Neurology_Adams

Neurology_Adams. In most of these cases, MRI shows abnormal T2 hyperintensity and edema in affected regions, though occasionally the brain appears normal. In severe cases, zones of focal necrosis may be seen. Odd seizures, including epilepsia partialis continua, have been observed with this disorder, but they must be uncommon. Sensory symptoms may be related to neuronal loss in the posterior horns of the spinal cord or the dorsal root ganglia as mentioned earlier and discussed further on.


Neurology_Adams

Neurology_Adams. Many patients with small cell lung cancer and any of the types of paraneoplastic encephalomyelitis have been found to harbor circulating polyclonal IgG antibodies (anti-Hu, or antineuronal nuclear antibody type 1 (ANNA 1)) that bind to the nuclei of neurons in many regions of the brain and spinal cord, dorsal root ganglion cells, and peripheral autonomic neurons. The antibodies are reactive with certain nuclear RNA-binding proteins. Cancers of the prostate and breast and neuroblastoma may rarely produce a similar antibody. The antibody titer is higher in the CSF than in the serum (as it is for the anti-Purkinje cell antibody, anti-Yo, in paraneoplastic cerebellar degeneration discussed further on), indicating production of antibody within the nervous system. Low titers of anti-Hu are found in approximately 15 percent of patients with small cell cancer who are neurologically normal, probably because these tumors have expressed only low levels of antigens that are recognized by anti-Hu.


Neurology_Adams

Neurology_Adams. in approximately 15 percent of patients with small cell cancer who are neurologically normal, probably because these tumors have expressed only low levels of antigens that are recognized by anti-Hu. Antibodies to the voltage-gated potassium channel (VGKC) and its associated proteins leucine-rich glioma inactivated 1 (LGI 1) and contactin-associated protein 2 (CASPR 2) have been identified in patients with limbic encephalitis without, or less often with, cancer (Vincent et al and van Sonderen et al).


Neurology_Adams

Neurology_Adams. Treatment Beyond identification and treatment of an underlying malignancy in cases of paraneoplastic encephalitis, plasma exchange or intravenous gamma globulin is used, with variable clinical outcomes that most likely reflect the extent of irreversible neuronal loss. Several unusual patterns have been observed from the effects of the anti-VGKC antibodies as well as antibodies to the associated proteins LGI 1 and CASPR 2. About half of patients with LGI 1 antibodies have faciobrachial dystonic seizures in addition to limbic encephalitis. VGKC and CASPR 2 antibodies are associated with peripheral motor hyperexcitability in addition to limbic encephalitis (discussed further in Chap. 46).


Neurology_Adams

Neurology_Adams. A form of paraneoplastic encephalitis that presents itself as an acute or subacute psychiatric syndrome consisting of some combination of hallucinations, panic, delusions, and incoherence, coupled with seizures, memory disturbance and hypoventilation was described by Vitaliani and colleagues in four women with ovarian teratoma. Many patients have a nondescript prodrome of malaise, fatigue, headache excessive sleepiness, or low fever. Dalmau and coworkers (2007) demonstrated that this syndrome is associated with antibodies against a component of the NMDA receptor. The teratoma in one of their patients was located in the mediastinum instead of the ovary and rare cases have occurred with small cell lung cancer, including in men. Dalmau’s series of 100 patients (2008) is instructive in that they were very predominantly women in their twenties with presentations or psychiatric or memory deterioration but a large number had dyskinesias, seizures, or hypoventilation. Almost all had several


Neurology_Adams

Neurology_Adams. they were very predominantly women in their twenties with presentations or psychiatric or memory deterioration but a large number had dyskinesias, seizures, or hypoventilation. Almost all had several or dozens of white blood cells in the CSF, a majority had oligoclonal bands and MRI showed abnormal T2 hyperintensity in the medial temporal lobes, similar to the anti-Hu type of limbic encephalitis.


Neurology_Adams

Neurology_Adams. Autonomic overactivity in patients with this syndrome is well described. Episodes of hypertension, tachycardia, and diaphoresis can be pronounced, as is excessive salivation, pupillary dilation, and other signs of sympathetic dysfunction, individually or concurrently. Dalmau and colleagues have identified the target of the antibody as the subunit of the NMDA receptor, NR1. There is a reasonable degree of certainty that the antibody is pathogenic.


Neurology_Adams

Neurology_Adams. Dalmau and colleagues have identified the target of the antibody as the subunit of the NMDA receptor, NR1. There is a reasonable degree of certainty that the antibody is pathogenic. Treatment A premium is attached to early identification of this disorder and rapid removal of the ovary containing the teratoma or resection of another inciting tumor. Vaginal ultrasound may be necessary for the demonstration of the ovarian lesion but a more extensive examination such as CT or PET is needed for the detection of other tumors. Improvement after tumor removal is associated with subsidence of the antibody titer over many weeks and a good outcome occurs in a majority of cases. Decisions regarding oophorectomy are difficult in view of reducing fertility in young women.


Neurology_Adams

Neurology_Adams. It has become apparent that a fair proportion of cases with circulating anti-NMDA antibody do not have a tumor that is detectable and immune treatments such as intravenous gamma globulin may then be used. It is reasonable to start these same immune treatments while awaiting tumor surgery in cases that are highly symptomatic. Paraneoplastic Sensory Neuronopathy (Ganglionopathy) (See Also Chap. 43) This is a distinctive syndrome that is associated in most cases with the anti-Hu antibody. It should be emphasized that a nondescript, mainly sensory neuropathy is a more common accompaniment of systemic cancer, and it may or may not be associated with the anti-Hu antibody. As discussed further in Chap. 43, a sensory polyneuropathy from chemotherapeutic agents, notably the platinum-based ones and vincristine, also needs to be distinguished from the anti-Hu neuropathy syndrome.


Neurology_Adams

Neurology_Adams. The sensory neuronopathy and neuropathy were first described by Denny-Brown in 1948 and are notable because they served to introduce the modern-day concept of paraneoplastic neurologic disease. The initial symptoms in both processes are numbness or paresthesias, sometimes painful, in a limb or in both feet. There may be lancinating pains at the onset. Over a period of days in some cases, but more typically over weeks, the initially focal symptoms become bilateral and may spread to all limbs and their proximal portions and then to the trunk. It is this widespread and proximal distribution and the involvement of the face, scalp, and often the oral and genital mucosa that mark the process as a sensory ganglionitis and radiculitis and when subacute are highly suggestive of a paraneoplastic process.


Neurology_Adams

Neurology_Adams. As the illness progresses, all forms of sensation are greatly reduced, resulting in disabling ataxia and pseudoathetoid movements of the outstretched hands. The reflexes are lost, but not always at the outset, and strength is relatively preserved. Autonomic dysfunction—including constipation or ileus, sicca syndrome, pupillary areflexia, and orthostatic hypotension—is sometimes associated. Also, a virtually pure form of peripheral autonomic failure has been recorded as a paraneoplastic phenomenon (paraneoplastic dysautonomia). One of our patients with sensory neuronopathy had gastric atony with fatal aspiration after vomiting and another died of unexpected cardiac arrhythmia. Very early in the illness, the electrophysiologic studies may be normal, but this soon gives way to a loss of all sensory potentials, sometimes with indications of a mild motor neuropathy.


Neurology_Adams

Neurology_Adams. The spinal fluid usually contains elevated protein and a few lymphocytes. As with paraneoplastic encephalomyelitis, most of the cases associated with small cell lung cancer demonstrate the anti-Hu antibody. A small but uncertain proportion of this same syndrome is due to anti-CRMP5 antibody, usually associated with small cell lung cancer. As mentioned, neuropathy and encephalomyelitis often occur together. The sensory neuronopathy–ganglionopathy that is related to Sjögren disease and an idiopathic variety do not have this antibody, making its presence a reliable marker for lung cancer in patients with sensory neuronopathy. The polyneuropathy and sensory neuronopathy is refractory to almost all forms of treatment, or there is a transient benefit, and most patients die within months of onset, but there have been reports of brief remissions with plasma exchange and intravenous gamma globulin applied early in the illness. Resection of a tumor can halt progression of the neurologic


Neurology_Adams

Neurology_Adams. of onset, but there have been reports of brief remissions with plasma exchange and intravenous gamma globulin applied early in the illness. Resection of a tumor can halt progression of the neurologic illness.


