Fundamentals of Neurology: An Illustrated Guide

6. Diseases of the Brain and Meninges

Congenital and Perinatally Acquired Diseases of the Brain

Traumatic Brain Injury

Intracranial Pressure and Brain Tumors

Circulatory Disorders of the Brain and Nontraumatic Intracranial Hemorrhage

Infectious Diseases of the Brain and Meninges

Metabolic Disorders and Systemic Illnesses Affecting the Nervous System

Diseases of the Basal Ganglia

Cerebellar Diseases

Dementing Diseases

Image  Congenital and Perinatally Acquired Diseases of the Brain

Fundamentals

The developing brain is vulnerable to damage by a number of different pathological mechanisms. The variably severe neurological deficits that result are known collectively as cerebral movement disorders or infantile cerebral palsy (CP). In general, this term implies the presence of deficits of multiple types:

Table 6.1 The most important cerebral movement disorders

Image

Image Disturbances of movement of many different kinds; the more common ones are summarized in Table 6.1. These are usually accompanied by a variably severe delay of motor development.

Image Mental retardation (sometimes designated “childhood psycho-organic syndrome”) is common and is characterized by the delayed acquisition of mental abilities, by impaired attention, and often also by hyperactivity and inability to concentrate. The term psychomotor retardation refers to a combination of movement disturbances and mental retardation.

Image Epileptic seizures often arise later on.

Common types and their causes. Tables 6.16.2 provide an overview of the major types of brain damage that are present at birth, or acquired in early childhood, and their causes. These include genetic disorders, cerebral hypoxia during the birth process, birth trauma, intrauterine infections (rubella embryopathy, toxoplasmosis, cytomegalovirus, syphilis, HIV), and chronic intoxications (alcohol embryopathy). Prematurity and difficult delivery are the most important risk factors.

Possible indications of brain damage in the newborn include cyanosis at birth, a weak cry, and hypotonia. In the early prenatal period, there may be further abnormalities of muscle tone, as well as pathological reflexes (cf. p. 43ff.). Later on, a squint or left-handedness may be a sign of brain damage.

Treatment consists of physical therapy (e.g., of the Bobath or Vojta type), which should be begun as early as possible, making use of the child's reflex behavior, as well as special education and rehabilitation. The goal of treatment is maximal independence.

Prognosis. Although the neurological deficits of cerebral palsy do not progress over time, certain manifestations may not appear until later in life (e.g., epileptic seizures), and certain symptoms may worsen over the course of the individual's life.

Table 6.2 Important causes of congenital and perinatally acquired brain damage

Perinatal asphyxia

(Genetically determined) structural anomalies of the brain, e.g.:

Image microcephaly

Image meningoencephalocele

Image meningomyelocele

Image micropolygyria

Image Arnold–Chiari malformation, with or without hydrocephalus

Phakomatoses

Image tuberous sclerosis (Bourneville disease)

Image encephalofacial angiomatosis (Sturge–Weber disease)

Image neurofibromatosis (von Recklinghausen disease)

Image von Hippel–Lindau disease

Brain damage acquired in utero

Image rubella embryopathy

Image congenital toxoplasmosis

Image congenital cytomegaly

Image congenital syphilis

Image congenital HIV infection

Image alcohol embryopathy

Severe neonatal jaundice (due to Rh incompatibility)

Synostosis and craniostenosis

Traumatic intracranial hemorrhage during delivery

Image subdural hematoma

Image intracerebral hemorrhage

Image intraventricular hemorrhage

Special Clinical Forms

Some of the more important etiological types of early childhood brain damage will now be discussed individually:

Hydrocephalus is a pathological dilatation of the inner (and sometimes also the outer) cerebrospinal fluid spaces. Various types of hydrocephalus are listed in Table 6.3. In terms of pathogenesis, the most common type of hydrocephalus in childhood is occlusive hydrocephalus (gliosis, stenosis, or malformation of the aqueduct, Arnold–Chiari malformation [Fig. 6.1] with impaired outflow through the foramina of Luschka and Magendie). In the Arnold–Chiari malformation, part of the medulla and the cerebellar tonsils are displaced below the foramen magnum into the cervical spinal canal. This anomaly may be combined with internal hydrocephalus and syringomyelia.

Image

Fig. 6.1 Arnold–Chiari malformation (MR image). The cerebellar tonsils are caudally displaced below the arch of the atlas deep into the cervical spinal canal (courtesy of Dr. D. Huber, Radiological Institute, Hirslanden–Klinik, Zurich).

Table 6.3 Types and terminology of hydrocephalus

Internal hydrocephalus

enlargement of the ventricles:

Image obstructive

due to obstruction of CSF flow within the ventricular system (e. g., aqueductal stenosis) or at its exits (e. g., obstruction of foramina of Magendie and Luschka)

Image communicating

nonobstructive internal hydrocephalus

Image malabsorptive

a subtype of communicating hydrocephalus due to impaired CSF resorption (e.g., cisternal adhesions or dysfunction of the pacchionian granulations)

External hydrocephalus

enlargement of the subarachnoid space over the cerebral convexities and/or in the cisterns

External and internal hydrocephalus

combination of the above

Hydrocephalus ex vacuo

internal and external hydrocephalus secondary to brain atrophy

There may also be communicating hydrocephalus, whose etiology and pathogenesis are often unclear.

