Neurology_Adams

Neurology_Adams. Bulbar paralysis is more common in young adults, but usually such patients have spinal involvement as well. The most frequently involved cranial muscles are those of deglutition, reflecting involvement of the nucleus ambiguus. The other great hazards of medullary disease are disturbances of respiration and vasomotor control—hiccough, shallowness and progressive slowing of respiration, cyanosis, restlessness and anxiety from air hunger, hypertension, and, ultimately, hypotension and shock. When these disturbances are added to paralysis of diaphragmatic and intercostal musculature, the patient’s survival is threatened and the institution of respiratory assistance and intensive care becomes urgent.


Neurology_Adams

Neurology_Adams. In fatal infections, lesions are found in the precentral (motor) gyrus of the brain (usually of insufficient severity to cause symptoms), brainstem, and spinal cord. The brunt of the disease in these cases is borne by the hypothalamus, thalamus, motor nuclei of the brainstem and surrounding reticular formation, vestibular nuclei and roof nuclei of the cerebellum, and mainly the neurons of the anterior and intermediate gray matter of the spinal cord. In these areas, nerve cells are destroyed and phagocytosed by microgliacytes (neuronophagia). A local leukocytic reaction is present for only a few days, but mononuclear cells persist as perivascular accumulations for many months. Inclusion bodies are not seen. The earliest histopathologic changes in the anterior horns of the cord are central chromatolysis of the nerve cells, along with an inflammatory reaction. These changes correlate with a multiplication of virus in the CNS and, in the infected monkey, precede the onset of paralysis by


Neurology_Adams

Neurology_Adams. chromatolysis of the nerve cells, along with an inflammatory reaction. These changes correlate with a multiplication of virus in the CNS and, in the infected monkey, precede the onset of paralysis by one or several days.


Neurology_Adams

Neurology_Adams. In Bodian’s experimental material, the infected motor neurons continued to function until a stage of severe chromatolysis was reached. Moreover, if damage to the cell had attained only the stage of central chromatolysis, complete morphologic recovery could be expected—a process that took a month or longer. After this time, the degrees of paralysis and atrophy were closely correlated with the number of motor nerve cells that had been destroyed; where limbs remain atrophic and paralyzed, less than 10 percent of neurons survived in corresponding cord segments. Lesions in the motor nuclei of the brainstem are associated with paralysis in corresponding muscles. Disturbances of swallowing, respiration, and vasomotor control are related to neuronal lesions in the medullary reticular formation, centered in the region of the nucleus ambiguus, as mentioned earlier.


Neurology_Adams

Neurology_Adams. Atrophic, areflexic paralysis of muscles of the trunk and limbs relates, of course, to destruction of neurons in the anterior and intermediate horns of the corresponding segments of the spinal cord gray matter. The affected regions can be quite focal or scattered, giving rise, for instance, to permanent paralysis of only one limb. Stiffness and pain in the neck and back, attributed to “meningeal irritation,” are probably related to the mild inflammatory exudate in the meninges and to the generally mild lesions in the dorsal root ganglia and dorsal horns. These lesions also account for the muscle pain and paresthesia in parts that later become paralyzed. Abnormalities of autonomic function are attributable to lesions of autonomic pathways in the reticular substance of the brainstem and in the lateral horn cells in the spinal cord.


Neurology_Adams

Neurology_Adams. It is of interest that poliovirus has been readily isolated from CNS tissue of fatal cases but can rarely be recovered from the CSF during clinical disease. This is in contrast to the closely related Coxsackie and echo picornaviruses, which have been isolated frequently from the CSF during the neurologic illness. Patients in whom acute poliomyelitis is suspected require careful observation of swallowing function, vital capacity, heart rate, and blood pressure in anticipation of respiratory and circulatory complications. With paralysis of limb muscles, footboards, hand and arm splints, and knee and trochanter rolls prevent foot-drop and other deformities. Frequent passive movement prevents contractures, ankylosis, and pressure sores.


Neurology_Adams

Neurology_Adams. Respiratory failure as a result of paralysis of the intercostal and diaphragmatic muscles or of depression of the respiratory centers in the brainstem calls for the use of a positive-pressure respirator and in most patients, for a tracheostomy as well. It was during the epidemics of the mid-twentieth century that the use of Drinker’s “iron lung” attained widespread use. The management of the pulmonary and circulatory complications does not differ from their management in diseases such as myasthenia gravis and Guillain-Barré syndrome and is best carried out in special respiratory or neurologic intensive care units. The authors know of no systematic study of the potency of antiviral agents in this disease.


Neurology_Adams

Neurology_Adams. Prevention, of course, has proved to be one of the outstanding accomplishments of modern medicine. The cultivation of poliovirus in cultures of human embryonic tissues and monkey kidney cells—the achievement of Enders and associates—made possible the development of effective vaccines. The first of these was the injectable Salk vaccine, containing formalin-inactivated virulent strains of the three viral serotypes. This was followed by the Sabin vaccine, which consists of attenuated live virus, administered orally in two doses 8 weeks apart; boosters are required at 1 year of age and again before starting school. Since 1965, the reported annual incidence rate of poliomyelitis in the United States has been less than 0.01 per 100,000 (compared to a rate of 24 cases per 100,000 during the years 1951 to 1955). Very rarely in the past, poliomyelitis followed vaccination with the attenuated live virus (0.02 to 0.04 cases per 1 million doses). Only the inactivated vaccine is used in the United


Neurology_Adams

Neurology_Adams. 1951 to 1955). Very rarely in the past, poliomyelitis followed vaccination with the attenuated live virus (0.02 to 0.04 cases per 1 million doses). Only the inactivated vaccine is used in the United States and polio is essentially eradicated in the Americas. The only obstacle to eradication of the disease elsewhere is inadequate utilization of vaccine. Conceivably, with an increasing lack of immunity in underdeveloped nations (so-called herd immunity), outbreaks of poliomyelitis could occur once again.


Neurology_Adams

Neurology_Adams. Mortality from acute paralytic poliomyelitis is between 5 and 10 percent—higher in the elderly and very young. If the patient survives the acute stage, paralysis of respiration and deglutition usually recovers completely; in only a small fraction of such patients is chronic respiratory care necessary. Many patients also recover completely from early muscular weakness, and even the most severely paralyzed often improve to some extent. The return of muscle strength occurs mainly in the first 3 to 4 months and is probably the result of morphologic restitution of partially damaged nerve cells. Branching of axons of intact motor cells with collateral reinnervation of muscle fibers of denervated motor units may also play a part. Slow recovery of slight degree may then continue for a year or more. The postpolio syndrome is discussed briefly in “Differential Diagnosis of ALS” in Chaps. 38 and 45.


Neurology_Adams

Neurology_Adams. As indicated earlier, a number of RNA viruses that infections are now the main causes of a sporadic poliomyelitic syndrome. Fifty-two such cases were recorded by the Centers for Disease Control over a 4-year period. Most of them were caused by one of the echoviruses and a smaller number to Coxsackie enteroviruses, and strains 68, 70, and 71. The echovirus illness leaves little residual paralysis, but the Coxsackie viruses, which have been studied in several outbreaks in the United States, Bulgaria, and Hungary, have had more variable effects. Enterovirus 70 causes acute hemorrhagic conjunctivitis in limited epidemics and is followed by a poliomyelitis in 1 of every 10,000 cases. European outbreaks of enterovirus 71, known in the United States as a cause of hand-foot-and-mouth disease and of aseptic meningitis, have resulted in poliovirus-type paralysis, including a few fatal bulbar cases (Chumakov et al). In a recent outbreak of enterovirus 71 in Taiwan, Huang and associates described


Neurology_Adams

Neurology_Adams. aseptic meningitis, have resulted in poliovirus-type paralysis, including a few fatal bulbar cases (Chumakov et al). In a recent outbreak of enterovirus 71 in Taiwan, Huang and associates described brainstem encephalitis with myoclonus and cranial nerve involvement in a high proportion of the patients. The tendency of West Nile virus to cause a poliomyelitis has already been mentioned. More recently, clustered outbreaks of respiratory illness from enterovirus 68 have been associated with a polio-like illness but the causal connection has been difficult to establish. Case control studies support such an association but viral isolation has proved elusive.


Neurology_Adams

Neurology_Adams. Our own experience with this form of poliomyelitis has consisted of several patients who were referred over the years for paralyzing illnesses initially thought to be Guillain-Barré syndrome (Gorson and Ropper). In each case, the illness began with fever and aseptic meningitis (50 to 150 lymphocytes/mm3 in the CSF), followed by backache and widespread, relatively symmetrical paralysis, including the oropharyngeal muscles in two cases and asymmetrical weakness limited to the arms in two patients. There were no sensory changes. One patient had a mild concurrent encephalitic illness and died months later. The evolving electromyographic changes indicated that the paralysis was caused by a loss of anterior horn cells rather than by a motor neuropathy or a purely motor radiculopathy, but this distinction was not always certain. MRI was remarkable in showing distinct changes in the gray matter of the cord, mainly ventrally (Fig. 32-3). No virus could be isolated from the CSF and serologic


Neurology_Adams

Neurology_Adams. distinction was not always certain. MRI was remarkable in showing distinct changes in the gray matter of the cord, mainly ventrally (Fig. 32-3). No virus could be isolated from the CSF and serologic tests in our patients failed to implicate any of the usual encephalitic RNA viruses, including poliovirus. The patients had been immunized against the poliomyelitis viruses.