Neurology_Adams

Neurology_Adams. For many years, this disorder was considered to be quite uncommon, but it is perhaps the most characteristic of the paraneoplastic syndromes. In reviewing this subject in an earlier edition of this textbook 1970, Adams and Victor were able to find only 41 pathologically verified cases; in a subsequent review (Henson and Urich), only a few more cases were added. The actual incidence is much higher than these figures would indicate. At the Cleveland Metropolitan General Hospital, in a series of 1,700 consecutive autopsies in adults, there were 5 instances of cerebellar degeneration associated with neoplasm. In the experience of Henson and Urich, about half of all patients with nonfamilial, late-onset cerebellar degeneration proved sooner or later to be harboring a neoplasm. Large series of cases have been reported from the Mayo Clinic and the Memorial Sloan-Kettering Cancer Center (Hammack et al and N.E. Anderson et al, respectively). We see several such cases yearly, but have also


Neurology_Adams

Neurology_Adams. of cases have been reported from the Mayo Clinic and the Memorial Sloan-Kettering Cancer Center (Hammack et al and N.E. Anderson et al, respectively). We see several such cases yearly, but have also encountered numerous instances of an identical syndrome with no cancer evident and no antibodies that are probably a result of diverse causes summarized in Chap. 5 and Table 5-1.


Neurology_Adams

Neurology_Adams. In approximately one-third of the cases, the underlying neoplasm has been in the lung (most often a small cell carcinoma)—a figure reflecting the high incidence of this tumor. However, the association of ovarian carcinoma and lymphoma, particularly Hodgkin disease, accounting for approximately 25 and 15 percent, respectively, is considerably higher than would be expected on the basis of the frequency of these malignancies. Carcinomas of the breast, bowel, uterus, and other viscera have accounted for most of the remaining cases (Posner, 1995). The cerebellar symptoms have a subacute onset and steady progression over a period of weeks to months; in more than half the cases, the cerebellar signs are recognized before those of the associated neoplasm.


Neurology_Adams

Neurology_Adams. Symmetrical ataxia of gait and limbs—affecting arms and legs more or less equally—dysarthria, and nystagmus are the usual manifestations; some have vertigo. Striking in fully developed cases has been the severity of the ataxia, matched by few other diseases. Occasionally, myoclonus and opsoclonus or a fast-frequency myoclonic tremor may be associated (“dancing eyes–dancing feet,” as noted later). In addition, there are quite often symptoms and signs not strictly cerebellar in nature, notably diplopia, vertigo, Babinski signs (common in our cases), sensorineural hearing loss, disorders of ocular motility, and alteration of affect and mentation—findings that serve to distinguish paraneoplastic from alcoholic and other varieties of cerebellar degeneration. Lambert-Eaton syndrome is known to occur with cerebellar degeneration as paraneoplastic illnesses, generally in association with anti-voltage-gated calcium channel (VGCC) antibodies. These are well emphasized in the series of 47


Neurology_Adams

Neurology_Adams. to occur with cerebellar degeneration as paraneoplastic illnesses, generally in association with anti-voltage-gated calcium channel (VGCC) antibodies. These are well emphasized in the series of 47 patients collected by Anderson and colleagues and the 55 cases by Peterson et al, who tabulated these noncerebellar neurologic features.


Neurology_Adams

Neurology_Adams. The CSF may show a mild pleocytosis (up to 50 cells/mm3 in a few of our patients) and increased protein, or it may be entirely normal. Early in the course of the disease, CT and MRI show no abnormality, but after a few months, atrophy of the brainstem and cerebellum may appear. In a few cases, T2-weighted MRI discloses increased signal of the cerebellar white matter (Hammack et al), but this has not been uniform in our experience, and furthermore does not correlate well to the presence or degree of Purkinje cell loss (Fig. 30-25). FDG-PET may show hypometabolism in the cerebellum before the MRI changes are detectable.


Neurology_Adams

Neurology_Adams. Purkinje cell loss (Fig. 30-25). FDG-PET may show hypometabolism in the cerebellum before the MRI changes are detectable. Pathologically, there are diffuse degenerative changes of the cerebellar cortex and deep cerebellar nuclei. Purkinje cells are affected prominently and all parts of the cerebellar cortex are involved. Degenerative changes in the spinal cord, involving the posterior columns and spinocerebellar tracts, have been found rarely. The cerebellar neuronal degeneration is frequently associated with perivascular and meningeal clusters of inflammatory cells. Henson and Urich regard the inflammatory changes as an independent process, part of a subacute paraneoplastic encephalomyelitis (see in the following text). This view is supported by the finding that the specific antibodies linked to cerebellar degeneration differ from those found in paraneoplastic inflammatory lesions in other parts of the nervous system.


Neurology_Adams

Neurology_Adams. Anti-Purkinje cell antibodies (termed anti-Yo) can be found in the sera of about half of patients with paraneoplastic cerebellar degeneration and in the large majority of those related to carcinoma of the breast or female genital tract, linking the clinical syndrome and this antibody closely. Antibodies against a nuclear antigen, termed anti-Hu, may also be present; they are more closely linked to the paraneoplastic encephalomyelitis discussed further on. (Hu and Yo are taken from the names of patients in whom the antibody was first found.) In the Mayo Clinic series of 32 patients with paraneoplastic cerebellar degeneration, 16 had such antibodies; all were women and most of them had breast or ovarian cancers. Anderson and colleagues report a similar proportion but point out that several other anti-Purkinje antibodies besides the highly characteristic one may be found (see Table 30-6). Death occurred in 4 to 18 months. In an equal number of cases without antibodies, half are men with


Neurology_Adams

Neurology_Adams. other anti-Purkinje antibodies besides the highly characteristic one may be found (see Table 30-6). Death occurred in 4 to 18 months. In an equal number of cases without antibodies, half are men with lung cancer, some of whom display the anti-Hu antibody. This leaves a proportion who have no circulating antibody but who are nonetheless found to have a concealed tumor that must be sought by other ancillary tests including CT or positron emission tomography (PET) of the body. In another small group, it must be conceded that no underlying tumor can be found despite extensive examinations and even at autopsy. The survival in these cases has varied widely from 6 months to several years and depends on the behavior of the underlying tumor.


Neurology_Adams

Neurology_Adams. Whether the anti-Yo antibodies are merely markers of an underlying tumor or the agents of destruction of the Purkinje cells is not clear. They bind to a C-myc protein that initiates a degeneration of Purkinje cells. Regardless of the pathogenic significance of the antibodies, their presence in a patient with the typical neurologic disorder has considerable diagnostic significance. As mentioned above, they usually indicate that there is an underlying breast or ovarian cancer, which may be asymptomatic and small enough to be completely resected. Other antibodies besides anti-Yo and anti-Hu are found on occasion, such as those against a glutamate receptor in patients with Hodgkin disease (Smitt et al). The differential diagnosis of subacute cerebellar ataxia is broad, as indicated in


Neurology_Adams

Neurology_Adams. Table 5-1. The main considerations are postinfectious cerebellitis, non-paraneoplastic autoimmune cerebellitis (in which the conventional antibodies are present without tumor), a rare variant of Creutzfeldt-Jakob disease, and various intoxications. Treatment Reports of plasma exchange or intravenous immunoglobulin treatment early in the course of neurological symptoms suggest some benefit, but it should not be assumed that this approach will succeed in most patients, and our own experience has been discouraging in this regard. Early identification and removal of a tumor yields the best outcomes; however, most patients are left with substantial deficits.