The chief clinical sign of hydrocephalus in childhood is abnormal enlargement of the head, which may already be noted in a prenatal ultrasound study or at birth, and which progresses over time. Protrusion of the frontal bone and depression of the orbital plate make the upper part of the sclera visible and cause the lower part of the iris to sink below the lower lid, in the so-called “setting-sun sign.” The essential diagnostic tests are CT and/or MRI. The treatment, if required, is neurosurgical, usually the implantation of a ventriculoperitoneal or ventriculoatrial shunt. The prognosis of isolated hydrocephalus, in the absence of other neurological abnormalities, is good: once the hydrocephalus is treated, two-thirds of children go on to have a normal physical and mental development.

Microcephaly is usually due to prenatal toxic influences (e. g., alcohol) or infections (e. g., cytomegalovirus), or to genetic factors. Affected persons are generally of lower than normal intelligence.

Dysraphic malformations. The most common type is spina bifida with meningomyelocele: in this disorder, there is a closure defect of the posterior arches of multiple vertebrae, usually in the lumbosacral region, accompanied by a prolapse of the meninges and spinal cord through the defect. The level and extent of spinal cord involvement determine whether paralysis of the lower limbs will be manifest at birth. Even if the defect is surgically repaired in the first few hours after birth, major sensorimotor impairment and urinary disturbances generally persist. This type of malformation may be accompanied by internal hydrocephalus and by anomalies of the craniocervical junction, which often require treatment. Other dysraphic syndromes include acrania (partial or total absence of the skull), anencephaly (absence or degeneration of most of the brain, with acrania—practically always a fatal condition), and encephalocele (prolapse of the meninges and brain tissue through a defect in the bony skull).

Areas of neuronal heterotopia (i. e, islands of gray matter anomalously lying outside the cerebral cortex) may be found in the periventricular zones or in a subcortical layer (lamina) that creates the appearance of a “double cortex” on MRI. Subcortical laminar heterotopia (SCLH) is a genetic disorder of dominant inheritance caused by a mutation of the doublecortin gene on the X chromosome. The disorder is more severe, and often lethal, in males, because they lack a normal copy of the gene. In surviving males, SCLH is often combined with lissencephaly (“smooth brain,” i. e., absence of the cerebral gyri and sulci). Heterotopia is a common cause of epilepsy.

Ulegyria is a type of early childhood brain damage characterized by scarring and abnormally small gyri (microgyria). These structural abnormalities can be seen on MRI.

Phakomatoses are genetic disorders that cause complex malformations and tumors predominantly affecting the ectodermally derived structures of the body, i. e., the brain, peripheral nervous system, and skin. They are also called neurocutaneous disorders. The internal organs may also be affected. An overview is provided in Table 6.4.

The main types of brain disorder acquired in utero are the following:

Image Rubella embryopathy occurs in 10% of infants that have been exposed by maternal infection in the first trimester of pregnancy. The associated anomalies include cataracts, deafness, microcephaly, and heart defects.

Image Congenital toxoplasmosis occurs when the fetus is infected in the second half of gestation by maternal infection in a mother without previous exposure to Toxoplasma gondii. Its manifestations include psychomotor retardation, convulsions, progressive hydrocephalus, and visual disturbances due to chorioretinitis. Plain radiographs and CT reveal intracerebral calcifications.

Image Congenital cytomegalovirus infection causes premature birth and low birth weight, microcephaly, hydrocephalus, convulsions, periventricular calcifications, and abnormalities in organs outside the nervous system as well.

Image Congenital HIV infection occurs in one-quarter of all babies born to HIV-positive mothers. It causes encephalopathy with psychomotor retardation, as well as immune deficiency, with later complications.

Image Congenital syphilis is now rare. Its typical stigmata include a saddle nose, cutaneous fissures at the corners of the mouth, and later crescentic defects of the teeth (Hutchinson teeth), interstitial keratitis, and hearing loss.

Image Malformations of the skull come in many different forms: there are dysraphic malformations characterized by faulty closure of the cranial vault (cranioschisis), premature closure of the cranial sutures (craniostenosis), and anomalies of the craniocervical junction including basilar impression, platybasia, Arnold–Chiari syndrome (p. 84), and Dandy–Walker syndrome (malformation of the posterior fossa with aplasia of the inferior portion of the cerebellar vermis, cystic enlargement of the fourth ventricle, and occlusive hydrocephalus). The more common types of craniosynostosis are listed and illustrated in Table 6.5.

Image

Image

Image

Image  Traumatic Brain injury

Fundamentals

Traumatic injuries of the bony skull and the underlying brain can be of different types and varying severity, depending on the nature and intensity of the causative event. There may be a skull fractureaffecting the cranial vault or the base of the skull, a brain contusion, an injury to larger sized blood vessels producing a traumatic hematoma, or any combination of these types of injury.

Image Brain injuries are either closed (i. e., with the dura mater intact) or open (with a wound extending into the subdural compartment or deeper into the brain parenchyma). Open brain injuries are associated with the risk of early or late intracranial infection.

Image The scale of clinical severity of traumatic brain injury extends from a simple contusion of the bony skull to the concussion syndrome and the brain contusion syndrome. The leading clinical manifestation of a traumatic parenchymal injury is impairment or loss of consciousness, usually accompanied by memory impairment (retrograde and anterograde amnesia). A neurological deficit or epileptic seizures may also be present.