Neurology_Adams

Neurology_Adams. The concept that viral infections may lead to chronic disease, especially of the nervous system, had been entertained since the 1920s, but only many decades later was it firmly established. This group is identified by a long latency between an initial infection and the reemergence of the virus to cause clinical effects and a slow evolution once symptoms begin. Indirect and direct evidence supported this view: (1) the demonstration of a slowly progressive noninflammatory degeneration of nigral neurons long after an attack of encephalitis lethargica; (2) the finding of inclusion bodies in cases of subacute and chronic sclerosing encephalitis; (3) the discovery of chronic neurologic disease in sheep caused by a conventional RNA virus (visna)—it was in relation to this disease in sheep that Sigurdsson and Rida first used the term slow virus infection to describe long incubation periods during which the animals appeared well; and (4) the demonstration by electron microscopy of viral


Neurology_Adams

Neurology_Adams. that Sigurdsson and Rida first used the term slow virus infection to describe long incubation periods during which the animals appeared well; and (4) the demonstration by electron microscopy of viral particles in the lesions of progressive multifocal leukoencephalopathy and, later, isolation of virus from the lesions. The suggestion that the late onset of progressive weakness after poliomyelitis (“postpolio syndrome”) might represent a slow infection has never been verified. Claims have also been made numerous times over the years for a viral causation of multiple sclerosis, amyotrophic lateral sclerosis, and other degenerative diseases, but the evidence in all instances has been questionable.


Neurology_Adams

Neurology_Adams. The established human slow infections of the nervous system caused by conventional viruses include subacute sclerosing panencephalitis (measles virus), progressive rubella panencephalitis, and progressive multifocal leukoencephalopathy (JC virus). These diseases, except for PML, are decidedly rare. They are caused by viruses and are not to be confused with a group of subacute and chronic neurologic diseases that are instead the result of prions, entirely distinct transmissible agents. These are accorded a separate section later in this chapter.


Neurology_Adams

Neurology_Adams. This disorder, due to JC virus, first observed clinically by Adams in 1952, was described morphologically in 1958 by Åstrom and coworkers, and then with a larger body of material by Richardson in 1961. It is characterized by widespread demyelinating lesions, mainly of the cerebral hemispheres but sometimes of the brainstem and cerebellum, and, rarely, of the spinal cord. The lesions vary greatly in size and severity—from microscopic foci of demyelination to massive multifocal zones of destruction of both myelin and axons involving large parts of a cerebral or cerebellar hemisphere. The abnormalities of the glia cells are distinctive. Many of the reactive astrocytes in the lesions are gigantic and contain deformed and bizarre-shaped nuclei and mitotic figures, changes that are seen otherwise only in malignant glial tumors. Also, at the periphery of the lesions, the nuclei of oligodendrocytes are greatly enlarged and contain abnormal inclusions. Many of these cells are destroyed,


Neurology_Adams

Neurology_Adams. only in malignant glial tumors. Also, at the periphery of the lesions, the nuclei of oligodendrocytes are greatly enlarged and contain abnormal inclusions. Many of these cells are destroyed, accounting for the demyelination. Vascular changes are lacking, and inflammatory changes are present but usually insignificant, except in a small number of interesting cases in which immune reconstitution by retroviral drugs for AIDS allows the emergence of intense inflammation.


Neurology_Adams

Neurology_Adams. PML usually develops in a patient with a neoplasm, mainly lymphoma and CML, or immunodeficiency state. Most cases are observed in patients with HIV in whom the incidence of PML approaches 5 percent but the disorder is increasingly occurring in patients who are being immunosuppressed for a variety of reasons including some of the potent drugs for treatment of multiple sclerosis. Other important associations are with nonneoplastic granulomatosis, such as tuberculosis or sarcoidosis. A series of the interesting occurrence of PML in the last of these, sarcoid, is given by Jamilloux and colleagues.


Neurology_Adams

Neurology_Adams. Personality changes and intellectual impairment may introduce the neurologic syndrome, which then evolves over a period of several days to weeks. Any one or some combination of hemiparesis progressing to quadriparesis, visual field defects, cortical blindness, aphasia, ataxia, dysarthria, dementia, confusional states, and coma are manifestations. Some of the cases under our observation had a predominantly an asymmetric cerebellar syndrome. Seizures are infrequent, occurring in only about 10 percent of cases. If untreated, usually meaning that immunosuppression is not ameliorated, death occurs in 3 to 6 months from the onset of neurologic symptoms and even more rapidly in patients with HIV unless antiretroviral treatment is undertaken. In the current era, the duration of disease is generally much longer.


Neurology_Adams

Neurology_Adams. Laboratory testing The CSF is usually normal. CT and MRI localize the usually nonenhancing, demyelinating lesions without mass effect (Fig. 32-4) but the variability in size, location, and multiplicity make the diagnosis more dependent on viral DNA isolation from CSF by PCR and on the context of immunosuppression. Up to 15 percent have faint peripheral contrast enhancement of lesions. Our colleagues have indicated to us that PCR from the CSF is generally 74 to 92 percent sensitive and 92 to 96 percent specific but less sensitive, approximately 60 percent in HIV patients receiving highly active anti-retroviral therapy. An associated syndrome, in which a fulminant inflammatory response surrounding PML lesions in relation to rapid treatment of the underlying immunosuppressive state (immune reconstitution inflammatory syndrome, IRIS) is discussed in the following text.


Neurology_Adams

Neurology_Adams. Waksman’s original suggestion (quoted by Richardson) that PML could be caused by viral infection of the CNS in patients with impaired immunologic responses proved to be correct. ZuRhein and Chou, in an electron microscopic study of cerebral lesions from a patient with PML later demonstrated crystalline arrays of particles resembling papovaviruses in the inclusion-bearing oligodendrocytes. The characteristic feature is enlargement of oligodendrocytes, some bizarrely shaped, with intranuclear inclusions. Since then a human polyomavirus, designated “JC virus” (initials of the patient, John Cunningham, who had Hodgkin disease, and from whom the virus was originally isolated), or JCV, has been shown to be the causative agent. JCV is ubiquitous, as judged by the presence of antibodies to the virus in approximately 70 percent of the normal adult population. It is thought to be dormant in the kidney or bone marrow until an immunosuppressed state permits its active replication. The virus has


Neurology_Adams

Neurology_Adams. in approximately 70 percent of the normal adult population. It is thought to be dormant in the kidney or bone marrow until an immunosuppressed state permits its active replication. The virus has been isolated from the urine, blood lymphocytes, bone marrow, and kidney, but there is no clinical evidence of damage to extraneural structures except for rare instances of nephropathy. The surface receptor that facilitates viral entry into oligodendrocytes has been characterized.


Neurology_Adams

Neurology_Adams. The circumstance of PML in the context of immune treatment of multiple sclerosis has evinced great interest and is discussed in Chap. 35.


Neurology_Adams

Neurology_Adams. Anecdotal reports of the efficacy of various medications such as cytosine arabinoside, cidofovir, mirtazapine, interferon, and topotecan, either have not been tested in, or have failed to be sustained in larger trials. In HIV patients, aggressive treatment using antiretroviral drug combinations, including protease inhibitors, slows the progression of PML and has led to remission in almost half of cases, as in the large series reported by Antinori and colleagues. Several series found that the disease occurs with a CD4 count below 200 cells/μL, most often with counts below 50/μL and a higher count makes the diagnosis of PML unlikely, although up to 10 percent of patients have higher values. A review of this subject, particularly relating to HIV and PML, is in the article by Berger and colleagues. Although titled as if a guideline, it contains extensive authoritative current material.


Neurology_Adams

Neurology_Adams. Immune reconstitution inflammatory syndrome (IRIS) A special comment should be made regarding the transient but sometimes severe clinical worsening of PML that may occur during the initial treatment of HIV infection with antiretroviral drugs. This syndrome has been attributed to the emergence of acute inflammation surrounding the demyelinating lesions as a result of reconstitution of the immune system (immune reconstitution inflammatory syndrome or IRIS that has been mentioned in the section on the treatment of HIV). In support of this mechanism, there is a parallel blossoming of the lesions with gadolinium enhancement on MRI. Treatment with corticosteroids has been suggested and is said to allow survival and temporary remission of PML, although we have seen at least one dramatic exception. Judicious use of corticosteroids is implemented to mute this reaction.


Neurology_Adams

Neurology_Adams. This disease was first described by Dawson in 1934 under the name “inclusion body encephalitis” and extensively studied by Van Bogaert, who renamed it subacute sclerosing panencephalitis. It is now recognized to be the result of chronic measles virus infection. Never a common disease, the condition occurred until recently at a rate of about 1 case per 1 million children per year and now, with the introduction and widespread use of measles vaccine, it has practically disappeared.