Neurology_Adams

Neurology_Adams. In children, this syndrome is usually a manifestation of neuroblastoma, but it is more common and occurs in adults in relation to breast cancer and small cell lung cancer. The unique feature of the neuroblastoma is a response of this syndrome to corticosteroids and ACTH in most children and in some adults, and resolution of the neurologic signs when the neuroblastoma is removed. A subgroup of breast cancers produce an antineuronal antibody directed against a different RNA-binding antigen from the anti-Hu antibody; thus it has been termed “anti-Ri” (antineuronal antibody type 2 (ANNA 2)). This antibody is not found in the opsoclonus–ataxic syndrome of neuroblastoma and is present only rarely with small cell lung cancer. More commonly present in patients with small cell lung cancer are glycine receptor autoantibodies, though these antibodies are also found in patients without opsoclonus-myoclonus (see Armangué et al). There have also been a limited number of positive serologic tests in


Neurology_Adams

Neurology_Adams. receptor autoantibodies, though these antibodies are also found in patients without opsoclonus-myoclonus (see Armangué et al). There have also been a limited number of positive serologic tests in children with opsoclonus, apparently without an underlying tumor. A few such patients have had a mild pleocytosis in the CSF; the MRI is usually normal. More complex syndromes have been reported with the anti-Ri antibody, manifest by rigidity and intense stimulus-sensitive myoclonus in addition to the core features of opsoclonus and ataxia.


Neurology_Adams

Neurology_Adams. The neuropathologic findings have not been distinctive; mild cell loss has been described in the Purkinje cell layer, inferior olives, and brainstem, with mild inflammatory changes (Luque et al). Besides in association with breast cancer, we have observed the opsoclonus–myoclonus syndrome in a middle-aged woman with bronchial carcinoma and in a man with gastric carcinoma. Similar cases occur with both cerebellar ataxia and an irregular tremor, which we have interpreted as myoclonic in character. These patients were found to have marked degeneration of the dentate nuclei. The prognosis in this syndrome is somewhat better than that for the other paraneoplastic diseases, but besides a trial of steroids, plasma exchange, or intravenous immunoglobulin, there is little that can be done but search for the tumor and resect it if possible.


Neurology_Adams

Neurology_Adams. In addition to subacute degeneration of spinal cord tracts that may be associated with paraneoplastic cerebellar degeneration (see earlier), there has been described a rapidly progressive form of more widespread degeneration of the spinal cord (Mancall and Rosales). The myelopathy is characterized by a rapidly ascending sensorimotor deficit that terminates fatally in a matter of weeks. There is a roughly symmetrical necrosis of both the gray and white matter of most of the cord. This necrotizing myelopathy is distinctly rare, being far less common than compression of the spinal cord from cancer and even less frequent than intramedullary spinal cord metastases. Flanagan and colleagues have summarized a large series of their cases and described a variety of presentations including longitudinally extensive involvement on imaging studies that simulate the pattern seen with anti-aquaporin antibodies of Devic disease as described in Chaps. 35 and 42. It can, therefore, be said that there is


Neurology_Adams

Neurology_Adams. extensive involvement on imaging studies that simulate the pattern seen with anti-aquaporin antibodies of Devic disease as described in Chaps. 35 and 42. It can, therefore, be said that there is a paraneoplastic type of neuromyelitis optica. Most of their cases had a CSF pleocytosis, half had oligoclonal bands, and one of the known paraneoplastic autoantibodies was found in the majority.


Neurology_Adams

Neurology_Adams. Better defined is subacute motor neuronopathy that occurs as a remote effect of bronchogenic carcinoma, Hodgkin disease, and other lymphomas as mentioned earlier in the discussion of encephalomyelitis (Schold et al). Some cases take the form of a relatively benign, purely motor weakness of the limbs, the course and severity of which are independent of the underlying neoplasm. Other cases are severe and progressive, causing respiratory failure and death, thus simulating amyotrophic lateral sclerosis (ALS); some of these will have the anti-Hu antibody (Verma et al; Forsyth et al). The basic neuropathologic change is a depletion of anterior horn cells; also seen are inflammatory changes and neuronophagia as in chronic poliomyelitis. The few autopsied cases have shown gliosis of the posterior columns, pointing to an asymptomatic affection of the primary sensory neuron, as well as a reduction in the number of Purkinje cells.


Neurology_Adams

Neurology_Adams. Forsyth and colleagues subdivided their cases of paraneoplastic motor neuron syndromes into three groups: (1) rapidly progressive amyotrophy and fasciculations with or without brisk reflexes—all of their 3 patients displayed anti-Hu antibodies, 2 with small cell lung cancer and 1 with prostate cancer; (2) a predominantly corticospinal syndrome that affected the oropharyngeal or limb musculature, without definite evidence of denervation, thus resembling primary lateral sclerosis—all were breast cancer patients and none showed antineuronal antibodies; and (3) a syndrome indistinguishable from ALS in 6 patients with breast or small cell lung cancer, Hodgkin disease, or ovarian cancer, none of whom had antineuronal antibodies. In the latter two groups one cannot be certain that the condition was not a chance occurrence of the idiopathic variety of motor neuron disease. Nevertheless, this is such a rare cause of motor neuron disease that an evaluation for tumor is not required in the


Neurology_Adams

Neurology_Adams. was not a chance occurrence of the idiopathic variety of motor neuron disease. Nevertheless, this is such a rare cause of motor neuron disease that an evaluation for tumor is not required in the typical case of ALS.


Neurology_Adams

Neurology_Adams. A rare paraneoplastic syndrome of spinal myoclonus with tonic spasms can occur and is assumed to be from inflammation of the spinal cord gray matter as discussed in Chaps. 4 and 42. Several more recently discovered antibodies, such as CRMP-5 (collapsin-responsive mediator protein) and anti-Ma1 and -Ma2, have been detected in cases of brainstem encephalitis including with ophthalmoplegia but there have been associations with limbic and diencephalic syndromes as well and a hypokinetic parkinsonian appearance (Dalmau et al 2004). The anti-Ma antibodies cross-react with testicular antigens and a search for a testicular tumor is undertaken (Voltz et al). Although rare, the clinical syndromes associated with the anti-Ma antibody and testicular tumors are diverse: limbic, brainstem, or hypothalamic inflammation and an ataxic–opsoclonic syndrome that is more typical of anti-Ri antibody (see earlier).


Neurology_Adams

Neurology_Adams. The antibody to CRMP-5 is reported in some series to be second in frequency only to anti-Hu. Lung carcinoma has been the most common source in the series of Yu and colleagues, with thymoma, renal cell, and other neoplasms accounting for a few of the cases. The clinical features have been as diverse as for anti-Hu, including seizures, dementia, confusion, depression, as well as a variety of peripheral and cranial neuropathies and the Lambert-Eaton syndrome. An illness similar to the one caused by anti-NMDA antibodies, under the name of Ophelia syndrome, has been reported as a paraneoplastic syndrome that is due to antibodies directed against the metabotropic glutamate receptor, mGluR5 (see Lancaster et al).


Neurology_Adams

Neurology_Adams. An optic neuropathy is probably the most specific associated syndrome with the CRMP-5 antibody, as described by Cross and colleagues. There is subacute visual loss, disc swelling, and a cellular reaction in the vitreous. Most patients have features of another paraneoplastic syndrome. Several authors have remarked on the occurrence of chorea as a presenting symptom along with basal ganglionic changes on MRI. It is difficult for us to make sense of the clinical features aside from the optic neuropathy (really an optic neuritis), but they seem comparable to the perivenous inflammatory encephalitis and neuritis of the anti-Hu syndromes. Presumably this antibody accounts for some of the odd subacutely progressive syndromes previously thought to be antibody-negative; testing for this antibody might be included when an unusual paraneoplastic syndrome is suspected. The heterogeneity of antibody response to these expressed proteins may account for different clinical manifestations of the


Neurology_Adams

Neurology_Adams. might be included when an unusual paraneoplastic syndrome is suspected. The heterogeneity of antibody response to these expressed proteins may account for different clinical manifestations of the immune process but there is no certain evidence yet of their pathogenetic role.