Image Large traumatic hematomas, or extensive damage to the brain parenchyma with accompanying edema, may lead to a rapid rise of intracranial pressure, causing brain compression and possibly brainstem herniation.

Image Traumatic hematomas may be located within the brain parenchyma (traumatic intracerebral hematoma) or in the adjacent meningeal compartments (subdural and epidural hematoma). Traumatic subarachnoid hemorrhage is less common.

Image Frequent late complications of severe traumatic brain injury include neuropsychological deficits, personality changes, and symptomatic epilepsy.

Relevant Aspects of the Clinical History and Neurological Examination

In the initial phase after trauma, the severity of injury is assessed, with particular attention to the following aspects of the history:

Image the duration of unconsciousness (as reported by eyewitnesses);

Image the duration of amnesia for events that occurred before the injury (retrograde amnesia);

Image the duration of amnesia for events that have occurred since the injury (anterograde amnesia, perhaps accompanied by confusion);

Image the duration of the entire period of amnesia, which is the sum of the durations of retro- and anterograde amnesia;

Image early epileptic seizures;

Image bleeding from the ear or nose (indicating a basilar skull fracture).

The depth of impaired consciousness or coma in a brain-injured patient is graded numerically on the Glasgow Coma Scale (Table 6.6).

Important aspects of the initial physical examination are:

Image the patient's level of consciousness (see above);

Image externally visible injuries, especially of the head;

Image bleeding and possibly flow of cerebrospinal fluid from the nose or ears, or in the pharynx (a CSF leak is conclusive evidence of an open brain injury, while bleeding is not);

Image injuries of the cervical spine;

Image periorbital hematoma; neurological findings (pupillary reflexes, visual impairment, nystagmus, deafness, weakness, pyramidal tract signs), general state of health, and, in particular, circulatory status.

Ancillary tests, to be performed as indicated by the clinical situation, include cervical spine radiographs and a CT and/or MRI scan of the head. Skull radiographs are hardly ever indicated.

Image Traumatic brain injuries are often accompanied by cervical spine injuries.

Grades of Severity of Traumatic Brain Injury

The clinical grade of severity of traumatic brain injury is closely correlated with the initially evident extent of structural damage to the skull and brain, but the correlation is not absolute. For example, a patient may have an extensive skull fracture, but no neurological deficit; another patient may sustain a relatively minor blow to the head that ruptures a bridging vein and produces a slowly growing subdural hematoma, which can compress the brain and ultimately cause coma and death. The clinical state of the patient after traumatic brain injury can be classified as follows (in order of increasing severity):

Table 6.6 The Glasgow Coma Scale

Category

Points

Best verbal response:

 

none

1

unintelligible sounds

2

inappropriate words

3

disoriented

4

oriented

5

Eye opening:

 

none

1

to painful stimuli

2

to auditory stimuli

3

spontaneous

4

Best motor response:

 

none

1

abnormal extension

2

abnormal flexion

3

withdraws (pulls away from pain)

4

localizes (fends off painful stimulus)

5

follows commands

6

Patient's overall score

...

The overall score is the sum of the scores in the three categories.

Skull contusion. Patients with the simple skull contusion syndrome have no evidence of a brain injury, i. e., no loss of consciousness or amnesia, a normal neurological examination, and normal intracranial findings on CT or MRI (if performed). Some patients with this syndrome have scalp lacerations, or even skull fractures, and headache may be present. Adequate therapy consists of a temporary restriction of activity and symptomatic medication, as required (analgesics, antiemetics).

Concussion (= mild traumatic brain injury) is characterized by a brief, transient loss of consciousness, usually lasting no more than a few minutes and sometimes followed by a period of confusion. The periods of retro- and anterograde amnesia are very brief. Headache, dizziness, nausea, and (sometimes) vomiting are common accompaniments of concussion in the early phase. A standard neurological examination reveals no deficit. In the past, it was generally assumed that concussion produced no structural damage to the brain, but T2-weighted MR images do, in fact, reveal diffuse axonal injury in some patients. Moreover, neuropsychological testing reveals that some patients said to have sustained no more than a concussion actually have deficits of certain characteristic types, collectively designated minimal brain injury. Occasional patients suffer from persistent posttraumatic headaches. The clinical distinction between concussion and brain contusion (see below) is not always easy to draw.

Treatment of concussion. As in the skull contusion syndrome, transient restriction of activity suffices (e.g., a few days of bed rest), combined with symptomatic medication as required (see above). The patient should on no account be immobilized any longer than necessary: as long as there is no contraindication (such as hemodynamic instability), the patient should stand up and walk with assistance on the day of injury, or within the next few days at latest. Rapidly mobilized patients tend to have less severe postconcussive symptoms with a lesser tendency toward chronification.

Brain contusion and penetrating injuries. By definition, these types of injury involve damage to the brain parenchyma. Compared with concussion, they produce considerably longer periods of unconsciousness and retro- and anterograde amnesia; indeed, the patient may not remember anything for a period of several days surrounding the time of the injury. Examination in the acute phase often reveals neurological deficits, which may persist. Residual anosmia is common (p. 180). CT or MRI reveals foci of contusion (Fig. 6.2) or intracranial hemorrhage, e.g., an acute epidural hematoma. Parenchymal injuries can be found both directly underlying the site of the external blow (“coup” injuries) and at the diametrically opposite location in the brain (“contrecoup” injuries). Injuries of the latter type are due to the violent, tissue-distorting force transmitted across the brain to the other side at the moment of injury. The Pathoanatomical findings in foci of brain contusion include ischemic and hemorrhagic tissue necrosis, small hemorrhages, tears of brain tissue and blood vessels, and secondary brain edema. Lumbar puncture, if performed (generally contraindicated!), yields bloody or xanthochromic cereobrospinal fluid.