Neurology_Adams

Neurology_Adams. Children and adolescents were affected for the most part, the disease rarely appearing beyond the age of 10 years. Typically, there is a history of primary measles infection at a very early age, often before 2 years, followed by a 6to 8-year asymptomatic period. The illness evolved in several stages. Initially there was a decline in proficiency at school, temper outbursts and other changes in personality, difficulty with language, and loss of interest in usual activities. These soon give way to a severe and progressive intellectual deterioration in association with focal or generalized seizures, widespread myoclonus, ataxia, and sometimes visual disturbances caused by progressive chorioretinitis. As the disease advances, rigidity, hyperactive reflexes, Babinski signs, progressive unresponsiveness, and signs of autonomic dysfunction appear. In the final stage, the child lies insensate, virtually “decorticated.”


Neurology_Adams

Neurology_Adams. The course is usually steadily progressive, death occurring within 1 to 3 years. A series of 39 such adult cases from India with mean age of 21 years was reported by Prashanth and coworkers, the oldest patient a 43-year-old. The main features were similar in most ways to childhood cases, except that several had visual disturbances and two had extrapyramidal features, raising the possibility of prion disease. Myoclonus was present early in the illness in 26 and developed later in all cases; the movements were described as “slow,” a characteristic alluded to in other series. In two cases that occurred in pregnant women, blurred vision and weakness of limbs was followed by akinetic mutism, without a trace of myoclonus or cerebellar ataxia. Nevertheless, the progressive ataxic-myoclonic chronic dementia in a child is so typical that bedside diagnosis was usually possible.


Neurology_Adams

Neurology_Adams. The EEG shows a characteristic abnormality consisting of periodic (every 5 to 8 s) bursts of 2 to 3/s high-voltage waves, followed by a relatively flat pattern. The CSF contains few or no cells, but the protein content is increased, particularly the gamma globulin fraction, and agarose gel electrophoresis discloses oligoclonal bands of IgG. These proteins have been shown to represent measles-virus-specific antibody (Mehta et al). MRI changes begin in the subcortical white matter and spread to the periventricular region (Anlar et al).


Neurology_Adams

Neurology_Adams. Histologically, the lesions involve the cerebral cortex and white matter of both hemispheres and the brainstem. The cerebellum is usually spared. Destruction of nerve cells, neuronophagia, and perivenous cuffing by lymphocytes and mononuclear cells indicate the viral nature of the infection. In the white matter there is degeneration of medullated fibers (both myelin and axons), accompanied by perivascular cuffing with mononuclear cells and fibrous gliosis (hence the term sclerosing encephalitis). Eosinophilic inclusions, the histopathologic hallmark of the disease, are found in the cytoplasm and nuclei of neurons and glia cells. Virions, thought to be measles nucleocapsids, have been observed in the inclusion-bearing cells examined electron microscopically.


Neurology_Adams

Neurology_Adams. How a ubiquitous and transient viral infection in a seemingly normal young child allows the development, many years later, of a rare encephalitis is a matter of speculation. Sever believes that there is a delay in the development of immune responses during the initial infection and a later inadequate immune response that is incapable of clearing the suppressed infection. The differential diagnosis of SSPE includes the childhood and adolescent dementing diseases such as lipid storage diseases (see Chap. 36), prion disease (Creutzfeldt-Jakob), and Schilder-type demyelinative disease (see Chap. 35). In presumptive clinical cases of SSPE, the findings of periodic complexes in the EEG, elevated gamma globulin and oligoclonal bands in the CSF, and elevated measles antibody titers in the serum and CSF are sufficient to make the diagnosis.


Neurology_Adams

Neurology_Adams. No effective treatment is available. The administration of amantadine and inosine pranobex (formerly inosiplex) was found by some investigators to lead to improvement and prolonged survival, but these effects have not been corroborated.


Neurology_Adams

Neurology_Adams. Whereas SSPE occurs in children who were previously normal, another rare type of measles encephalitis has been described that affects both children and adults with defective cell-mediated immune responses (Wolinsky et al). In this type, measles or exposure to measles precedes the encephalitis by 1 to 6 months. Seizures (often epilepsia partialis continua), focal neurologic signs, stupor, and coma are the main features of the neurologic illness and lead to death within a few days to a few weeks. The CSF may be normal, and levels of measles antibodies do not increase. Aicardi and colleagues have isolated measles virus from the brain of such a patient. The lesions are similar to those of SSPE (eosinophilic inclusions in neurons and glia, with varying degrees of necrosis) except that inflammatory changes are lacking. In a sense, this subacute measles encephalitis is an opportunistic infection of the brain in an immunodeficient patient. The relatively short interval between exposure and


Neurology_Adams

Neurology_Adams. changes are lacking. In a sense, this subacute measles encephalitis is an opportunistic infection of the brain in an immunodeficient patient. The relatively short interval between exposure and onset of neurologic disease, the rapid course, and lack of antibodies distinguish this form of subacute measles encephalitis from both SSPE and postmeasles (postinfectious) encephalomyelitis (see Chap. 35).


Neurology_Adams

Neurology_Adams. The deficits associated with congenital rubella infection of the brain are nonprogressive at least after the second or third year of life. There are, however, descriptions of children with the congenital rubella syndrome in whom a progressive neurologic deterioration occurred after a stable period of 8 to 19 years (Townsend et al; Weil et al). In 1978, Wolinsky described 10 instances, a few of them apparently related to acquired rather than to congenital rubella. Since then, this late-appearing progressive syndrome seems to have disappeared, no definite new cases having been reported in the past 30 years but it nonetheless remains of biological interest.


Neurology_Adams

Neurology_Adams. The clinical syndrome was quite uniform. On a background of the features of congenital rubella, a decade later there occurred a deterioration in behavior and school performance, often associated with seizures, and, soon thereafter, a progressive impairment of mental function (dementia). Clumsiness of gait was an early symptom, followed by a frank ataxia of gait and then of the limbs. Spasticity and other corticospinal tract signs, dysarthria, and dysphagia ensue. Encephalitis Lethargica (von Economo Disease, Sleeping Sickness)


Neurology_Adams

Neurology_Adams. Encephalitis Lethargica (von Economo Disease, Sleeping Sickness) Although examples of a somnolent-ophthalmoplegic encephalitis dot the early medical literature (e.g., nona, fébre lethargica, Schlafkrankheit), it was in the wake of the influenza pandemic of World War I that this disease appeared prominently and continued to reappear for about 10 years. The viral agent was never identified, but the clinical and pathologic features were typical of viral infection. Nevertheless, recent testing of archived brain material has failed to reveal influenzal RNA, so that encephalitis lethargica may be considered a putative viral disease. An alternative view of an immune pathogenesis is presented below.


Neurology_Adams

Neurology_Adams. The importance of encephalitis lethargica relates to its unique clinical syndromes and sequelae and to its place as the first recognized “slow virus infection” (ironically, without identification of the agent) of the nervous system in humans. The unique symptoms were ophthalmoplegia and pronounced somnolence, from which the disease took its name. Some patients were overly active, and a third group manifested a disorder of movement in the form of bradykinesia, catalepsy, mutism, chorea, or myoclonus. Lymphocytic pleocytosis was found in the spinal fluid of half the patients, together with variable elevation of the CSF protein content. More than 20 percent of the victims died within a few weeks, and many survivors were left with varying degrees of impairment of mental function. However, the most extraordinary feature was the appearance of a parkinsonian syndrome, after an interval of weeks or months (occasionally years), in a high proportion of survivors. Myoclonus, dystonia, oculogyric


Neurology_Adams

Neurology_Adams. most extraordinary feature was the appearance of a parkinsonian syndrome, after an interval of weeks or months (occasionally years), in a high proportion of survivors. Myoclonus, dystonia, oculogyric crises (Chap. 13) and other muscle spasms, bulimia, obesity, reversal of the sleep pattern, and, in children, a change in personality with compulsive behavior (“organic driveness”) were other distressing sequelae. This is not the only form of encephalitis known to cause a delayed extrapyramidal syndrome of this type (a similar though not identical syndrome with a much shorter latency may follow Japanese B encephalitis and other arboviral encephalitis).


Neurology_Adams

Neurology_Adams. The pathology was typical of a viral infection, localized principally to the midbrain, subthalamus, and hypothalamus. In the patients who died years later with Parkinson syndrome, the main findings were depigmentation of the substantia nigra and locus ceruleus because of nerve cell destruction. Neurofibrillary changes in the surviving nerve cells of the substantia nigra and the oculomotor and adjacent nuclei were also described, indistinguishable from those of progressive supranuclear palsy. Lewy bodies were not seen, in contrast to idiopathic Parkinson disease, where they are consistently present. Only a few new cases of postencephalitic type have been seen in the United States and western Europe since 1930.