Neurology_Adams

Neurology_Adams. In recent years, there have been reports of retinopathy as a paraneoplastic syndrome that is distinct from the above-described optic neuropathy. Small cell carcinoma of the lung has been the most common underlying malignancy. In about half of the reported cases, retinal symptoms preceded the discovery of the tumor by several months. The lesion is in the photoreceptor cells, and antiretinal antibodies (directed against a calcium-binding protein, recoverin) have been identified in the serum. Photosensitivity, ring scotomas, and attenuation of the retinal arterioles are the main clinical features; Jacobson and coworkers suggested that they constitute a diagnostic triad. Paraneoplastic Stiff Person Syndrome and Related Neuromuscular Disorders (See Chap. 46)


Neurology_Adams

Neurology_Adams. Paraneoplastic Stiff Person Syndrome and Related Neuromuscular Disorders (See Chap. 46) Occasionally stiff person syndrome occurs as a paraneoplastic disease. Lesser degrees of unexplained mild rigidity are seen from time to time, perhaps as a consequence of loss of spinal cord interneurons. Folli and associates described 3 female patients with breast cancer who developed a state of generalized motor hyperexcitability and rigidity. These patients generally have no antibodies to glutamic acid decarboxylase (GAD), as in the sporadic cases of stiff person syndrome; probably there are antibodies to other synaptic proteins.


Neurology_Adams

Neurology_Adams. The “chorée fibrillaire” of Morvan is an extraordinary disorder of continuous muscle fiber activity, insomnia, and hallucinosis that may be caused by a paraneoplastic antibody to voltage-gated potassium channels, as discussed in Chap. 46. This same antibody, as well as acetylcholine receptor antibodies, has been associated with paraneoplastic neuromyotonia (Isaac syndrome), seen in cases of lung cancer, lymphoma, and thymoma. The subtleties that distinguish these syndromes of continuous muscle fiber activity are discussed in Chap. 46.


Neurology_Adams

Neurology_Adams. The Lambert-Eaton syndrome is perhaps the most common paraneoplastic neurologic syndrome; it is associated with antibodies directed against calcium channels, as mentioned earlier. This disorder, which may occur concurrently with other paraneoplastic syndromes such as cerebellar ataxia, is discussed in Chap. 46. Basal ganglia syndromes, chorea in particular, are associated with the anti-Hu and CRMP-5 antibodies as already noted. A myoclonus syndrome without ataxia or opsoclonus is reported from time to time in the literature and probably is a derivative of one of the better-characterized antibody diseases.


Neurology_Adams

Neurology_Adams. Injury to the CNS from radiation is appropriately discussed here, since it occurs mainly in relation to therapy for brain tumors. Three syndromes of radiation damage have been delineated: acute, early delayed, and late delayed, although these syndromes often blend into one another. The acute reaction may begin during the latter part of a series of fractionated treatments or soon thereafter. There may be a seizure, a transitory worsening of the tumor symptoms, or signs of increased intracranial pressure. Although the condition has been attributed to brain edema, this is not always visible on MRI and its basis is unknown. The symptoms subside in days to weeks. Corticosteroids are usually administered, but with the exception of cases with demonstrable edema, their effect is uncertain. A novel syndrome of migraine-like headache and focal neurologic deficits, usually developing many years after cranial radiation, is described in more detail below.


Neurology_Adams

Neurology_Adams. The early radiation syndrome has been more troublesome in our experience than has the very acute form. As with the acute syndrome, focal tumor symptoms may increase, and as seen on MRI (Fig. 30-26), the tumor mass enlarges, raising the possibility of further tumor growth, but again the symptoms usually reflect extensive demyelination, loss of oligodendrocytes beyond the confines of the tumor, and varying degrees of tissue necrosis. The administration of dexamethasone or a similar corticosteroid may hasten resolution of this condition.


Neurology_Adams

Neurology_Adams. The late-delayed process is the most serious of radiation complications. Here one finds—in structures adjacent to a cerebral neoplasm, the pituitary gland, or other structures of the head and neck—necrosis of the white matter of the brain and, occasionally, of the brainstem. In some areas, the tissue undergoes softening and liquefaction, with cavitation. With lesser degrees of injury, the process is predominantly a demyelinating one, with partial preservation of axons. Later reactions are thought to be caused by diffuse vascular changes as a result of radiation exposure. Endothelial cells multiply frequently and, because ionizing radiation injures dividing cells, the vessels are most vulnerable. The result is hyaline thickening of vessels with fibrinoid necrosis and widespread microthrombosis. There is a lesser degree of damage to glial cells. Neurons are relatively resistant though they can be secondarily affected by loss of glial support as well as reduced tissue perfusion.


Neurology_Adams

Neurology_Adams. The symptoms of delayed injury, coming on 3 months to many years after radiation therapy, are either those of a subacutely evolving mass, difficult to separate from those of tumor growth, or of a subacute dementia. The clinical pattern varies with the site of the lesion: focal or generalized seizures, impairment of mental function, and, sometimes, increased ICP. Whole-brain radiation for metastatic tumor or acute lymphoblastic leukemia can lead to multifocal zones of necrosis and holohemispheric spongiform changes in the white matter, with diffuse cerebral atrophy and enlarged ventricles. Progressive dementia, ataxia, and urinary incontinence are the main clinical features of this state (DeAngelis et al). In its mildest form there are no radiographic changes aside from the tumor, but the patient becomes mentally dull, slightly disinhibited, and often sleepy for large parts of the day. Panhypopituitarism is another complication of whole-brain radiotherapy, particularly in children, who


Neurology_Adams

Neurology_Adams. becomes mentally dull, slightly disinhibited, and often sleepy for large parts of the day. Panhypopituitarism is another complication of whole-brain radiotherapy, particularly in children, who may also suffer growth retardation. Radiation necrosis of the spinal cord is described in Chap. 42.


Neurology_Adams

Neurology_Adams. In the production of radiation necrosis, the total and fractional doses of radiation and the time over which treatment is administered are obviously important factors, but the exact amounts that produce such damage cannot be stated. Accepted levels of large-field radiation are tolerated in amounts approaching 6,000 cGy, provided it is given in small daily doses (200 to 300 cGy) 5 days per week over a period of 6 weeks. Other factors, still undefined, must play a part, as similar courses of radiation treatment may damage one patient and leave another unaffected. The severe necrotizing encephalopathy that has followed the combined use of methotrexate (intrathecally but also intravenously) was discussed earlier, under “Involvement of the Nervous System in Leukemia,” the condition in which it was first described and formerly was most prevalent.


Neurology_Adams

Neurology_Adams. CT and MRI show a contrast-enhancing lesion, and by angiography there is an avascular mass. Small calcifications may appear many years after the radiation. MRI is somewhat more sensitive in distinguishing radiation necrosis from tumor and peritumor products, but PET is the most reliable way of differentiating the two, perhaps obviating the need for biopsy (Glantz et al, 1991). Single-photon emission tomography (SPECT) can be useful for this purpose as well (Carvalho et al). CT or MRI perfusion imaging can also be used to differentiate radiation necrosis from tumor progression; cerebral blood volume is reduced in the former and most often elevated in the latter.


Neurology_Adams

Neurology_Adams. Treatment has consisted of the administration of corticosteroids, which may cause regression of symptoms and of edema surrounding the lesion. Very high doses may be necessary, 40 mg or more of dexamethasone or its equivalent daily. Rarely, surgical resection of an edematous necrotic mass is attempted; this would only be considered to abrogate severe mass effect or herniation.


Neurology_Adams

Neurology_Adams. Stroke-like migraine attacks after radiation therapy (SMART) syndrome A difficult to classify migraine-like syndrome following cranial irradiation has been described by Partap and colleagues and by Pruitt and coworkers. This syndrome has been given the acronym SMART, for “stroke-like migraine attacks after radiation therapy.” The typical case is of a young adult who, years or decades after receiving radiation as a child for an intracranial neoplasm, develops episodes of severe headache and simultaneous symptoms such as aphasia, hemiparesis, or hemianopia, sometimes lasting days. There may be an independent headache suggestive of migraine. The syndrome can occur in the absence of an intracranial malignancy supporting the notion that the syndrome is the result of radiation exposure alone.


Neurology_Adams

Neurology_Adams. In many cases there is diffuse gyriform enhancement and edema over a large region of cortex spanning several arterial territories (Fig. 30-27). Perfusion imaging studies have shown that a transient period of regional hyperperfusion precedes these imaging abnormalities as well as epiphenomena such as seizures (Olsen et al). This suggests that radiation-induced endothelial injury leading to impairment of cerebrovascular autoregulation is the underlying pathology. In the early phase of the disorder, headache and seizures may not be present. The clinical symptoms and imaging abnormalities typically resolve over the course of weeks to a month or two. SMART syndrome can recur, and different parts of the cortex may be affected during different episodes. Corticosteroids seem helpful in some cases.