Large brain contusions and extensive traumatic hematomas (see below), combined with the associated secondary brain edema, can cause very rapid and pronounced increases in intracranial pressure, leading to brain compression and herniation of the midbrain and diencephalon through the tentorial notch, and/or of the medulla through the foramen magnum. The clinical signs of brainstem herniation are: progressive impairment of consciousness leading to coma; a dilated pupil, initially only on the side of the expansive lesion; flexor and, later, extensor spasms; and, finally, a loss of autonomic regulatory functions (breathing, temperature, cardiac activity, vascular tone), bilaterally fixed and dilated pupils, and death.

Image All patients with traumatic brain injury must be care fully clinically observed for signs of increasing intracranial pressure. In patients with a diminished level of consciousness, or coma, the width and reactivity of the pupils and other brainstem reflexes should be checked regularly, so that intracranial hypertension can be detected at the earliest possible moment. In some patients, pressure-measuring devices will be implanted intracranially for continuous, invasive ICP monitoring.

Treatment of the brain contusion syndrome. Depending on his or her clinical state, the patient may need to be observed in an intensive care unit or dedicated neurotrauma unit, with frequent checking of the vital signs and neurological functions, and possibly with invasive ICP monitoring. Extensive parenchymal injuries and the associated brain edema usually elevate the intracranial pressure; thus, ICP-reducing measures may need to be taken, including elevation of the patient's head, hyperventilation (in some patients), osmotherapy, or even craniectomy to relieve brain compression (p. 93). Recent studies have shown a positive effect of therapeutic hypothermia, in which the patient is cooled to ca. 34 °C.

Image

Fig. 6.2 Brain contusion (CT scan). There are extensive hemorrhagic contusions in both temporal lobes and smaller ones in both frontal lobes (arrowheads).

If the patient survives, MRI may reveal a permanent injury to the brain parenchyma (Fig. 6.3). The late posttraumatic symptoms resemble those of concussion, but they are more intense and usually persist longer. For further details, see p. 91.

Traumatic Hematomas

Traumatic hematomas come about when the traumatic injury tears a larger artery or vein (Fig. 6.4). They are classified as follows:

Intracerebral hematomas are usually found in the frontal or temporal lobe. They may exert considerable mass effect; combined with the surrounding edema, they may cause sufficient pressure on the brain to produce a progressive decline of consciousness and increasingly severe neurological deficits. In such patients, neurosurgical evacuation of the hematoma should be considered, depending on its size and location.

Image

Fig. 6.3 Parenchymal defects 6 years after brain contusion. The T2-weighted MR images reveal cortical defects in the left temporal (a) and frontal lobes (b), accompanied by signal changes in the underlying white matter.

Epidural hematomas (Fig. 6.5) are generally produced by traumatic tearing of a dural artery, usually the middle meningeal a. The tear itself is usually the result of a temporoparietal skull fracture, but sometimes occurs in the absence of a skull fracture. The blood collection lies between the periosteum and the dura mater. The arterial hemorrhage can compress the brain very rapidly: a patient who is initially comatose because of a coexisting brain contusion may fail to emerge from coma because of the development of an epidural hematoma in the minutes or hours after injury. On the other hand, an initially awake or only transiently unconscious patient may lapse into coma after a so-called “lucid interval” lasting minutes or hours. The side of the hematoma can often be ascertained by clinical examination: incipient uncal herniation compresses the ipsilateral oculomotor n. and causes dilation of the ipsilateral pupil, while the hemiparesis is contralateral to the hematoma. When an acute epidural hematoma is suspected, a CT scan should be performed immediately to confirm the diagnosis (not plain films or MRI; see note, below). The hematoma is usually seen as a hyperdense, biconvex zone that is sharply demarcated from the adjacent brain tissue. Once diagnosed, it must be neurosurgically evacuated immediately to prevent brainstem herniation and death. Patients often make an excellent recovery if they have no other accompanying brain injuries and if the hematoma has been removed early enough.

Image

Fig. 6.4 Traumatic brain injuries and posttraumatic complications (schematic diagram).

Image

Fig. 6.5 Epidural hematoma (CT scan).

Note: when an epidural hematoma is suspected, plain radiographs of the skull and MRI are both contraindicated. The former might reveal a fracture, but cannot reveal the hematoma; the latter will show the hematoma, but takes longer than CT, and time is of the essence.

Subdural hematomas can be acutesubacute, or chronic. The blood collection lies between the dura mater and the arachnoid and comes about because of a tear in a bridging vein.