Neurology_Adams

Neurology_Adams. More often currently, a postinfectious extrapyramidal syndrome is putatively the result of circulating autoantibodies. While not necessarily viral in origin, this is an appropriate place to summarize the findings of Dale and colleagues, who have studied the problem carefully and presented 20 cases that were remarkably similar to the ones described by von Economo. Half of their patients had a preceding pharyngitis that was followed by somnolence or pathologic insomnia, parkinsonism, dyskinesias, and psychiatric symptoms. Many had oligoclonal bands in the cerebrospinal fluid and some had changes on MRI in the basal ganglia. Their singular finding was that 95 percent had serum autoantibodies against basal ganglia neural antigens (two-thirds also had antibodies to anti– streptolysin O). Pathologic examination in one case showed perivascular inflammation. Thus, the long-held notion that this form of encephalitis was, and is, a viral illness might be challenged. Sporadic cases, such as the


Neurology_Adams

Neurology_Adams. examination in one case showed perivascular inflammation. Thus, the long-held notion that this form of encephalitis was, and is, a viral illness might be challenged. Sporadic cases, such as the four reported by Howard and Lees, may be examples of this disease, but there is no way of proving their identity. Dale and colleagues comment that von Economo and his contemporaries in fact doubted that there was a connection to influenza.


Neurology_Adams

Neurology_Adams. This category of infections includes a quartet of human diseases—Creutzfeldt-Jakob disease (and a variant that infects cows and may be rarely transmitted to humans), the Gerstmann-Sträussler-Scheinker syndrome, kuru, and fatal familial insomnia.


Neurology_Adams

Neurology_Adams. Although this group of diseases has been included for discussion in the chapter on viruses that affect the nervous system, it has been evident for some time that the cause of these diseases is neither a virus nor a viroid (nucleic acid alone, without a capsid structure). The transmissible, or “infectious” nature of prions was discovered by Gibbs and Gadjusek in the Fore tribes of New Guinea, who practiced ritual cannibalism and ate the brains of the deceased. The resulting disease, kuru, is described further on but the important point is that the aforementioned workers were able to transmit the disease to chimpanzees after a long latent period of years. Prusiner is credited with doggedly pursuing this problem, for which he was awarded the Nobel Prize. He (1993, 1994, 2001) has presented evidence that the transmissible pathogen is a proteinaceous infectious particle that is devoid of nucleic acid, resists the action of enzymes that destroy RNA and DNA, fails to produce an immune


Neurology_Adams

Neurology_Adams. evidence that the transmissible pathogen is a proteinaceous infectious particle that is devoid of nucleic acid, resists the action of enzymes that destroy RNA and DNA, fails to produce an immune response, and electron microscopically does not have the structure of a virus. To distinguish this pathogen from viruses and viroids, Prusiner introduced the term “prion.”


Neurology_Adams

Neurology_Adams. The very same prion protein (PrP) is normally encoded by a gene on the short arm of chromosome 20 in humans. The discovery of mutations in the PrP genes of patients with familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome (described in the following text) attests to the fact that prion diseases may be both genetic and infectious. This is another way in which prions are unique among all pathogens. It is now possible to detect inherited types of prion diseases during life, using DNA extracted from leukocytes. How prions arise in sporadic forms of spongiform encephalopathy is not fully understood. The conversion of the normal cellular protein to the infectious form involves a conformational change in the protein structure as described in Prusiner’s review in 2001. Remarkably, as discussed below, the current theory holds that an abnormally folded prion protein can act as a template for the conversion of normal PrP to PrPsc (the latter denoting the scrapie prion;


Neurology_Adams

Neurology_Adams. as discussed below, the current theory holds that an abnormally folded prion protein can act as a template for the conversion of normal PrP to PrPsc (the latter denoting the scrapie prion; see Pathogenesis). A description of the human prion diseases is given here, the most important by far being Creutzfeldt-Jakob disease.


Neurology_Adams

Neurology_Adams. These terms refer to a distinctive cerebral disease in which a rapidly or subacutely progressive and profound dementia is associated with diffuse myoclonic jerks and a variety of other neurologic abnormalities, mainly visual or cerebellar. The major neuropathologic changes are found in the cerebral and cerebellar cortices, and the outstanding features are widespread neuronal loss and gliosis accompanied by a striking vacuolation or spongy state of the affected regions—hence the designation, more frequently used in the past, subacute spongiform encephalopathy (SSE). The widely used term Creutzfeldt-Jakob disease (CJD) may not be an entirely appropriate eponym as it is most unlikely that the patient described by Creutzfeldt and at least three of the five patients described by Jakob did not have the same disease that we now recognize as subacute spongiform encephalopathy. However, decades of use make it virtually impossible to displace.


Neurology_Adams

Neurology_Adams. One of the more interesting aspects of the development of the prion concept has been the hypothesis that many conditions, most in the category of degenerative neurologic disease and characterized by the accumulation of specific proteins such as amyloid, tau, synuclein, and ubiquitin may have a similar mechanism in sequential, contiguous conformational change in protein aggregation. The disease appears in all parts of the world and in all seasons, with an annual incidence of 1 to 2 cases per million of population. The incidence is higher in Israelis of Libyan origin, in immigrants to France from North Africa, and perhaps in Slovakia. The incidence of spongiform encephalopathy is somewhat higher in urban than in rural areas, but a consistent temporal or spatial clustering of cases has not been observed, at least in the United States.


Neurology_Adams

Neurology_Adams. A small proportion of all series is familial—varying from 5 percent reported by Cathala and associates to 15 percent of 1,435 cases analyzed by Masters and coworkers (1979). The occurrence of familial cases that are not in the same household may indicate a genetic susceptibility to infection. A small number of conjugal cases have also been reported suggesting the possibility of common exposure. However, the only clearly demonstrated mechanism of spread of the usual type of CJD is iatrogenic, having occurred in a few cases after transplantation of corneas or dural grafts from infected individuals, after implantation of infected electroencephalographic depth electrodes, and after the injection of human growth hormone or gonadotropins that had been prepared from pooled cadaveric sources (see Gibbs et al 1985). At least one neurosurgeon is known to have acquired the disease. Of some interest is the finding by Zanusso and colleagues of the infectious prion protein in the nasal mucosa of


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Neurology_Adams. Gibbs et al 1985). At least one neurosurgeon is known to have acquired the disease. Of some interest is the finding by Zanusso and colleagues of the infectious prion protein in the nasal mucosa of all nine patients studied with the sporadic disease. This suggests a route for entry into the nervous system of the aberrant prion and also a potential diagnostic test. The tonsils of patients affected with variant CJD may also show immunostaining for prions (see Hill et al).


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Neurology_Adams. Attention has been drawn to an outbreak of prion disease among cows in the British Isles (“mad cow disease,” bovine spongiform encephalopathy, BSE). Cows elsewhere have sporadically been found to be infected. The mini-epidemic began in 1986, with putative transmission of the disease to 24 humans. These patients were younger (average age of onset 27 years) than those with typical CJD (average age of onset 65 years) and manifested psychiatric and sensory symptoms as the first sign of illness; they did not exhibit the usual EEG findings even as the illness advanced to its later stages (Will et al). This has been called “new variant Creutzfeldt-Jakob disease (vCJD).” One reason for including a lengthy explanation of this illness is the potential for cases to appear in future years. It was shown that the prion strain in affected patients is identical to the one from affected cattle and different from the prion agent that causes sporadic CJD. The mode of transmission, presumed to be the


Neurology_Adams

Neurology_Adams. shown that the prion strain in affected patients is identical to the one from affected cattle and different from the prion agent that causes sporadic CJD. The mode of transmission, presumed to be the ingestion of infected meat, is reminiscent of the propagation of kuru in New Guinea by ceremonial ingestion of brain tissue from infected individuals that opened the era of understanding of prion disease.


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Neurology_Adams. Prion (spongiform) encephalopathy of all types has now been firmly associated with the conversion of a normal cellular protein, PrPc to an abnormal isoform, PrPsc. The transformation involves a change in the physical conformation of the protein in which its helical proportion diminishes and the proportion of the b pleated sheet increases (see reviews by Prusiner). The current understanding is that the “infectivity” of prions and their propagation in brain tissue result from the susceptibility of the native PrP to alter its shape as a result of physical contiguity to the abnormal protein, a so-called conformational disease. Conformationally altered prions have a tendency to aggregate, and this may be the mode of cellular destruction that leads to neuronal disease. In contrast, familial cases of prion disease are thought to be the result of one of several gene aberrations residing in the region that code for PrPc.