Neurology_Adams

Neurology_Adams. It is also known that tumors, usually sarcomas, can be induced by radiation, as mentioned earlier (Cavin et al). While well documented, this occurs rarely and only after an interval of many years. We have seen two cases of fibrosarcoma of the brachial plexus region in the radiation field for breast tumors (Gorson et al). These lesions appeared more than 10 years after the initial treatment, and many cases of even longer latency are on record. Tumors of the spinal cord and peripheral nerves are discussed in Chaps. 42 and 43, respectively. The various neurologic effects of chemotherapy for systemic tumors, especially polyneuropathy, are discussed in Chaps. 43. The interesting problem of the effects on the nervous system of graft-versus-host disease is taken up in Chap. 35 with other inflammatory conditions. Adams RD, Wegner W: Congenital cyst of the spinal meninges as cause of intermittent compression of the spinal cord. Arch Neurol Psychiatry 58:57, 1947.


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Neurology_Adams. Ropper AH: Hyperosmolar therapy for raised intracranial pressure. N Engl J Med 367:746, 2012. Rosenberg GA, Saland L, Kyner WT: Pathophysiology of periventricular tissue changes with raised CSF pressure in cats. J Neurosurg 59:606, 1983. Rubinstein LJ: Embryonal central neuroepithelial tumors and their differentiating potential. J Neurosurg 62:795, 1985. Rubinstein LJ: Tumors of the central nervous system: Fasc 6, 2nd series, in Atlas of Tumor Pathology. Washington, DC, Armed Forces Institute of Pathology, 1972. Rubinstein AB, Shalit MN, Cohen ML, et al: Radiation-induced cerebral meningioma: A recognizable entity. J Neurosurg 61:966, 1984. Rudin CM, Hann CL, Laterra J, et al: Treatment of medulloblastoma with hedgehog inhibitor GDC-0449. N Engl J Med 361:1173, 2009. Russell DS: Cellular changes and patterns of neoplasia. In: Haymaker W, Adams RD (eds): Histology and Histopathology of the Nervous System. Springfield, IL, Charles C Thomas, 1982, pp 1493–1515.


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Neurology_Adams. Russell DS: Cellular changes and patterns of neoplasia. In: Haymaker W, Adams RD (eds): Histology and Histopathology of the Nervous System. Springfield, IL, Charles C Thomas, 1982, pp 1493–1515. Rutkowski S, Bode U, Deinlein F, et al: Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978, 2005. Sanai N, Alvarez-Buylla A, Berger MS: Neural stem cells and the origin of gliomas. N Engl J Med 353:811, 2005. Sanai N, Mirzadeh Z, Berger MS: Functional outcome after language mapping for glioma resection. N Engl J Med 358:18, 2008. Schmidek HH: Some current concepts regarding medulloblastomas. In: Levine AJ, Schmidek HH (eds): Molecular Genetics of Nervous System Tumors. New York, Wiley-Liss, 1993, pp 283–286. Schold SC, Cho E-S, Somasundaram M, Posner JB: Subacute motor neuronopathy: A remote effect of lymphoma. Ann Neurol 5:271, 1979.


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Neurology_Adams. Schold SC, Cho E-S, Somasundaram M, Posner JB: Subacute motor neuronopathy: A remote effect of lymphoma. Ann Neurol 5:271, 1979. Seizinger BR, Roulean GA, Ozelius LJ, et al: Von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal carcinoma. Nature 332:268, 1988. Shapiro WR: Therapy of adult malignant brain tumors: What have the clinical trials taught us? Semin Oncol 13:38, 1986. Shaw EG, Daumas-Duport C, Scheithauer BS, et al: Radiation therapy in the management of low-grade supratentorial astrocytomas. J Neurosurg 70:853, 1989. Sheibani K, Battifora H, Winberg CD, et al: Further evidence that “malignant angioendotheliomatosis” is an angiotropic large-cell lymphoma. N Engl J Med 314:943, 1986. Slotman B, Faivre-Finn C, Kramer G, et al: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664, 2007.


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Neurology_Adams. Slotman B, Faivre-Finn C, Kramer G, et al: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664, 2007. Smitt PS, Kinoshita A, Leeuw B, et al: Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 342:21, 2000. Söderberg-Nauclér C, Rahbar A, Stragliotto G: Survival in patients with glioblastoma receiving valgangciclovir. N Engl J Med 369:985, 2013. Sorenson SC, Eagan RT, Scott M: Meningeal carcinomatosis in patients with primary breast or lung cancer. Mayo Clin Proc 59:91, 1984. Sparling HJ, Adams RD, Parker F: Involvement of the nervous system by malignant lymphoma. Medicine 26:285, 1947. Stupp R, Mason W, van den Bent M, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987, 2005. Ulmer S, Braga TA, Barker FG, et al: Clinical and radiographic features of peritumoral infarction following resection of glioblastoma. Neurology 67:1688, 2006.


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Neurology_Adams. N Engl J Med 352:987, 2005. Ulmer S, Braga TA, Barker FG, et al: Clinical and radiographic features of peritumoral infarction following resection of glioblastoma. Neurology 67:1688, 2006. Van den Bent MJ, Afra D, de Witte O, et al: Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: The EORTC 22845 randomised trial. Lancet 366:985, 2005. Van Sonderen A, Thijs RD, Coenders EC, et al: Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up. Neurology 87:1449, 2016. Verma A, Berger JR, Snodgrass S, Petito C: Motor neuron disease: A paraneoplastic process associated with anti-Hu antibody and small-cell lung carcinoma. Ann Neurol 40:112, 1996. Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody-associated encephalopathy: A potentially immunotherapy-responsive form of limbic encephalitis. Brain 127:701, 2004.


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Neurology_Adams. Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody-associated encephalopathy: A potentially immunotherapy-responsive form of limbic encephalitis. Brain 127:701, 2004. Vitaliani R, Mason W, Ances B, et al: Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 58:594, 2005. Voltz R, Gultekin SH, Rosenfeld MR, et al: A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 340:1788, 1999. Wasserstrom WR, Glass JP, Posner JB: Diagnosis and treatment of leptomeningeal metastases from solid tumors: Experience with 90 patients. Cancer 49:759, 1982. Weiss HD, Richardson EP: Solitary brainstem metastasis. Neurology 28:562, 1978. Wick W, Meisner C, Hentschl B, et al: Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81:1515, 2013.


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Neurology_Adams. Neurology 28:562, 1978. Wick W, Meisner C, Hentschl B, et al: Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81:1515, 2013. Yan H, Parsons DW, Jin, GJ, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765, 2009. Yu Z, Kryzer TJ, Griesmann GE, et al: CRMP-5 neuronal antibody: Marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 49:164, 2001. Yung WA, Horten BC, Shapiro WR: Meningeal gliomatosis: A review of 12 cases. Ann Neurol 8:605, 1980. Zentner J, Wolf HK, Ostertun B, et al: Gangliogliomas: Clinical, radiological, and histopathological findings in 51 patients. J Neurol Neurosurg Psychiatry 57:1497, 1994. Zülch KJ: Brain Tumors, Their Biology and Pathology, 3rd ed. New York, Springer-Verlag, 1986.


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Neurology_Adams. J Neurol Neurosurg Psychiatry 57:1497, 1994. Zülch KJ: Brain Tumors, Their Biology and Pathology, 3rd ed. New York, Springer-Verlag, 1986. Figure 30-1. A. Schematic representation of the astrocytes and endothelial cells of the capillary wall in the normal state (above) and in vasogenic edema (below). Heightened permeability in vasogenic edema is partly the result of a defect in tight endothelial junctions, but mainly a result of active vesicular transport across endothelial cells. B. Cellular (cytotoxic) edema, showing swelling of the endothelial, glial, and neuronal cells at the expense of the extracellular fluid space of the brain. (Reproduced by permission from Fishman.) Figure 30-2. Glioblastoma. Contrast-enhanced T1-weighted MRI illustrates a large irregularly enhancing tumor with internal necrosis deep within the left cerebral hemisphere.