Acute subdural hematoma is usually a component of severe traumatic brain injury with extensive intra-parenchymal contusional hemorrhages. Clinical examination alone does not enable a clear-cut distinction between subdural and epidural hematomas: subdural hematoma, too, is characterized by a rapidly progressive decline of consciousness, ipsilateral pupillary dilatation, and contralateral hemiparesis. The diagnosis is established by CT: a subdural hematoma is typically seen as a hyperdense or isodense area (depending on the time elapsed since the traumatic event), either crescent shaped or closely applied to the skull; unlike an epidural hematoma, a subdural hematoma is poorly demarcated from the underlying brain tissue. Subdural hematomas, too, are treated by immediate neurosurgical evacuation.

Chronic subdural hematoma may arise in the aftermath of a mild traumatic brain injury or even after a relatively trivial blow to the head, of which the patient may no longer have any recollection. A few weeks or (rarely) months after the causative event, the patient begins to suffer from increasingly severe headache, fluctuating disturbances of consciousness, confusion, and ultimately progressive somnolence.Hemiparesis, if present, is usually mild and signs of intracranial hypertension are usually absent. The diagnosis is established by CT or MRI. The treatment is by neurosurgical evacuation through one or two burr holes (this is a relatively brief and uncomplicated procedure and can be performed under local anesthesia in cooperative patients). Therapeutic anticoagulation is a risk factor for the development of a chronic subdural hematoma.

Complications of Traumatic Brain Injury

Early Complications

Early posttraumatic infection. Any open or penetrating brain injury (e. g., depressed skull fractures, gunshot wounds) provides a route of access for bacterial contamination of the meningeal spaces and the brain. Early posttraumatic meningitis, subdural empyema, cerebritis, or a brain abscess may appear a few days or weeks after the traumatic event.

Later Complications

Late infection. A skull base fracture associated with a dural tear may create a cerebrospinal fluid fistula, manifesting clinically as leakage of clear fluid out the nose or ear (CSF rhino- or otorrhea) or into the pharynx. Leaking CSF fistulae are sometimes accompanied by orthostatic headache due to intracranial hypotension. If the fistula remains undiscovered or untreated, it can serve as a portal for bacterial infection. The patient may present with meningitisand/or a brain abscess, perhaps years after the initial trauma. The presence and exact location of a CSF fistula can be demonstrated by isotope cisternography (Fig. 4.12p. 53); other useful studies include MRI and thin-section CT, which may reveal a bony defect or fracture. CSF fistulae should be surgically repaired.

Posttraumatic neurological deficits. The commonest cranial nerve deficit after traumatic brain injury is anosmia (p. 180), which is permanent in two-thirds of patients, followed by optic nerve injuries and palsies of the nerves to the eye muscles. Optic nerve dysfunction only rarely improves, but palsies of cranial nerves III, IV, and VI usually resolve in two to three months. Fractures of the petrous pyramid(s) may cause facial nerve palsy as well as deafness, due to injury either to the vestibulocochlear nerve or to the cochlea itself; when caused by a transverse fracture, deafness is usually permanent. A fracture extending into the jugular foramen may cause a combined palsy of the glossopharyngeal, vagus, and accessory nerves (Siebenmann syndrome). Focal brain lesions cause deficits according to their localization. Diencephalic lesions often cause diabetes insipidus. Spasticity may be uni- or bilateral. Cerebellar lesions are characterized by ataxia, which does not always resolve.

Posttraumatic epilepsy is seen within two years in 80 % of the patients who develop it, but it can also arise many years after the initial trauma in rare cases. The seizures may be focal, secondarily generalized, or primarily generalized (cf. p. 164).

Neuropsychological deficits and personality changes. Posttraumatic neuropsychological deficits (variously designated focal organic brain syndrome, psycho-organic syndrome, or posttraumatic encephalopathy) and personality changes are often the most disabling sequelae of traumatic brain injury for the patient and his or her family. The severity of these problems is positively correlated with the length of the initial loss of consciousness and with the duration of retrograde and anterograde amnesia around the time of the injury. Both short- and long-term memory are impaired and the attention span is shorter than normal. The patient has difficulty coping with complex tasks and situations and is easily fatigued. Impatience, irritability, diminished initiative, poor concentration, and lack of interest ranging to apathy characterize the patient's behavior. The adverse psychosocial effects in personal and professional life are often very serious.

Rarer posttraumatic phenomena include a persistent Lhermitte sign (p. 157) or malresorptive hydrocephalus.

Malresorptive hydrocephalus most commonly arises after a traumatic subarachnoid hemorrhage and consists of an impairment of CSF flow and resorption due to adhesions of the arachnoid and of the arachnoid granulations. It can also arise in the aftermath of aneurysmal subarachnoid hemorrhage (p. 108), meningitis, or venous sinus thrombosis, or spontaneously, i.e., without any known risk factor. Impaired CSF (out-)flow causes ventricular dilatation. The clinical findings include:

Image a progressively severe gait disturbance with spastic paraparesis,

Image urinary incontinence,

Image fluctuating neuropsychological abnormalities,

Image and sometimes also headache.

CT reveals enlarged and rounded lateral ventricles, while the subarachnoid space appears tight or of normal dimensions, but never widened. The CSF pressure measured at lumbar puncture is within normal limits (hence the alternative name of this condition, “normal pressure hydrocephalus”). If 20–50 mL of CSF are removed, the symptoms listed above all improve, particularly the gait disturbance: the originally “sticky” and small-stepped gait suddenly becomes much more fluid.