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Neurology_Adams. As the isoforms of the prions that causes the sporadic disease have been characterized, clinical patterns have emerged as more or less typical of certain protein configurations and their underlying genotypes. The main classification system is based on: (a) the variant at codon 129 of the prion protein, which is characterized by methionine (M) or valine (V) and (b) which of two physicochemical properties (termed types 1 or 2) based on the fragment resulting from protease cleavage; see Parchi et al. The most common variants in most studies have been MM and the least common, VV, and type 1 is more frequent than type 2; MM1 and MV1 are the most common types overall, present in approximately two-thirds of sporadic cases. However, classification is complicated by the fact that some brain samples show more than one type of protein. Although several studies conflict on these points, a typical EEG pattern was most common in type 1 cases with at least one methionine, whereas MV2 cases were most


Neurology_Adams

Neurology_Adams. show more than one type of protein. Although several studies conflict on these points, a typical EEG pattern was most common in type 1 cases with at least one methionine, whereas MV2 cases were most likely to have MRI changes (see Laboratory Diagnosis). Some studies have suggested that the MV2 subtype, comprising a small proportion of cases, was likely to present with ataxia, psychiatric changes, a lack of positive sharp waves on EEG, and a prolonged duration of disease, but none of the distinctions has been absolute. There has also been controversy regarding the relationship of the genotype to the sensitivity of diagnostic tests discussed below. Details of these putative associations can be found in an extensive international study of 2,541 pathologically confirmed cases of CJD reported by Collins and colleagues.


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Neurology_Adams. Prion encephalopathy is in most cases a spontaneously occurring disease of late middle age, although it occurs in young adults. The sexes are affected equally. In the large series of pathologically verified cases reported by Brown and coworkers, prodromal symptoms—consisting of fatigue, depression, weight loss, and disorders of sleep and appetite lasting for several weeks—were observed in about one-third of the patients.


Neurology_Adams

Neurology_Adams. The early stages of the neurologic disease are characterized by a great variety of clinical manifestations, but the most frequent are changes in behavior, emotional response, and intellectual function, often followed by ataxia and abnormalities of vision, such as distortions of the shape and alignment of objects or impairment of visual acuity. Typically, the early phase of the disease is dominated by symptoms of confusion, with hallucinations, delusions, and agitation. In other instances, cerebellar ataxia (Brownell-Oppenheimer variant) or visual disturbances (Heidenhain variant) precede the mental changes and may be the most prominent features for several months. Headache, vertigo, and sensory symptoms are complaints in some patients but become quickly obscured by dementia and muteness.


Neurology_Adams

Neurology_Adams. As a rule, the disease progresses rapidly, so that obvious deterioration is seen from week to week and even day to day. Sooner or later, in almost all cases, myoclonic contractions of various muscle groups appear, perhaps unilaterally at first but later becoming generalized. Or, infrequently, the myoclonus may not appear for weeks or months after the initial mental changes. In a few patients, a startle response, that is elicitable for a brief period of time, is the only manifestation of myoclonus. In general, the myoclonic jerks are evocable by sudden sensory stimuli of all sorts, a startle response (to noise, bright light, touch) but they occur spontaneously as well. Twitches of individual fingers are typical but it should be emphasized that well-formed seizures are not a component of the illness. These changes gradually give way to a mute state, stupor, and coma, but the myoclonic contractions may continue to the end. Signs of degeneration of the pyramidal tracts or anterior horn


Neurology_Adams

Neurology_Adams. the illness. These changes gradually give way to a mute state, stupor, and coma, but the myoclonic contractions may continue to the end. Signs of degeneration of the pyramidal tracts or anterior horn cells, palsies of convergence and upgaze, and extrapyramidal signs occur in a small number of patients as the disease advances.


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Neurology_Adams. The clinical diagnosis during life rests mostly on the recognition of one of the clusters of typical clinical features, particularly the special rate of rapid progression of dementia—much more quickly than that of common degenerative diseases—coupled with stimulus-sensitive myoclonus and the characteristic MRI and EEG changes that occur in most patients (see below). The disease is invariably fatal, usually in a few months and almost always less than a year from the onset. In approximately 10 percent of patients, the illness begins with almost stroke-like suddenness and runs its course rapidly, in a matter of a few weeks. At the other extreme, a small number of patients have reportedly survived for 2 to 10 years, but these reports should be accepted with caution; in some of them, the illness appears to have been superimposed on Alzheimer or Parkinson disease or some other chronic condition that predated the prion illness.


Neurology_Adams

Neurology_Adams. The routine CSF and other laboratory tests are normal—useful findings in that they exclude a number of chronic inflammatory causes of dementia such as neurosyphilis. In most patients, the EEG pattern is distinctive, changing over the course of the disease from one of diffuse and nonspecific slowing to one of stereotyped high-voltage slow(1to 2-Hz) and sharp-wave complexes on an increasingly slow and low-voltage background (see Fig. 2-5G). The high-voltage sharp waves, which give the appearance of periodicity (they have been called pseudoperiodic), are synchronous with the myoclonus, but may persist in its absence.


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Neurology_Adams. MRI of the brain has now been appreciated to show hyperintensity of the lenticular nuclei on T2-weighted and diffusion-weighted images in the basal ganglia and cortex when the disease is fully established (Fig. 32-5). Long contiguous segments of the cortex, as well as various parts of the basal ganglia, show these alterations in a pattern that is characteristic and mistakable only perhaps for the appearance of diffuse cerebral anoxia. According to Shiga and colleagues, these changes occur in 90 percent of cases (cortex more often than caudate or lenticular nuclei and sometimes both), making them potentially the most sensitive test for the disease but the proportion has been lower in our patients. Complicating the interpretation of the MRI findings in this disease have been reports from Japan of extensive white matter lesions in several autopsy-proven cases (Matsusue et al).


Neurology_Adams

Neurology_Adams. There are helpful confirmatory laboratory tests but they are not always necessary. Hsich and colleagues described the finding by immunoassay of peptide fragments of normal brain proteins, termed “14-3-3.” This test was useful in separating CJD from other chronic noninflammatory dementing diseases but it has been sometimes disappointing, giving both false-positive and false-negative results. A summary publication has indicated an overall sensitivity from pooled reports of 92 percent and specificity of 80 percent (report of the Guidelines Development Committee of the American Academy of Neurology). The 14-3-3 test has been supplanted by RT-QuIC (real-time quaking induced conversion), which is protein amplification technique based on seeding by recombinant prion protein (see McGuire et al). It can be used in CSF, brushings of nasal mucosal (see Orru et al), or other tissue. Prions have been detected in the urine of patients with variant CJD (see Moda et al).


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Neurology_Adams. The National Prion Disease Pathology Surveillance Center, which was established at Case Western Reserve University, is available to assist clinicians by performing, free of charge, a variety of specific diagnostic tests (accessible through http://www.cjdsurveillance.com).


Neurology_Adams

Neurology_Adams. Pathology The disease affects principally the cerebral and cerebellar cortices, generally in a diffuse fashion, although in some cases the occipitoparietal regions are almost exclusively involved, as in those described by Heidenhain. In others, such as the cases of Brownell and Oppenheimer alluded to earlier, the cerebellum has been most extensively affected, with early and prominent ataxia. The degeneration and disappearance of nerve cells are associated with extensive astroglial proliferation; ultrastructural studies have shown that the microscopic vacuoles, which give the tissue its typically spongy appearance, are located within the cytoplasmic processes of glia cells and dendrites of nerve cells. The loss in particular of certain inhibitory neurons in the thalamic reticular nuclei seems to correspond to the presence of myoclonus and positive sharp waves in the EEG according to Tschampa and colleagues. Despite the fact that the disease is caused by a transmissible agent, the


Neurology_Adams

Neurology_Adams. seems to correspond to the presence of myoclonus and positive sharp waves in the EEG according to Tschampa and colleagues. Despite the fact that the disease is caused by a transmissible agent, the lesions show no evidence of an inflammatory reaction and no viral particles are seen.


Neurology_Adams

Neurology_Adams. Differential diagnosis The diagnosis of most cases presents no difficulty if the rapidity of progression and the myoclonus are recognized. Not infrequently, however, we have been surprised by a “typical” case that proves to be some other disease. Lithium intoxication, Hashimoto encephalopathy (as emphasized by Seipelt and colleagues who found a number of these cases in an epidemiologic survey of SSE; Chap. 39), Whipple disease (see Chap. 31), intravascular lymphoma, and carcinomatous meningitis—all of them characterized by myoclonus and dementia—may mimic CJD in the early weeks of illness. Contrariwise, the early mental changes of SSE may be misinterpreted as an atypical or unusually intense emotional reaction, as one of the major psychoses, as an unusual form of Alzheimer disease with myoclonus, corticobasal degeneration (see Chap. 38), or as Lewy-body disease. Despite the designation of CJD as a progressive dementia, the similarities to even rapidly developing Alzheimer disease are


Neurology_Adams

Neurology_Adams. corticobasal degeneration (see Chap. 38), or as Lewy-body disease. Despite the designation of CJD as a progressive dementia, the similarities to even rapidly developing Alzheimer disease are superficial. Also, diagnosis may be difficult in patients who present with dizziness, gait disturbance, diplopia, or visual disturbances until the rapidly evolving clinical picture clarifies the issue. Subacute sclerosing panencephalitis (see earlier in this chapter) in its fully developed form may resemble CJD, but the former is chiefly a disease of children or young adults, and the CSF shows elevation of gamma globulin (IgG), whereas the latter is essentially a disease of middle age and the presenile period and the CSF is normal. Limbic-brainstem-cerebellar encephalitis in patients with an occult tumor and HIV dementia (discussed earlier) also figure in the differential diagnosis. Cerebral lipidosis in children or young adults can result in a similar combination of myoclonus and dementia, but


Neurology_Adams

Neurology_Adams. tumor and HIV dementia (discussed earlier) also figure in the differential diagnosis. Cerebral lipidosis in children or young adults can result in a similar combination of myoclonus and dementia, but the clinical course in such cases is extremely chronic and there are retinal changes that do not occur in spongiform encephalopathy. Well-formed convulsions should direct attention to another diagnosis.


