriptyline) for 90 days within the initial months after shingles reduces the likelihood of developing PHN. The most severe cases require IV opioids and regional anesthetic approaches, such as epidural catheter placement.

Because of the clearly defined clinical course and subsequent potential for onset of PHN, the efficacy of analgesics has been studied extensively. Research supports the use of four medication categories: tricyclic antidepressants, anticonvulsants, topical agents, and opioids. Tricyclic antidepressants were the initial medication that proved to have demonstrated efficacy in treatment of PHN. These therapies remain first-line agents. However, anticholinergic side effects and tolerability lead to limitations in the use of these medications.

Prompt trials with other medications may be required if moderate to severe pain persists. The anticonvulsant agent gabapentin and topical sodium channel blockers (lidocaine patches) are current standards of care. Adverse effects (most commonly somnolence and dizziness) are minimized, and patient adherence to treatment is improved when gabapentin is initiated at low doses. The opioid analgesics oxycodone and morphine provide very significant relief of neuropathic pain and often without the hangover associated with mild to increasing doses of gabapentin. Patients with PHN preferred controlled-release morphine in comparison to tricyclic antidepressants. This related to improved outcomes in pain relief and sleep improvement.

The recently approved shingles vaccine can be given in adults age 60 years and older. This vaccine was shown, in a clinical trial of about 20,000 subjects, to prevent shingles in 51% and postherpetic neuralgia in 67% of study participants. It was most effective in the 60–69-year age groups but provided some protection for older groups as well.

Etiology and Epidemiology

Animals predominantly infected and involved in rabies transmission vary by geographic area. During 2007 in the United States, 7258 cases of rabies were identified by the CDC in animals, representing a 4.6% increase. Approximately 93% of the cases were in wildlife, and 7% were in domestic animals. Relative contributions by the major animal groups included 2659 raccoons (36.6%), 1973 bats (27.2%), 1478 skunks (20.4%), 489 foxes (6.7%), 274 cats (3.8%), 93 dogs (1.3%), and 57 cattle (0.8%). This represents a significant increase in those related to bats and foxes with a diminution in the incidence of raccoon source whereas skunks maintain an important steady-state source (Fig. 49-5). Among domestic sources, cats are three times more likely than dogs to be a potential human source. Cases of rabies in dogs and in sheep and goats increased 17.7% and 18.2% in 2007, respectively, whereas cases reported in cattle, cats, and horses and mules decreased 30.5%, 13.8%, and 20.8%, respectively. These are unusual sources of animal rabies in the United States because of the prevalence of rabies vaccinations. Nevertheless, dog and cat bites continue to account for the vast majority of human rabies cases worldwide. Just one case of human rabies was reported in the United States in 2007.

After a rabid dog bite, the rabies virus may travel through the nerves to the spinal cord and into the brain, where it disseminates widely, traveling centrifugally along nerves to retina, cornea, salivary glands, skin, and other organs. The incubation period ranges from 15 days to more than 1 year. If the virus involves the salivary glands, it usually manifests in 10–14 days. Quarantined animals always manifest the disease within 2 weeks if infected.

Clinical Presentation

There are two main “phenotypes”: (1) encephalitic (furious) and (2) paralytic (dumb) rabies. There are often paresthesias at the bite site. A prodrome usually occurs with headache, anxiety, and fever. The encephalitic form predominates in frequency of occurrence (80%). Typically these patients present with agitation, delirium, seizures, nuchal rigidity, severe pharyngeal spasms, stridor, autonomic instability, and sometimes hydrophobia or aerophobia. These symptoms occur approximately 2–10 days after the prodromal period. The paralytic form (20% of cases) presents with progressive paralysis until death. The clinical course is more indolent, with a clear sensorium sometimes preserved until late in the course.

Diagnosis

This is made through demonstration of anti-rabies glycoprotein antibodies in serum or CSF or through immunofluorescence for glycoprotein antigens in the nuchal skin or brain biopsy. Molecular techniques detect the virus nucleoprotein in CSF, saliva, or biopsy samples.

Clinical manifestations contrast strikingly with neuropathologic findings. Only mild congestion and perivascular inflammation are noted. The Negri body, a neuronal cytoplasmic inclusion with a dark central inner body, is pathognomonic of rabies at autopsy (Fig. 49-6).

Figure 49-6 Rabies.

Therapy

Improvements in vaccine grown in human cells and human anti-rabies globulin have made early postexposure prophylaxis safe and effective. The Centers for Disease Control and Prevention’s (CDC’s) postexposure prophylaxis for rabies includes immediate and thorough wound cleansing with soap and water, administration of human rabies immune globulin around the wound, and rabies vaccine intramuscularly on Days 0, 3, 7, 14, and 28. No effective treatment is available after clinical illness develops.