Image  Intracranial Pressure and Brain Tumors

Intracranial Pressure

Intracranial masses rapidly elevate the intracranial pressure because the skull is a closed compartment. Intracranial hypertension is most commonly caused by tumorhemorrhageextensive stroketrauma(and the edema accompanying these conditions), and hydrocephalus. It can also be caused by a variety of other conditions (cf. Table 6.7). Intracranial hypertension impairs cerebral perfusion and CSF circulation and may also result in compression of intracranial structures (e. g., compression of cranial nerves against the base of the skull, occlusive compression of the posterior cerebral a.) and to shifting of large portions of the brain within the skull (e.g., herniation of the medial portion of the temporal lobe into the tentorial notch, or of the cerebellar tonsils into the foramen magnum). Intracranial hypertension may arise acutely, i. e., in a few minutes or hours (especially in brain hemorrhage), or chronically (for example, when caused by a slowly growing brain tumor). Its clinical manifestations vary accordingly (Table 6.8). Its treatment consists of general measures to lower intracranial pressure as well as specific treatment of the underlying cause.

Intracranial hypertension is diagnosed from its characteristic clinical manifestations and ancillary test results, as listed in Table 6.8. Lumbar puncture for direct measurement of the CSF pressure is nearly always con-traindicated.

Image

Table 6.8 Signs of intracranial hypertension

subjective

headache (diffuse and persistent, most severe in the morning); with acute or rapidly progressive elevation of intracranial pressure, nausea and vomiting (typically in the morning–paroxysmal dry heaves), hiccups; with chronic elevation of intracranial pressure, progressive lack of motivation, apathy

signs of impending herniation

with acute or rapidly progressive elevation of intracranial pressure, confusion, respiratory disturbance, bradycardia, hypertension, cerebellar fits (opisthotonus and extensor spasms of arms and legs), dilated pupils

ocular findings

papilledema (present in ca. two-thirds of cases, may appear within hours), occas. retinal hemorrhage; enlarged blind spot, attacks of amblyopia with transient blindness; occas. oculomotor nerve palsy or abducens nerve palsy (the abducens n. has the longest course in the subarachnoid space of any of the cranial nerves)

skull radiograph

the plain skull radiograph is abnormal only in chronic intracranial hypertension–increased digitate markings, enlarged sella turcica with demineralized dorsum sellae, diastasis of one or more cranial sutures in children and adolescents

CT/MRI

slit ventricles (when elevation of ICP is due to cerebral edema), compressed gyri, periventricular signal change; CT and MRI may reveal the causative lesion for intracranial hypertension (e.g., tumor, hemorrhage)

EEC

diffusely abnormal, nonspecific

lumbar puncture

contraindicated when a dangerous elevation of ICP is suspected!

If LP is nonetheless performed in the face of intracranial hypertension, the opening pressure is generally over 200 mm CSF; may be normal, however, if CSF flow is blocked at the occipitocervical or spinal level

Image A lumbar puncture should, in general, not be performed if there is clinical evidence of intracranial hypertension. It may be performed only if the imaging studies and ophthalmoscopic examination have yielded no evidence of acutely elevated ICP with impending brain herniation.

Treatment of intracranial hypertension includes the following general measures to lower the intracranial pressure:

Image elevation of the head of the patient to 30°;

Image hyperventilation (if the patient is intubated);

Image osmotic diuretics, such as mannitol, given intravenously, in fractionated daily doses; rapid infusion is important for the generation of an effective osmotic gradient; saluretics, too, can transiently lower the intracranial pressure (caution: excessive use of diuretics can lead to dehydration and impairment of cerebral perfusion);

Image corticosteroids (e.g., dexamethasone, given intravenously) are used to counteract cerebral edema, particularly of the vasogenic type; they are mainly effective against peritumoral and inflammatory brain edema, less so against ischemic and traumatic brain edema, which are predominantly of the cytotoxic type.

Brain Tumors

Fundamentals

The prevalence of brain tumors is roughly one per 10 000 to 20 000 individuals. Brain tumors are one of the more common causes of intracranial hypertension. They are subdivided into primary brain tumors arising from the brain tissue itself (either the neuroepithelial tissue or the neighboring mesenchymal tissues, e.g., the meninges) and brain metastases. Brain tumors produce focal brain signs of different types depending on the location of the tumor, as well as signs of intracranial hypertension that may be more or less rapidly progressive depending on the rate of tumor growth.

General clinical manifestations of brain tumors include the following:

Image epileptic seizures (focal or generalized);

Image mental changes (irritability, fatigability, impairment of memory and concentration);

Image focal neurological and/or neuropsychological deficits depending on the location and type of the tumor;

Image less commonly, headache (diffuse, at night as well as in the daytime) and occasionally nausea and vomiting;

Image in some patients, further signs of intracranial hypertension (as listed in Table 6.8).

The clinical manifestations of a brain tumor progress more or less rapidly depending on the type and growth rate of the tumor. Malignant tumors typically present with a “crescendo” course, in which overt signs and symptoms arise soon after the onset of the illness, then progress steadily and rapidly. The manifestations of benign tumors, on the other hand, often progress slowly and insidiously, perhaps over many years. Indeed, the tumor may be present for years before it becomes clinically evident.