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Neurology_Adams. Management No specific treatment is known. Antiviral agents have been ineffective. In view of the transmissibility of the disease from humans to primates and iatrogenically from person to person with infected materials, certain precautions should be taken in the medical care and handling of materials from affected patients. Special isolation rooms are unnecessary, and the families of affected patients and nursing staff can be reassured that casual contact poses no risk. Needle punctures and cuts are not thought to pose a risk, but some uncertainty remains. The transmissible agent is resistant to boiling, treatment with formalin and alcohol, and ultraviolet radiation but can be inactivated by autoclaving at 132°C (269.6°F) at 15 lb/in2 for 1 h or by immersion for 1 h in 5 percent sodium hypochlorite (bleach). Workers exposed to infected materials (butchers, abattoir workers, healthcare workers) should wash thoroughly with ordinary soap. Needles, glassware, needle electrodes, and other


Neurology_Adams

Neurology_Adams. (bleach). Workers exposed to infected materials (butchers, abattoir workers, healthcare workers) should wash thoroughly with ordinary soap. Needles, glassware, needle electrodes, and other instruments should be handled with great care and immersed in appropriate disinfectants and autoclaved or incinerated. The performance of a brain biopsy or autopsy requires that a set of special precautions be followed, as outlined by Brown but this surgical procedure is not necessary as more diagnostic tools have become available. Obviously such patients or any others known to have been demented should not be donors of organs or corneas for transplantation or blood for transfusion.


Neurology_Adams

Neurology_Adams. This is a rare, strongly familial disease inherited as an autosomal dominant trait. It begins insidiously in midlife and runs a chronic course (mean duration 5 years). The main characteristics are progressive cerebellar ataxia, corticospinal tract signs, dysarthria, and nystagmus. Dementia is often associated but is relatively mild. Dysesthesias and proximal weakness of the legs have been emphasized as an early feature by Arata and colleagues. Their report may be consulted for details of 11 well-studied cases. The MRI is usually normal; with progression, generalized atrophy is found.


Neurology_Adams

Neurology_Adams. There are characteristic spongiform changes in brain tissue, as in CJD. Brain tissue from patients with this disease, when inoculated into chimpanzees, has produced a spongiform encephalopathy (Masters et al, 1981). Molecular genetic studies of affected family members demonstrate a mutation of the prion protein gene. This syndrome should be considered as a small familial subset of SSE, of slowly progressive type.


Neurology_Adams

Neurology_Adams. This is another rare and usually familial disease in the spongiform encephalopathy group. It is characterized by intractable insomnia, sympathetic overactivity, and dementia, leading to death in 7 to 15 months (see also Chap. 18). The pathologic changes, consisting of neuronal loss and gliosis, are found mainly in the medial thalamic nuclei. Studies of a few families have shown a mutation of the prion protein gene and brain material was found to contain a protease-resistant form of the gene that is characterized by a mutation in the prion gene at codon 178 in conjunction with the presence of methionine at codon 129 on chromosome 20, the latter being a feature of sporadic CJD. Transmission of the disease by inoculation of infected brain material has not been accomplished (Medori et al). There is also a rare sporadic form of this disease and the configuration of the prion alteration is different from the familial variety.


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Neurology_Adams. This disease occurs exclusively among the Fore linguistic group of natives of the New Guinea highlands and is included here because of its historical interest as the first slow infection caused by an unconventional transmissible agent to be documented in human beings. It was known as “laughing sickness” because of pathological outbursts of laughter that it induced in affected individuals. Clinically the disease takes the form of an afebrile, progressive cerebellar ataxia, with abnormalities of extraocular movements, weakness progressing to immobility, incontinence in the late stages, and death within 3 to 6 months of onset. In some ways it is similar to the ataxic (Brownell-Oppenheimer) variant of CJD. The remarkable epidemiologic and pathologic similarities between kuru and scrapie in sheep were pointed out in 1959 by Hadlow, who suggested that it might be possible to transmit kuru to subhuman primates. This was accomplished in 1966 by Gajdusek and coworkers; inoculation of


Neurology_Adams

Neurology_Adams. in sheep were pointed out in 1959 by Hadlow, who suggested that it might be possible to transmit kuru to subhuman primates. This was accomplished in 1966 by Gajdusek and coworkers; inoculation of chimpanzees with brain material from affected humans produced a kuru-like syndrome in chimpanzees after a latency of 18 to 36 months. Since then the disease has been transmitted from one chimpanzee to another and to other primates by using both neural and nonneural tissues. Histologically there is a noninflammatory loss of neurons and spongiform change throughout the brain, but predominantly in the cerebellar cortex, with astroglial proliferation and periodic acid-Schiff–positive stellate plaques of amyloid-like material (“kuru plaques”). The transmissible agent has not been visualized, however.


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Neurology_Adams. Kuru has gradually disappeared because of the cessation of ritual cannibalism by which the disease had been transmitted. In this ritual, infected brain tissue was ingested and rubbed over the body of the victim’s kin (women and young children of either sex), permitting absorption of the infective agent through conjunctivae, mucous membranes, and abrasions in the skin. Adams H, Miller D: Herpes simplex encephalitis: A clinical and pathological analysis of twenty-two cases. Postgrad Med J 49:393, 1973. Aicardi J, Gouthieres F, Arsenio-Nunes HL, Lebon P: Acute measles encephalitis in children with immunosuppression. Pediatrics 55:232, 1977. Anderson NE, Willoughby EW: Chronic meningitis without predisposing illness—a review of 83 cases. Q J Med 63:283, 1987. Anderson NE, Willoughby EW, Synek BK: Leptomeningeal and brain biopsy in chronic meningitis. Aust N Z J Med 26:703, 1995.


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Neurology_Adams. Anderson NE, Willoughby EW, Synek BK: Leptomeningeal and brain biopsy in chronic meningitis. Aust N Z J Med 26:703, 1995. Anlar B, Saatçi I, Köse, et al: MRI finding in subacute sclerosing panencephalitis. Neurology 47:1278, 1996. Antinori A, Cingolani A, Lorenzini P, et al: Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 9(Suppl 1):47, 2003. Arata H, Takashima H, Hirano R, et al: Early clinical signs and imaging findings in Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu). Neurology 66:1672, 2006. Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 75(2):317–323, 2014. Asnis DS, Conetta R, Teixeira AA, et al: The West Nile virus outbreak of 1999 in New York: The flushing hospital experience. Clin Infect Dis 30:413, 2000.


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Neurology_Adams. Asnis DS, Conetta R, Teixeira AA, et al: The West Nile virus outbreak of 1999 in New York: The flushing hospital experience. Clin Infect Dis 30:413, 2000. Åstrom KE, Mancall EL, Richardson EP Jr: Progressive multifocal leukoencephalopathy. Brain 81:93, 1958. Aurelius E, Johansson B, Sköldenberg B, et al: Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 337:189, 1991. Barnett GH, Ropper AH, Romeo J: Intracranial pressure and outcome in adult encephalitis. J Neurosurg 68:585, 1988. Bartleson JD, Swanson JW, Whisnant JP: A migrainous syndrome with cerebrospinal fluid pleocytosis. Neurology 31:1257, 1981. Beghi E, Nicolosi A, Kurland LT, et al: Encephalitis and aseptic meningitis, Olmstead County, Minnesota, 1950–1981: Epidemiology. Ann Neurol 16:283, 1984. Berger JR, Askanit AJ, Clifford DB: PML diagnostic criteria. Consensus statement from the AAN Neuroinfectious Disease Section. Neurology 80:1430, 2013.


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Neurology_Adams. Epidemiology. Ann Neurol 16:283, 1984. Berger JR, Askanit AJ, Clifford DB: PML diagnostic criteria. Consensus statement from the AAN Neuroinfectious Disease Section. Neurology 80:1430, 2013. Bodian D: Histopathologic basis of clinical findings in poliomyelitis. Am J Med 6:563, 1949. Brown P: Guidelines for high risk autopsy cases: Special precautions for Creutzfeldt-Jakob disease. In: Autopsy Performance and Reporting. Northfield, IL, College of American Pathologists, 1990, pp 67–74. Brown P, Cathala F, Castaigne P, et al: Creutzfeldt-Jakob disease: Clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 20:597, 1986. Brownell B, Oppenheimer DR: An ataxic form of subacute presenile polioencephalopathy (Creutzfeldt-Jakob disease). J Neurol Neurosurg Psychiatry 20:350, 1965.