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Neurology_Adams. Figure 30-2. Glioblastoma. Contrast-enhanced T1-weighted MRI illustrates a large irregularly enhancing tumor with internal necrosis deep within the left cerebral hemisphere. HistologyAstrocytomaOligoastrocytomaOligodendrogliomaGlioblastomaIDH statusIDH mutantIDH mutantGlioblastoma, IDH mutantGlioblastoma, IDH wild-typeGenetic testing not doneor inconclusiveIDH wild-typeIDH wild-type1p/19q andother geneticparameters1p/19q codeletionOligodendroglioma, IDH mutant and 1p/19q codeletedAfter exclusion of other entities:Diffuse astrocytoma, IDH wild-typeOligodendroglioma, NOS* = characteristic but notrequired for diagnosisDiffuse astrocytoma, NOSOligodendroglioma, NOSOligoastrocytoma, NOSGlioblastoma, NOSDiffuse astrocytoma, IDH mutantATRX loss*TP53 mutation*


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Neurology_Adams. Figure 30-3. Simplified molecular genetic analysis of gliomas as a supplement to histological classification. IDH, Isocitrate dehydroxygenase; TP53, tumor (suppressor) protein 53; ATRX, alpha-thalassemia/mental retardation syndrome X-linked. (From Louis DN, Ohgaki H, Wiestler OD, Cavenee WK: World Health Organization Histological Classification of Tumours of the Central Nervous System. France, International Agency for Research on Cancer, 2016. Reproduced with permission from David N. Louis, MD.) Figure 30-4. Astrocytoma of the left frontal lobe; the T2-weighted MRI shows an infiltrating tumor with minimal mass effect and mild edema. The degree of contrast enhancement is variable but most often less than glioblastoma.


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Neurology_Adams. Figure 30-5. Gliomatosis cerebri invading both hemispheres. T2-weighted MRI shows a large confluent area of involvement in the frontal lobes with effacement of overlying cortical sulci. There was slight enhancement along the margins of the lesions after gadolinium infusion. The patient was mentally slow but had no other neurologic signs. Figure 30-6. A partially cystic oligodendroglioma of the right frontotemporal region. There was no abnormal contrast enhancement. Figure 30-7. A. Parafalcine meningioma; coronal image, MRI with gadolinium. Note the rightward displacement of an anterior cerebral artery (hypointense flow void) trapped between the right lateral margin of the mass and the right medial frontal lobe. B. Small and asymptomatic left olfactory groove meningioma, MRI with gadolinium.


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Neurology_Adams. Figure 30-8. Gadolinium-enhanced MRI of meningioma. Large subfrontal extraaxial mass with central calcification and surrounding vasogenic edema. Homogeneous avid enhancement is characteristic of the tumor. Figure 30-9. Primary central nervous system lymphoma. Left: Axial T2-FLAIR MRI showing hyperintensity in the right periatrial white matter, without mass effect. Right: Contrast-enhanced MRI reveals two foci of nodular parenchymal enhancement. Figure 30-10. Contrast-enhanced MRI (left) showing multiple metastases from renal cell carcinoma. Note the extensive hypointense edema surrounding each lesion. The right image is a gradient echo MRI in which blood products appear hypointense (dark). This sequence can aid in detection of small or nonenhancing hemorrhagic metastases, such as the lesion in the left occipital lobe.


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Neurology_Adams. Figure 30-11. Leptomeningeal carcinomatosis from breast cancer showing infiltration of the cortical and cerebellar subarachnoid spaces on axial T1 post-gadolinium MRI. There is a small metastases in the pontine tegmentum. Figure 30-12. Medulloblastoma. MRI in the sagittal (above) and axial (below) planes, illustrating involvement of the cerebellar vermis and neoplastic obliteration of the fourth ventricle. Figure 30-13. Ependymoma of the fourth ventricle. A. Coronal T2 MRI shows an ependymoma growing out of the fourth ventricle. B. Axial T2 FLAIR MRI shows that the mass completely obliterates the fourth ventricle. Figure 30-14. Hemangioblastoma. Contrast-enhanced MRI in the axial plane (left) shows the vascular tumor in the left cerebellar hemisphere. Selective left vertebral angiogram (right) defines a hypervascular nodule with dilated draining veins.


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Neurology_Adams. Figure 30-15. Pineal tumor. T2-weighted MRI in the sagittal plane (above) demonstrates a tumor that compresses the tectum and the cerebral aqueduct. Axial T2 FLAIR MRI (below) shows the tumor and evidence of hydrocephalus and transependymal flow of CSF from the lateral ventricles, resulting from aqueductal compression. Figure 30-16. Lhermitte-Duclos disease. T2-weighted MRI showing the characteristic “tiger stripe” appearance of this hamartomatous tumor in the right cerebellar hemisphere. Figure 30-17. Contrast-enhanced MRI of a cystic and nodular dysembryoplastic neuroepithelial tumor (DNET) of the left temporal lobe in an adult who had a single seizure. The nodule had an inflammatory component and the seizures ceased with resection. Figure 30-18. Colloid cyst of the third ventricle. MRI in the axial and sagittal planes. Hydrocephalus due to obstruction at the foramen of Monro can occur, but is not apparent here.


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Neurology_Adams. Figure 30-18. Colloid cyst of the third ventricle. MRI in the axial and sagittal planes. Hydrocephalus due to obstruction at the foramen of Monro can occur, but is not apparent here. Figure 30-19. Bilateral vestibular schwannomas in neurofibromatosis type 2. T1-weighted MRI in the axial plane before (left) and after (right) contrast administration. Figure 30-20. A. MRI of a small vestibular schwannoma emanating from the left porus acusticus, showing typical homogenous gadolinium enhancement. B. A larger atypical vestibular schwannoma with rim enhancement, causing compression of the left middle cerebellar peduncle. Figure 30-21. Pituitary macroadenoma. Coronal T1 MRI before (left) and after (right) contrast administration. A homogenously enhancing mass originating in the sella protrudes into the suprasellar cistern and displaces the optic chiasm and inferior hypothalamus. The lesion also extends into the adjacent cavernous sinuses.


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Neurology_Adams. Figure 30-22. Pontine glioma. Contrast-enhanced T1 MRI demonstrates a mass with prominent irregular peripheral gadolinium enhancement. The patient was a 3-year-old male with progressive cranial nerve and long tract deficits. Figure 30-23. MRI demonstrating an epidermoid cyst in the left cerebellopontine angle just above the foramen magnum. The cyst is heterogenous and hyperintense on T2-weighted MRI (A) and demonstrates reduced diffusivity (B), a characteristic feature. Figure 30-24. Axial T2 FLAIR MRI from a woman with anti-voltage-gated potassium channel (VGKC) paraneoplastic limbic encephalitis associated with thyroid cancer. The hippocampus and amygdala appear abnormally T2 hyperintense. Figure 30-25. Paraneoplastic cerebellar degeneration. Coronal T2 FLAIR MRI showing subtle diffuse abnormal T2 hyperintensity of the cerebellar cortex.


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Neurology_Adams. Figure 30-25. Paraneoplastic cerebellar degeneration. Coronal T2 FLAIR MRI showing subtle diffuse abnormal T2 hyperintensity of the cerebellar cortex. Figure 30-26. Radiation leukoencephalopathy. (Left panel) A patient who underwent proton beam radiation therapy for carcinoma of the left mastoid area presented several years later with radiation necrosis presenting as a seizure. There is extensive edema in the left hemisphere and obstructive hydrocephalus of the contralateral ventricle. (Right panel) Another patient with lung cancer who was treated with prophylactic whole-brain radiation, presented years later with gait difficulties and cognitive decline and was found to have extensive symmetric leukoencephalopathy with ex vacuo ventricular dilation.


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Neurology_Adams. Figure 30-27. Stroke-like migraine attacks after radiation therapy (SMART). A 68-year-old man who had prophylactic cranial radiation presented several years later with dysphasia and right hemiparesis. MRI showed abnormal T2 hyperintensity (left) and more prominent enhancement (right) of the cortex of the left hemisphere. These imaging abnormalities resolved after several weeks. (Images reproduced from Olsen et al with permission from Wolters Kluwer.) Bacterial, Fungal, Spirochetal, and Parasitic Infections of the Nervous System


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Neurology_Adams. Bacterial, Fungal, Spirochetal, and Parasitic Infections of the Nervous System This chapter is concerned mainly with bacterial infections of the central nervous system (CNS), particularly bacterial meningitis, septic thrombophlebitis, brain abscess, epidural abscess, and subdural empyema. The granulomatous infections of the CNS, notably tuberculosis, syphilis and other spirochetal infections, and certain fungal infections are also discussed in some detail. In addition, consideration is given to infections and infestations caused by rickettsias, protozoans, worms, and tick borne infections.