Diagnosis. Neuroimaging studies are essential (contrast-enhanced CT or, better, MRI; cf. Table 6.9) but cannot always unequivocally identify the type of tumor. A definitive determination is often not possible until the tumor has been at least partly removed and the tumor tissue can be histopathologically examined. If a brain tumor is inoperable because of its location, or if primary resection is contraindicated by the patient's general condition or other illnesses, then a stereotactic brain biopsy can be performed to obtain tissue for diagnosis. This should, in general, be done before any nonsurgical treatment is undertaken, such as chemotherapy or radiotherapy, so that the form of treatment can be chosen for maximum effectiveness. A further reason for doing so is that a small percentage of suspected “brain tumors” will turn out, on biopsy, to be brain abscesses. These can often be effectively treated with antibiotics (and, in some patients, resection).

Treatment. Complete resection of the tumor is indicated whenever it is possible. The operability of brain tumors, however, depends largely on their size, location, histological grade, and relation to the surrounding brain tissue (infiltration vs. displacement). Not every tumor is neurosurgically accessible or fully resectable. Depending on the type of tumor, radiotherapy and/or chemotherapy may have to be used, either as the primary form of treatment, or as adjuvant therapy after a complete or incomplete surgical removal.

The brain edema that usually accompanies malignant tumors is treated with corticosteroids (usually dexamethasone).

Individual Types of Brain Tumor

The WHO classification of brain tumors (1993) is summarized in Table 6.9, which also includes figures concerning the relative frequency of tumor types. The characteristic locations, clinical manifestations, and course of brain tumors all depend on the type of tumor.

Astrocytoma, the most common category of neuroepithelial tumor, has the following histological subtypes:

Glioblastoma multiforme is the most malignant grade of astrocytoma (grade IV astrocytoma). This most common and most malignant tumor of the cerebral hemispheres usually arises between the ages of 40 and 60. It grows by infiltration into brain tissue and is thus nearly impossible to resect totally, as nests of tumor cells nearly always remain beyond the margins of resection even if all macroscopically evident tumor tissue is removed. Though it generally arises in a single hemisphere, it can infiltrate across the corpus callosum into the opposite hemisphere, creating a so-called butterfly tumor. Glioblastomas grow rapidly, causing rapidly progressive clinical manifestations; they are, therefore, usually diagnosed within a few weeks or (at most) months of the onset of symptoms. Focal neurological and/or neuropsychological deficits arise first, sometimes accompanied by epileptic seizures, soon followed by general manifestations of intracranial hypertension (see above). The diagnosis can be made with a fair degree of confidence from the typical appearance in neuroimaging studies (Fig. 6.6), though this does not obviate the need for histological examination of tumor tissue. CT characteristically reveals a central hypodense area, corresponding to necrosis in the interior of the tumor. There may be hyperdense areas indicating intratumoral hemorrhage. Peritumoral brain edema is often extensive, causing mass effect and midline shift. Ringlike enhancement is seen after the administration of contrast medium.

Image

Fig. 6.6 Glioblastoma multiforme in the right frontal lobe. The T1- and T2-weighted spin-echo images (a and b, respectively) reveal a polycystic tumor surrounded by marked edema.

Table 6.9 Classification and diagnosis of brain tumors

WHO Classification (1993)

WHO grade *

Neuroepithelial tumors

Image astrocytic tumors

 

Image fibrillary, protoplasmic, mixed

II

Image anaplastic (malignant) astrocytoma

III

Image glioblastoma multiforme

IV

Image pilocytic astrocytoma

I

Image pleomorphic xanthoastrocytoma

I

Image subependymal giant cell astrocytoma (in tuberous sclerosis)

I

Image oligodendroglial tumors

 

Image oligodendroglioma

II

Image anaplastic (malignant) oligodendroglioma

III

Image ependymal cell tumors

 

Image ependymoma

II

Image anaplastic (malignant) ependymoma

III

Image myxopapillary ependymoma, subependymoma

I

Image mixed gliomas

 

Image oligoastrocytoma

II

Image anaplastic (malignant) oligoastrocytoma

III

Image choroid plexus tumors

Image choroid plexus papilloma

I

Image choroid plexus carcinoma

III, IV

Image neuroepithelial tumors of uncertain origin

variable

Image neuronal and mixed neuronal–glial tumors

I–III

Image pineal parenchymal tumors

 

Image pineocytoma

II

Image mixed pineocytoma/pineoblastoma

III, IV

Image pineoblastoma

IV

Image embryonal tumors

 

Image medulloepithelioma; neuroblastoma; ependymoblastoma

IV

Image primitive neuroectodermal tumors (PNETs)

IV

Image medulloblastoma and variants

IV

Tumors of the cranial and spinal nerves

 

Image schwannoma (neurilemmoma, neurinoma)

I

Image neurofibroma

I

Image malignant peripheral nerve sheath tumor (MPNST), neurogenic sarcoma, neurofibrosarcoma, anaplastic neurofibroma, “malignant schwannoma”

III, IV

Tumors of the meninges

Image meningothelial tumors

 

Image meningioma and its variants

I

Image atypical meningioma

II

Image papillary meningioma

II, III

Image anaplastic (malignant) meningioma

III

Image mesenchymal, nonmenigothelial tumors (benign, e.g., lipoma; malignant, e.g., meningeal sarcoma)

 

Image primary melanocytic lesions

 

Image diffuse melanosis, melanocytoma, malignant melanoma

 

Image tumors of uncertain histogenesis

 

Image hemangioblastoma

 

Lymphoma and neoplasms of the hematopoietic system

“Kiel classification”

Image malignant lymphoma

 

Image plasmacytoma

 

Image others

 

Germ cell tumors

 

Image germinoma, embryonal sarcoma, choriocarcinoma

III, IV

Image teratoma

I

Image mixed germ cell tumors

 

Cysts and tumorlike lesions

Tumors of the sellar region

Image pituitary adenoma

I

Image pituitary carcinoma

III, IV

Image craniopharyngioma

I

Local extensions of regional tumors

Metastases

Unclassified tumors

* Grading, on a scale of increasing malignancy from I to IV, is based on histologic criteria (mitoses, etc.).