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Neurology_Adams. Brownell B, Oppenheimer DR: An ataxic form of subacute presenile polioencephalopathy (Creutzfeldt-Jakob disease). J Neurol Neurosurg Psychiatry 20:350, 1965. Buescher EL, Artenstein MS, Olson LC: Central nervous system infections of viral etiology: The changing pattern. In: Zimmerman HM (ed): Infections of the Nervous System. Baltimore, Williams & Wilkins, 1968, pp 147–163. Cathala F, Brown P, Chatelain J, et al: Maladie de Creutzfeldt-Jacob en France: Intérêt des formes familiales. Presse Med 15:379, 1986. Charleston AJ, Anderson NE, Willoughby EW: Idiopathic steroid responsive chronic lymphocytic meningitis: Clinical features and long term outcome in 17 patients. Aust N Z J Med 28:784, 1998. Chumakov M, Voroshilova M, Shindarov L, et al: Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol 60:329, 1979.


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Neurology_Adams. Neurology 82:1307, 2014. Jeffery KJ, Read SJ, Petro TE, et al: Diagnosis of viral infections of the central nervous system: Clinical interpretation of PCR results. Lancet 349:313, 1997. Jeha LE, Sila CA, Lederman RJ, et al: West Nile virus infection. A new acute paralytic illness. Neurology 61:55, 2003. Jemsek J, Greenberg SB, Taber L, et al: Herpes zoster associated encephalitis: Clinicopathologic report of 12 cases and review of the literature. Medicine (Baltimore) 62:81, 1983. Johnson RT: Arboviral encephalitis. In: Warren KS, Mahmoud AAF (eds): Tropical and Geographical Medicine. New York, McGraw-Hill, 1990, pp 691–699. Johnson RT: Selective vulnerability of neural cells to viral infections. Brain 103:447, 1980. Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia, Lippincott-Raven, 1998.


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Neurology_Adams. Johnson RT: Selective vulnerability of neural cells to viral infections. Brain 103:447, 1980. Johnson RT: Viral Infections of the Nervous System, 2nd ed. Philadelphia, Lippincott-Raven, 1998. Kalayjian RC, Coehn ML, Bonomo RA, et al: Cytomegalovirus ventriculoencephalitis in AIDS: A syndrome with distinct clinical and pathological features. Medicine (Baltimore) 72:67, 1993. King RB: Concerning the management of pain associated with herpes zoster and of post-herpetic neuralgia. Pain 33:73, 1988. Kupila L, Vuorinen T, Vanjonpää R, et al: Etiology of aseptic meningitis and encephalitis in adult population. Neurology 66:75, 2006. Lakeman FD, Whitley RJ: Diagnosis of herpes simplex encephalitis: Application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. J Infect Dis 171:857, 1995.


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Neurology_Adams. Lehky TJ, Flerlage N, Katz D, et al: Human T-cell lymphotropic virus type II-associated myelopathy: Clinical and immunologic profiles. Ann Neurol 40:714, 1996. Linnemann CC Jr, Alvira MM: Pathogenesis of varicella-zoster angiitis in the CNS. Arch Neurol 37:239, 1980. Mahalingam R, Wellis M, Wolf W, et al: Latent varicella-zoster viral DNA in human trigeminal and thoracic ganglia. N Engl J Med 323:627, 1990. Marra CM: Update on neurosyphilis. Curr Infect Dis Rep. 11: 127-34. 2009. Masters CL, Gajdusek DC, Gibbs CJ Jr: Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Sträussler syndrome. Brain 104:559, 1981. Masters CL, Harris JO, Gajdusek C, et al: Creutzfeldt-Jakob disease: Patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 5:177, 1979.


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Neurology_Adams. Masters CL, Harris JO, Gajdusek C, et al: Creutzfeldt-Jakob disease: Patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 5:177, 1979. Matsusue E, Kinoshita T, Sugihara S, et al: White matter lesions in panencephalopathic type of Creutzfeldt-Jakob disease: MR imaging and pathologic correlation. AJNR Am J Neuroradiol 25:910, 2004. Mayo DR, Booss J: Varicella zoster-associated neurologic disease without skin lesions. Arch Neurol 46:313, 1989. McGuire LI, Peden AH, Orrú CD: RT-QuIC analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol 72:278, 2012. McJunkin JE, De los Reyes E, Irazuzta JE, et al: La Crosse encephalitis in children. N Engl J Med 344:801, 2001. McKendrick MW, McGill JI, Wood MJ: Lack of effect of acyclovir on postherpetic neuralgia. BMJ 298:431, 1989.


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Neurology_Adams. McKendrick MW, McGill JI, Wood MJ: Lack of effect of acyclovir on postherpetic neuralgia. BMJ 298:431, 1989. Medori R, Tritschler HJ, LeBlanc A, et al: Fatal familial insomnia: A prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med 326:444, 1992. Mehta PD, Patrick BA, Thormar H: Identification of virus-specific oligoclonal bands in subacute sclerosing panencephalitis by immunofixation after isoelectric focusing and peroxidase staining. J Clin Microbiol 16:985, 1982. Moda F, Gambetti P, Notari S, et al: Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 371:530, 2014. Nagel MA, Bennett JL, Khmeleva N, et al: Multifocal VZV vasculopathy with temporal artery infection mimics giant cell arteritis. Neurology 80:2017, 2013. Nagel MA, Forghani B, Mahalingam R, et al: The value of detecting anti-VZV IgG antibody in CSF to diagnose V2V vasculopathy. Neurology 68:1069, 2007.


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Neurology_Adams. Nagel MA, Forghani B, Mahalingam R, et al: The value of detecting anti-VZV IgG antibody in CSF to diagnose V2V vasculopathy. Neurology 68:1069, 2007. Navia BA, Chos E-S, Petito CK, et al: The AIDS dementia complex: II. Neuropathology. Ann Neurol 19:525, 1986. Navia BA, Petito CK, Gold JWM, et al: Cerebral toxoplasmosis complicating the acquired immune deficiency syndrome: Clinical and neuropathological findings in 27 patients. Ann Neurol 19:224, 1986. Navia BA, Price RW: The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection. Arch Neurol 44:65, 1987. Orru CD, Bongianni M, Tonoli G, et al: A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med 371:519, 2014. Oxman MN, Levin MJ, Johnson GR, et al: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271, 2005.


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Neurology_Adams. Wolinsky JS: Progressive rubella panencephalitis. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 34. Amsterdam, North-Holland, 1978, pp 331–342. Wolinsky JS, Swoveland P, Johnson KP, Baringer JR: Subacute measles encephalitis complicating Hodgkin’s disease in an adult. Ann Neurol 1:452, 1977. Wulff EA, Simpson DM: Neuromuscular complications of the human immunodeficiency virus type 1 infection. Semin Neurol 19:157, 1999. Zanusso G, Ferrari S, Cardone F, et al: Detection of pathologic prion protein in the olfactory epithelium in sporadic Creutzfeldt-Jakob disease. N Engl J Med 348:711, 2003. Zeidler M, Stewart GE, Barraclough CR, et al: New variant Creutzfeldt-Jakob disease: Neurological features and diagnostic tests. Lancet 350:903, 1997. Zerr I, Bodemer M, Otto M, et al: Diagnosis of Creutzfeldt-Jakob disease by two-dimensional gel electrophoresis of cerebrospinal fluid. Lancet 348:846, 1996.


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Neurology_Adams. Zerr I, Bodemer M, Otto M, et al: Diagnosis of Creutzfeldt-Jakob disease by two-dimensional gel electrophoresis of cerebrospinal fluid. Lancet 348:846, 1996. ZuRhein GM, Chou SM: Particles resembling papova-viruses in human cerebral demyelinative disease. Science 148:1477, 1965. Figure 32-1. Herpes simplex encephalitis. A. T2-FLAIR coronal MRI, taken during the acute stage of the illness. There is increased signal in the inferior and medial temporal lobe and the insular cortex of the left hemisphere. B. T1-weighted image after gadolinium infusion showing enhancement of the left insular and medical temporal cortices (arrows). Figure 32-2. MRI of HIV leukoencephalopathy. There are large areas of white matter change that underlie one form of AIDS dementia; cortical atrophy and ventricular enlargement are evident.


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Neurology_Adams. Figure 32-2. MRI of HIV leukoencephalopathy. There are large areas of white matter change that underlie one form of AIDS dementia; cortical atrophy and ventricular enlargement are evident. Figure 32-3. MRI of the cervical cord in a patient with nonpoliovirus poliomyelitis and an asymmetrical, flaccid, bibrachial paralysis. There is T2 signal change in the anterior regions of the gray matter. Figure 32-4. Progressive multifocal leukoencephalopathy (PML). MRI, T2-FLAIR, demonstrates multiple subcortical white matter lesions in both hemispheres (A) and in the left pons (B) in a 31-year-old man with HIV. The lesions did not enhance. Figure 32-5. MRI showing T2 signal changes in the striatum in a patient with sporadic CJD (left) of 1 month’s duration. DWI sequence showing restriction of diffusion in contiguous bands of cortex and in the striatum (right) in the same case. Chapter 32 Viral Infections of the Nervous System and Prion Diseases


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Neurology_Adams. Chapter 32 Viral Infections of the Nervous System and Prion Diseases Among all the neurologic diseases of adult life, stroke ranks first in frequency and importance. The common mode of expression of stroke is a relatively sudden occurrence of a focal neurologic deficit. Strokes are broadly categorized as ischemic or hemorrhagic. Ischemic stroke is due to occlusion of a cerebral blood vessel and causes cerebral infarction. Knowledge of the stroke syndromes, the signs and symptoms that correspond to the region of brain that is supplied by each vessel, allows a degree of precision in determining the particular vessel that is occluded and from the temporal evolution of the syndrome, the underlying cause of vascular occlusion can be deduced.