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Neurology_Adams. A number of other important infectious diseases of the nervous system are discussed elsewhere in this book. Viral infections, because of their frequency and importance, are allotted a chapter of their own (see the following Chap. 32). Diseases caused by bacterial exotoxins—diphtheria, tetanus, botulism—are considered with other toxins that affect the nervous system (see Chap. 41). Leprosy, which is essentially a disease of the peripheral nerves, is described in Chap. 43, and trichinosis, mainly a disease of muscle, in Chap. 45.


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Neurology_Adams. These infections reach the intracranial structures by one of two pathways, either by hematogenous spread (emboli of bacteria or infected thrombi) or by extension from cranial structures adjacent to the brain (ears, paranasal sinuses, osteomyelitic foci in the skull, penetrating cranial or congenital sinus tracts) (see Durand et al and Thigpen et al for summaries of this subject). In a number of cases, infection is iatrogenic, being introduced in the course of cerebral or spinal surgery, the placement of a ventriculoperitoneal shunt or, rarely, by a lumbar puncture needle. Increasingly, craniospinal infections are nosocomial, that is, acquired in-hospital; in urban hospitals, nosocomial meningitis is now as frequent as the non–hospital-acquired variety as noted in the review by van der Beek and colleagues.


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Neurology_Adams. Surprisingly little is known about the mechanisms of hematogenous spread and animal experiments involving the injection of virulent bacteria into the bloodstream have yielded somewhat contradictory results. In most instances of bacteremia or septicemia, the nervous system seems not to be infected; yet sometimes a bacteremia caused by pneumonia or endocarditis is the only apparent predecessor to meningitis. With respect to the formation of brain abscess, cerebral tissue has a notable resistance to infection. Direct injection of virulent bacteria into the brain of an animal seldom results in abscess formation. In fact, this condition has been produced consistently only by injecting culture medium along with the bacteria or by causing necrosis of the tissue at the time bacteria are inoculated. In humans, infarction of brain tissue because of arterial occlusion (thrombosis or embolism) or venous occlusion (thrombophlebitis) may be a common and perhaps necessary antecedent by way of


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Neurology_Adams. In humans, infarction of brain tissue because of arterial occlusion (thrombosis or embolism) or venous occlusion (thrombophlebitis) may be a common and perhaps necessary antecedent by way of causing of a necrotic nidus.


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Neurology_Adams. The mechanism of meningitis and brain abscess from infection of the middle ear and paranasal sinuses is easier to understand. The cranial epidural and subdural spaces are practically never the sites of blood-borne infections, in contrast to the spinal epidural space, where such infections are either by hemtogenous spread or from contiguous osteomyelitis. Furthermore, the cranial bones and the dura mater (which essentially constitutes the inner periosteum of the skull) protect the cranial cavity against the ingress of bacteria. This protective mechanism may fail if suppuration occurs in the middle ear, mastoid cells, or frontal, ethmoid, and sphenoid sinuses. Two pathways from these sources have been demonstrated: infected thrombi may form in diploic veins and spread along these vessels into the dural sinuses (into which the diploic veins flow), and from there, in retrograde fashion, along the meningeal veins into the brain, and an osteomyelitic focus may erode the inner table of bone


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Neurology_Adams. the dural sinuses (into which the diploic veins flow), and from there, in retrograde fashion, along the meningeal veins into the brain, and an osteomyelitic focus may erode the inner table of bone and invade of the dura, subdural space, pia-arachnoid, and even brain. Each of these pathways has been observed by the authors in fatal cases of epidural abscess, subdural empyema, meningitis, cranial venous sinusitis with meningeal thrombophlebitis, and brain abscess. However, in many cases coming to autopsy, the pathway of infection cannot be determined.


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Neurology_Adams. With a hematogenous infection in the course of a bacteremia, usually a single type of virulent bacterium gains entry to the cranial cavity. In the adult the most common spontaneous or community-acquired pathogenic organisms are pneumococcus (Streptococcus pneumoniae), meningococcus (Neisseria meningitidis), group B streptococcus, Listeria monocytogenes, and staphylococcus; in the neonate, Escherichia coli and group B streptococcus; in the infant and unvaccinated child, H. influenzae. By contrast, when septic material embolizes from infected lungs, pulmonary arteriovenous fistulas, or congenital heart lesions, or extends directly from ears or sinuses, more than one type of bacterial flora common to these sites may be transmitted. Such “mixed infections” pose difficult problems in therapy. Occasionally in these latter conditions, culture of the causative organisms may be unsuccessful, even from the pus of an abscess (mainly because of difficulty in culturing for anaerobic organisms and


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Neurology_Adams. Occasionally in these latter conditions, culture of the causative organisms may be unsuccessful, even from the pus of an abscess (mainly because of difficulty in culturing for anaerobic organisms and due to the prior use of antibiotics). Infections that follow neurosurgery or the insertion of a cranial appliance are usually staphylococcal or due to anaerobic gram negative organisms; a small number are a result of mixed flora, including anaerobic ones, or one of the enteric organisms. In determining the most likely invading organism, the age of the patient, the clinical setting of the infection (community-acquired, postsurgical, or nosocomial), the immune status of the patient, and evidence of systemic and local cranial disease all must be taken into account.


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Neurology_Adams. The Biology of Bacterial Meningitis The immediate effect of bacteria or other microorganisms in the subarachnoid space is to cause an inflammatory reaction in the pia and arachnoid as well as in the cerebrospinal fluid (CSF). Because the subarachnoid space is continuous around the brain, spinal cord, and optic nerves, an infective agent gaining entry to any one part of the space allows it to spread rapidly to all of it, even its most remote recesses; in other words, meningitis is always cerebrospinal. Infection also reaches the ventricles, either directly from the choroid plexuses or by reflux through the foramina of Magendie and Luschka.


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Neurology_Adams. The first reaction to bacteria or their toxins is hyperemia of the meningeal venules and capillaries and an increased permeability of these vessels, followed shortly by exudation of protein and the migration of neutrophils into the pia and subarachnoid space. The subarachnoid exudate increases rapidly, particularly over the base of the brain; it extends into the sheaths of cranial and spinal nerves and, for a very short distance, into the perivascular spaces of the cortex. During the first few days, mature and immature neutrophils, many of them containing phagocytosed bacteria, are the predominant cells. Within a few days, lymphocytes and histiocytes increase gradually in numbers. During this time, there is exudation of fibrinogen, which is converted to fibrin after a few days. In the latter part of the second week, plasma cells appear and subsequently increase in number. At about the same time the cellular exudate becomes organized into two layers—an outer one, just beneath the


Neurology_Adams

Neurology_Adams. latter part of the second week, plasma cells appear and subsequently increase in number. At about the same time the cellular exudate becomes organized into two layers—an outer one, just beneath the arachnoid membrane, made up of neutrophils and fibrin, and an inner one, next to the pia, composed largely of lymphocytes, plasma cells, and mononuclear cells or macrophages. Although fibroblasts of the meninges begin to proliferate early, they are not conspicuous until later, when they take part in the organization of the exudate, resulting in fibrosis of the arachnoid and loculation of pockets of exudate.


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Neurology_Adams. During the process of resolution, the inflammatory cells disappear in almost the reverse order as they had appeared. Neutrophils begin to disintegrate by the fourth to fifth day, and soon thereafter, with treatment, no new ones appear. Lymphocytes, plasma cells, and macrophages disappear more slowly, and a few lymphocytes and mononuclear cells may remain in small numbers for several months. The completeness of resolution depends on the stage at which the infection is arrested. If it is controlled in the very early stages, there may not be any residual change in the arachnoid; following an infection of several weeks’ duration, there is a permanent fibrous overgrowth of the meninges, resulting in a thickened, cloudy, or opaque arachnoid and often in adhesions between the pia and arachnoid and even between the arachnoid and dura.