Clinical Vignette

An 18-year-old man raised by parents who sought their medical care in faith and not from physicians, and particularly refused immunizations, reported headache, fever, nausea, and general malaise 1 week after camping. Two days later, he felt better, but 48 hours after that, the general symptoms returned, with more headache, generalized muscle aching and pain, and some drowsiness. When weakness supervened a week after illness onset, he was brought to the emergency department.

The patient’s temperature was 39.5° C (103.1° F), his pulse was 100 beats/min, and his blood pressure 130/70 mm Hg. He had a stiff neck, generalized muscle tenderness, asymmetric weakness (right arm and left leg more than elsewhere), preserved though hypoactive muscle stretch reflexes, flexor plantar responses, normal sensation, and intact cranial nerves.

His cough was weak, with a vital capacity of barely 1 L. His WBC count was 15,000/mm³ (40% lymphocytes). Lumbar puncture revealed somewhat cloudy fluid under increased pressure (220 mm Hg), 170/mm³ nucleated cells (60% polymorphonuclear leukocytes), 150 mg/dL protein, and 80 mg/dL glucose. Spinal MRI showed enhancement of the cord interiorly, especially the right cervical region.

Comment: this is a classic case of infantile poliomyelitis as one would have experienced prior to the widespread utilization of oral and parenteral polio vaccines. In this instance, the patient was at high risk of developing polio either from exposure to a baby recently immunized with live vaccines or the more remote setting here wherein this young man was inadvertently exposed to wild-type polio virus.

Epidemiology and Etiology

Poliomyelitis is a word derived from the Greek polio (gray) and myelin (marrow), indicating the spinal cord. Spinal cord infection with poliomyelitis virus leads to the classic paralysis secondary to destruction of the anterior horn cells. The incidence of polio peaked in the United States in 1952 with more than 21,000 cases but rapidly decreased after introduction of effective killed parenteral Salk vaccines in 1954 and the live Sabin vaccine a few years later.

The last case of wild-virus polio acquired in the United States was in 1979, and the Global Polio Eradication Program dramatically reduced transmission elsewhere. Polio is eradicated from most of the world but still circulates in many developing countries, particularly in Africa and the Indian subcontinent, and to a lesser degree in Indonesia, a few remote parts of Russia, as well as China and the Arabian Peninsula. Travelers to areas where naturally occurring poliovirus still circulates need to be vaccinated as follows: persons who completed an adequate primary series during childhood should have a one-time booster dose of inactivated poliovirus vaccine (IPV); those who have not received a primary series should receive it although even a single dose prior to travel is of benefit.

Humans are the only known reservoir. Transmission occurs most frequently with an unapparent infection. An asymptomatic carrier state occurs only in those with immunodeficiency. Person-to-person spread occurs predominantly via the fecal–oral route. Infection typically peaks in summer in temperate climates, with no seasonality in the tropics. Poliovirus is highly infectious and may be present in stool up to 6 weeks; seroconversion in susceptible household contacts of children is nearly 100%, and that of adults is greater than 90%. Persons are most infectious from 7 to 10 days before and after symptom onset.

IPV, an inactive, killed vaccine, was licensed in 1955 and used until the early 1960s, when trivalent oral poliovirus vaccine (OPV), containing attenuated strains of all three serotypes of poliovirus in 10 : 1 : 3 ratios, largely replaced it. Enhanced potency trivalent poliovirus vaccine (IPV) was introduced in 1988. The viruses are grown in monkey kidney (Vero) cells and are inactivated with formaldehyde. An occasional live vaccine–associated case of paralytic polio continued to occur in infants after their first immunization at approximately 3 months of age until the CDC mandated in the late 1990s that initial vaccinations must be with the Salk IPV. Since then, no such incidents have been reported. Between 1980 and 1999, a total of 152 confirmed cases of paralytic polio occurred in the United States. Of these, 145 (95%) were vaccine-associated. For this reason, in 2000, the recommendation was made to use IPV exclusively in the United States. Vaccine-associated paralytic polio is thought to occur from a reversion or mutation of the vaccine virus to a more neurotropic form.

Live attenuated polioviruses replicate in the intestinal mucosa and lymphoid cells and draining lymph nodes. Vaccine viruses are excreted in stool for up to 6 weeks, with maximal shedding in the first 1–2 weeks after vaccination. IPV is highly effective in producing immunity (99% after three doses) and protection from paralytic poliomyelitis. IPV seems to produce less local gastrointestinal immunity than OPV. Thus, persons immunized with IPV could still become infected with wild-type poliovirus and shed it on return to the United States, with subsequent potential spread. Although most individuals in economically privileged countries are immunized, occasionally, an instance such as described in the vignette in this chapter is seen. Asymmetric weakness distribution and CSF findings help to differentiate it from Guillain–Barré syndrome.