Neurology_Adams

Neurology_Adams. Ischemic strokes are classified by the underlying cause of the vascular occlusion. One of three main processes is usually operative: (i) atherosclerosis with superimposed thrombosis affecting large cerebral or extracerebral blood vessels, (ii) cerebral embolism, and (iii) occlusion of small cerebral vessels within the parenchyma of the brain. There are many other pathologic processes that lead to ischemic brain damage, not all associated with occlusion of cerebral vessels, including arterial dissection, inflammatory conditions such as vasculitis, thrombosis of cerebral veins and dural sinuses, in situ thrombosis of large or small cerebral vessels due to hypercoagulable conditions, vasospasm from any of several mechanisms, unusual types of embolic materials such as fat, tumor, cholesterol, and several unique diseases that involve the cerebral vasculature (see further on). Closely allied with ischemic strokes is the transient ischemic attack (TIA), a temporary neurologic deficit caused


Neurology_Adams

Neurology_Adams. and several unique diseases that involve the cerebral vasculature (see further on). Closely allied with ischemic strokes is the transient ischemic attack (TIA), a temporary neurologic deficit caused by a cerebrovascular disease that leaves no clinical or imaging trace. The causes of stroke are so numerous that the listing given in Table 33-1 offers only a guide to the remainder of this chapter. As helpful is knowledge of the major causes of stroke by each epoch of age, particularly in childhood and young adults, a subject taken up in a later section and summarized in Table 33-2.


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Neurology_Adams. The second broad category consists of hemorrhage, which occurs either within the substance of the brain, called intracerebral hemorrhage; or blood contained within the subarachnoid spaces, called subarachnoid hemorrhage. The causes of the first category are numerous and include chronic hypertension, coagulopathies that arise endogenously or because of anticoagulant medications, vascular malformations of the brain, cranial trauma, and hemorrhage that occurs within the area of an ischemic stroke. Subarachnoid hemorrhage has fewer fundamental causes, the most common being the rupture of a developmental aneurysm arising from the vessels of the circle of Willis, but also includes cerebral trauma and arteriovenous malformations, and rarer processes.


Neurology_Adams

Neurology_Adams. There are all gradations of severity, but in all forms of stroke the essential feature is abruptness with which the neurologic deficit develops—usually a matter of seconds that stamps the disorder as vascular. In its most severe form, the patient with a stroke becomes hemiplegic or even comatose—an event so dramatic that it had, in the past, been given vivid designations: apoplexy, cerebrovascular accident (CVA), or shock (colloquial). However, stroke is the preferred term. In its mildest form, a stroke may consist of a trivial and transient neurologic disorder insufficient for the patient even to seek medical attention. More often, there is an easily identifiable neurological deficit.


Neurology_Adams

Neurology_Adams. Vascular occlusion, the fundamental underlying cause of ischemic stroke, can be from embolic particles originating in the cardiovascular system distant from the region of the stroke, or thrombotic, in which a clot forms within a vessel in proximity to the area of infarction. Most embolic strokes occur suddenly and the deficit reaches its peak almost at once. Thrombotic strokes tend to evolve somewhat more slowly over a period of minutes or hours and occasionally days; in the latter case, the stroke usually progresses in a saltatory fashion, that is, in a series of steps rather than smoothly. In cerebral hemorrhage, also abrupt in onset, the deficit may be virtually static or steadily progressive over a period of minutes or hours, while subarachnoid hemorrhage is almost instantaneous. It follows that gradual downhill course over a period of several days or weeks will usually be traced to a nonvascular disease. There are, however, many exceptions, such as the additive effects of


Neurology_Adams

Neurology_Adams. It follows that gradual downhill course over a period of several days or weeks will usually be traced to a nonvascular disease. There are, however, many exceptions, such as the additive effects of multiple vascular occlusions and the progression that is caused by secondary brain edema surrounding large infarctions and cerebral hemorrhages. A focal stroke syndrome that reverses itself entirely and dramatically over a period of minutes or up to an hour is called a TIA. The first distinction is to separate ischemic from hemorrhagic stroke; features that are characteristic of the latter such as headache and vomiting at the onset, rapid progression to coma, and severe hypertension are emphasized in the later section on cerebral hemorrhage. Often, however, the distinction is not so clear because sudden onset of a focal neurologic problem is the core syndrome of both processes.


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Neurology_Adams. The second essential feature of stroke is its focal signature. The neurologic deficit reflects both the location and the size of the infarct or hemorrhage. Hemiplegia stands as the most typical sign of stroke, whether in the cerebral hemisphere or brainstem, but there are many other manifestations, occurring in recognizable combinations. These include paralysis, numbness, and sensory deficits of many types on one side of the body, aphasia, visual field defects, diplopia, dizziness, dysarthria, and so forth. The neurovascular syndromes enable the physician to localize the lesion—sometimes so precisely that even the affected arterial branch can be specified—and to indicate whether the lesion is an infarct or a hemorrhage. These syndromes are described in the sections that follow. This group of diseases has also provided the most instructive approach to localization in neurology. As our colleague C.M. Fisher aptly remarked, neurology is learned “stroke by stroke.” Also, the focal


Neurology_Adams

Neurology_Adams. group of diseases has also provided the most instructive approach to localization in neurology. As our colleague C.M. Fisher aptly remarked, neurology is learned “stroke by stroke.” Also, the focal ischemic lesion has divulged some of our most important ideas about the function of the human brain. Currently, various forms of cerebral imaging have overtaken this traditional, careful clinical approach in order to shorten the time to diagnosis and allow for acute treatment of vascular occlusion.


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Neurology_Adams. The severity of the stroke deficit may be partly independent of these factors. Instead, it may reflect some combination of infarcted and ischemic, but not yet infarcted, tissue. The ischemic portion is called the penumbra and current therapy of acute stroke is focused on determining the extent of the size of the region reversible ischemia and reversing it by re-establishing blood flow.


Neurology_Adams

Neurology_Adams. The analysis of a stroke involves several steps. First, the clinician must determine whether the event is a stroke rather than some other process that may have a similar sudden onset, such as migraine, seizure, or syncope. Second, if the event is considered likely to be a stroke or TIA, then the pathophysiology must be ascertained (e.g., cerebral embolism from the heart or a proximal artery, large vessel atherothrombotic occlusion, venous occlusive disease). Third, acute treatment (e.g., tissue plasminogen activator or endovascular thrombectomy) is initiated, if appropriate. Fourth, a plan for the prevention of future strokes is undertaken.


Neurology_Adams

Neurology_Adams. In the last decades, imaging technology has been introduced that allow the physician to make physiologic distinctions among normal, ischemic, and infarcted brain tissue. This approach to stroke will likely guide the next generation of treatments and has already had a pronounced impact on the direction of research in the field. Salvageable brain tissue in the acute phase of stroke can be delineated by these methods. To identify such ischemic but not yet infarcted tissue is a major goal of modern acute stroke medicine.


Neurology_Adams

Neurology_Adams. The introduction of effective treatments for acute stroke has led to greater dependence on sophisticated imaging techniques, but the authors believe it remains essential for the neurologist to understand the details of the cerebral vascular anatomy and the corresponding stroke syndromes for several reasons. Imaging techniques, though increasingly accurate, are not perfect. In cases in which the imaging does not reveal a stroke, the clinician remains dependent on careful history and neurologic examination. Furthermore, in many parts of the world, imaging techniques are unavailable at the pace necessary to initiate acute treatment. Finally, understanding the detailed anatomy helps the neurologist understand how the nervous system functions, lessons which are applicable to many other categories of illness other than stroke.


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Neurology_Adams. Despite these valuable imaging and therapeutic advances in stroke neurology, three points should be made. First, all physicians have a role to play in the prevention of stroke by encouraging the reduction of risk factors, such as hypertension, smoking, and hyperlipidemia and the identification of signs of potential impending stroke, such as transient ischemic attacks, atrial fibrillation, and carotid artery stenosis. Second, careful clinical evaluation integrated with the newer testing methods still provides the most powerful approach to this category of disease. Finally, there has been a departure from the methodical clinicopathologic studies in individual patients that have been the foundation of our understanding of cerebrovascular disease. Increasingly, randomized trials involving several hundred and even thousands of patients and conducted simultaneously in dozens of institutions have come to dominate investigative activity in this field. These multicenter trials have yielded