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Neurology_Adams. From the earliest stages of meningitis, changes are also found in the small and medium-sized subarachnoid arteries. The endothelial cells swell, multiply, and crowd into the lumen. This reaction appears within 48 to 72 h and increases in the days that follow. The adventitial connective tissue sheath becomes infiltrated by neutrophils. Foci of necrosis of the arterial wall sometimes occur. Neutrophils and lymphocytes migrate from the adventitia to the subintimal region, often forming a visible layer. Later there is subintimal fibrosis. This vascular reaction is a striking feature of nearly all types of subacute and chronic infections of the meninges but most notably of tuberculous and syphilitic meningitis (Heubner arteritis). In the veins, swelling of the endothelial cells and infiltration of the adventitia also occur. Subintimal layering, as occurs in arterioles, is not observed in veins, but there may be a diffuse infiltration of the entire wall of the vessel. It is in veins so


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Neurology_Adams. of the adventitia also occur. Subintimal layering, as occurs in arterioles, is not observed in veins, but there may be a diffuse infiltration of the entire wall of the vessel. It is in veins so affected that focal necrosis of the vessel wall and mural thrombi are most often found. Thrombophlebitis of the larger cortical veins, which may be part of this process, does not usually develop before the end of the second week of the infection.


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Neurology_Adams. The unusual prominence of the vascular changes may be related to their anatomic peculiarities. The adventitia of the subarachnoid vessels, both of arterioles and venules, is actually formed by an investment of the arachnoid membrane, which is invariably involved by the infectious process. Thus, in a sense, the outer vessel wall is affected from the beginning by the inflammatory process—an infectious vasculitis. The much more frequent occurrence of thrombosis in veins than in arteries is probably accounted for by the thinner walls and the slower current of blood flow in the former.


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Neurology_Adams. Although the spinal and cranial nerves are surrounded by purulent exudate from the beginning of the infection, the perineurial sheaths become infiltrated by inflammatory cells only after several days. Exceptionally, there is infiltration of the endoneurium and degeneration of myelinated fibers, leading to the appearance of fatty macrophages and fibroblasts. More often, there is little or no acute damage to nerve fibers traversing the subarachnoid space. Occasionally cellular infiltrations may be found in the optic nerves or olfactory bulbs.


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Neurology_Adams. The arachnoid membrane tends to serve as an effective barrier to the spread of infection into the adjacent subdural compartment, but some secondary reaction in this space may occur nevertheless (subdural effusion). Subdural effusions occur far more often in infants than in adults; according to Snedeker and coworkers, approximately 40 percent of infants with meningitis younger than 18 months of age develop effusions. As a rule, there is no subdural pus and no bacteria, only a sterile yellowish exudate. In proportion of cases, small amounts of fibrinous exudate are found in microscopic sections that include the spinal dura.


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Neurology_Adams. In the early stages of meningitis, very little change in the substance of the brain can be detected. Neutrophils appear in the Virchow-Robin perivascular spaces but enter the brain only if there is necrosis. After several days, microglia and astrocytes increase in number, at first in the outer zone and later in all layers of the cortex. The associated nerve cell changes may be very slight. Obviously some disorder of the cortical neurons must take place from the beginning of the infection to account for the stupor, coma, and convulsions that are sometimes observed, but several days must elapse before any change can be demonstrated microscopically. It is uncertain whether these cortical changes are a result of the diffusion of toxins from the infected meninges, of a circulatory disturbance, or of some other factor, such as increased intracranial pressure or cortical venous thrombosis. The early cortical changes are therefore not because of invasion of brain substance by bacteria and


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Neurology_Adams. or of some other factor, such as increased intracranial pressure or cortical venous thrombosis. The early cortical changes are therefore not because of invasion of brain substance by bacteria and should therefore be regarded as a noninfectious encephalopathy as contrasted with a true infectious meningoencephalitis, which is discussed later in the chapter. When macrophages are exposed to endotoxins, they synthesize and release cytokines, among which are interleukin-1 and tumor necrosis factor. These cytokines are believed to stimulate and modulate the local immune response but may also affect neurons.


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Neurology_Adams. There is also little change initially in the ependyma and the subependymal tissues; but in later stages of meningitis, conspicuous changes are invariably found. The most prominent finding is infiltration of the subependymal perivascular spaces and often of the adjacent brain tissue with neutrophilic leukocytes and later with lymphocytes and plasma cells. Microglia and astrocytes proliferate, the latter sometimes overgrowing and burying remnants of the ependymal lining. The bacteria may pass through the ependymal lining and set up this inflammatory reaction in part because this sequence of events is favored by a developing hydrocephalus, which stretches and breaks the ependymal lining. Collections of subependymal astrocytes then begin to protrude into the ventricle, giving rise to a granular ependymitis, which, if prominent, may narrow and obstruct the aqueduct of Sylvius. As any meningitis becomes more chronic, the pia-arachnoid exudate tends to accumulate around the base of the brain


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Neurology_Adams. ependymitis, which, if prominent, may narrow and obstruct the aqueduct of Sylvius. As any meningitis becomes more chronic, the pia-arachnoid exudate tends to accumulate around the base of the brain (basilar meningitis), obstructing the flow of CSF and giving rise to hydrocephalus. In a survey of community-acquired bacterial meningitis, hydrocephalus occurred in only 5 percent, but it was associated with poor outcome (Kasanmoentalib et al).


Neurology_Adams

Neurology_Adams. The reader may question this digression into matters that are more pathologic than clinical, but knowledge of the morphologic features and their temporal sequence in meningitis enables one to understand the clinical state and its sequelae. The meningeal and ependymal reactions to bacterial infection and the clinical correlates of these reactions are summarized in Table 31-1. Types of Bacterial Meningitis Almost any bacterium gaining entrance to the body may produce meningitis but the most common are S. pneumoniae, N. meningitidis, group B streptococcus, H. influenzae,


Neurology_Adams

Neurology_Adams. Types of Bacterial Meningitis Almost any bacterium gaining entrance to the body may produce meningitis but the most common are S. pneumoniae, N. meningitidis, group B streptococcus, H. influenzae, L. monocytogenes, which together account for approximately 75 percent of sporadic cases as noted by Thigpen and coworkers. As discussed in the introduction, the following are less frequent causes: Staphylococcus aureus and group A (Streptococcus pyogenes) and group D streptococci, usually in association with brain abscess, epidural abscess, head trauma, neurosurgical procedures, or cranial thrombophlebitis; E. coli and group B streptococci in newborns; Pseudomonas and the Enterobacteriaceae, such as Klebsiella, Proteus, which are usually a consequence of lumbar puncture, spinal anesthesia, or shunting procedures to relieve hydrocephalus. Less-common meningeal pathogens include Salmonella, Shigella, Clostridium,


Neurology_Adams

Neurology_Adams. Neisseria gonorrhoeae, Bacillus cereus, and Acinetobacter calcoaceticus. In endemic areas, mycobacterial infections (to be considered further on) are as frequent as those caused by other bacterial organisms and they now assume greater importance as the number of immunosuppressed persons increases. Pneumococcal, influenzal (H. influenzae), and meningococcal forms of meningitis have a worldwide distribution, occurring mainly during the winter and early spring and, in the case of the first two, also in the fall, and predominating slightly in males. Each has a relatively constant incidence, although epidemics of meningococcal meningitis seem to occur roughly in 10-year cycles. Drug-resistant strains appear with varying frequency, and such information, gleaned from surveillance reports issued by the Centers for Disease Control and Prevention and from reports of local health agencies and hospital infection surveillance, are of great practical importance.


Neurology_Adams

Neurology_Adams. H. influenzae meningitis, formerly encountered mainly in infants and young children, has been nearly eliminated in this age group as a result of vaccination programs. Noteworthy is the report of Schuchat and colleagues, who found that in 1995, some 5 years after the introduction of the conjugate H. influenzae vaccine, the incidence of bacterial meningitis in the United States had been halved. However, the incidence of meningitis from this organism continues to be common in developing nations, where it is now occurring with increasing frequency in adults.