Pathogenesis

Poliovirus is a member of the family Picornaviridae, enterovirus subgroup. Enteroviruses are transient inhabitants of the gastrointestinal tract and are stable at acid pH. Picornaviruses have an RNA genome; the three poliovirus serotypes (P1, P2, and P3) have minimal heterotypic immunity among them. The virus enters through the mouth and multiplies primarily at the implantation site in the pharynx and gastrointestinal tract; usually, it is present in the throat and stool before clinical onset (Fig. 49-7). Within 1 week of clinical onset, little virus exists in the throat, but it continues to be excreted in the stool for several weeks. The virus invades local lymphoid tissue, enters the bloodstream, and then may infect CNS cells. Viral replication in anterior horn and brainstem motor neuron cells results in cell destruction and paralysis.

Figure 49-7 Poliomyelitis-I.

Clinical Presentation

The incubation period for poliomyelitis is usually 6–20 days, with a range of 3–35 days. Clinical response to poliovirus infection varies. Up to 95% of all polio infections are asymptomatic even though infected persons shed virus in stool and are contagious.

Abortive poliomyelitis occurs in 4–8% of infections. It causes a minor illness, without evidence of CNS infection. Complete recovery characteristically occurs within 1 week. Upper respiratory infection (sore throat and fever), gastrointestinal disturbances (nausea, vomiting, abdominal pain, constipation, or rarely diarrhea), and influenza like illness can all occur and are indistinguishable from other enteric viral illnesses.

Nonparalytic aseptic meningitis, usually occurring several days after a prodrome similar to the minor illness, occurs in a small percentage of infections. Increased or abnormal sensations may occur with stiffness in the neck, back, leg, or a combination of those areas, typically last 2–10 days, and are then followed by complete recovery.

Flaccid paralysis occurs in less than 1% of polio infections. Paralytic symptoms typically begin 1–10 days after the prodromal symptoms and evolve for 2–3 days. Paralysis does not usually progress after defervescence. In children, the prodrome may be biphasic, with initial minor symptoms separated by 1–7 days from major symptoms. Initially, severe muscle aches and spasms are typically seen with significant meningismus and a Kernig sign. The illness evolves into asymmetric flaccid paralysis with diminished muscle stretch reflexes, typically reaching a plateau within days or weeks. Some strength gradually returns. No sensory or cognitive loss occurs. Most patients recover some function, and many recover completely; however, weakness or paralysis that is still discernible 12 months after onset is usually permanent.

Three types of paralytic polio are described. Most common is spinal polio (approximately 79% of cases in the 1970s), characterized by asymmetric paralysis usually involving the legs (Fig. 49-8). Bulbar polio (2%) causes weakness of muscles innervated by cranial nerves. Bulbospinal polio (19%) is a combination of the two. Mortality in paralytic polio cases is lower in children (2–5%) than in adults (15–30%) and highest (25–75%) with bulbar involvement.

Figure 49-8 Poliomyelitis-II.

Postpolio Syndrome

This clinical picture usually presents 30–40 years after paralytic poliomyelitis early in life, especially during childhood; in these later, and often more advanced years of life, 25–40% of previous acute polio patients note a seeming increased weakness. This, per se, does not constitute recurrence of a dormant infectious process likened to herpes zoster. Rather, it is thought to involve failure of oversized previously reinnervated motor units that developed during the recovery process from the initial paralytic syndrome.

Diagnostic Approach

Poliovirus can be isolated from the pharynx or stool; however, paradoxically this is rarely isolated from CSF. Sequencing can distinguish wild-type from vaccine-type virus in acute flaccid paralysis. Neutralizing antibodies are often present early and at high levels. CSF usually shows an increased WBC count (10–200 cells/mm³, primarily lymphocytes) and a mildly increased protein level (generally 40–50 mg/dL).

Prognosis

At its most severe bulbospinal form, poliomyelitis often can be fatal. Today with very much enhanced intensive care support, the fatality rate more than likely would be significantly lessened if poliomyelitis reoccurred with the same incidence so typical of 50 years ago. Fortunately, this disease is now so rare that it is difficult to begin to predict what the outcome might be today. When West Nile virus first appeared about 10 years ago, with its similar predilection for the anterior horn cell, those of us who lived through poliomyelitis as children and adolescents paused to wonder whether this terrible clinical disorder might once again appear in the mask of this virus previously unknown to the western hemisphere. Very fortunately, our fears were not correct.