Relative frequency of primary brain tumors: pilocytic astrocytoma 1 %, low-grade astrocytoma 27%, anaplastic astrocytoma 3%, glioblastoma 28%, oligodendroglioma 2 %, ependymoma 1 %, medulloblastoma 2%, meningioma 22 %, neurinoma 4%, primary CNS lymphoma 1 %

Ancillary diagnostic tests Imaging studies:

Image reveal the site and extent of the tumor before surgery (biopsy or resection)

Image CT with contrast: often the method by which a mass is first diagnosed, but of limited diagnostic value:

Image advantages: good at displaying tumor calcification and the relation of certain types of tumor (e. g., meningioma) to adjacent bony structures

Image disadvantages: even with contrast, some tumors such as low-grade astrocytomas are revealed poorly or not at all; poor distinction between tumor tissue and surrounding brain edema; artifact impairs visibility at the skull base and in the posterior fossa

Image MRI with contrast: the imaging method of choice for all intracranial tumors:

Image advantages: highly sensitive (reveals clinically “silent” metastases), clear visualization of the site and borders of the tumor in multiple imaging planes

Image disadvantage: calcification not reliably seen

Image angiography: preoperative visualization of blood vessels is useful for certain types of tumor (e. g., medial sphenoid wing meningiomasimpinging on the internal carotid a.); reveals possible infiltration or occlusion of the venous sinuses; provides access for intravascular treatment (“embolization”) of meningiomas; enables diagnosis and precise anatomical characterization of vascular malformations andaneurysms

Image

Fig. 6.7 Grade III astrocytoma (partly cystic) in the right parietotemporal region, as revealed by MRI.

Even with the best currently available treatment, i. e., gross total resection of the tumor with or without adjuvant radio- or chemotherapy, patients with glioblastoma survive only a few months, or a few years at most, because of the nearly inevitable recurrences. Grade III astrocytoma (Fig. 6.7) is another type of histologically malignant astrocytoma. The prognosis of patients with this type of tumor, though marginally better than that of glioblastoma patients, is still poor.

Grade I and II astrocytomas (so-called “benign” astrocytomas) are less malignant than grades III and IV. Astrocytomas of the cerebral hemisphere(s) generally affect adults aged 30 to 40. Though these tumors displace and infiltrate the surrounding brain tissue, they are better demarcated from it than glioblastoma; they often grow quite slowly, sometimes over many years. Their clinical manifestations include behavioral and neuropsychological changes, increasingly severe focal neurological deficits (e.g., hemiparesis), focal or secondarily generalized epileptic seizures, and signs of intracranial hypertension. If epileptic seizures are the only manifestation, tumor resection may be useful for seizure control, if the location of the tumor permits. After a tumor is totally resected, it may not recur until years later.

Cerebellar astrocytoma is considerably more benign than the other varieties, usually affects children aged 5 to 15, and is well demarcated from the surrounding brain tissue. It is usually found in the cerebellar hemispheres or vermis and may extend into the pons. Its main clinical manifestations are thus ataxia, disequilibrium, nystagmus, and, often, signs of intracranial hypertension (esp. papilledema) secondary to occlusive hydrocephalus. Total resection often results in permanent cure.

Brainstem astrocytoma is usually inoperable, though tumors of this type are sometimes at least partly resectable in special cases.

Ependymoma is a benign tumor usually seen in children and adolescents. On pathological examination, these tumors are often cystic and partly calcified. They develop from the neuroepithelium of the walls of the cerebral ventricles and the central canal of the spinal cord; as they grow, they displace, but do not invade, the adjacent neural tissue. Ependymomas usually arise in the posterior fossa, most commonly near the fourth ventricle, and in the conus medullaris of the spinal cord (Fig. 7.7p. 147). Their main clinical manifestations are focal (often cerebellar) neurological deficits and signs of intracranial hypertension, secondary to compression of the CSF pathways and occlusive hydrocephalus. An unusually persistent, continuous headache in children should arouse suspicion of an ependymoma or other mass in the posterior fossa. The treatment is by resection, followed by radiotherapy of the entire neuraxis. Seventy percent of treated patients survive for 10 years or longer.

Medulloblastoma also mainly affects children (in three-quarters of cases). This is an undifferentiated, highly malignant tumor characterized by rapid growth and rapidly progressive clinical manifestations.Medulloblastomas usually arise from the roof of the fourth ventricle, sometimes filling the entire ventricle, and grow into the inferior portion of the vermis. They grow by infiltration and often metastasize via the CSF into the spinal canal (drop metastases).The signs and symptoms resemble those of cerebellar astrocytoma (headache, nausea, truncal ataxia—see above), possibly combined with manifestations referable to the spinal cord and cauda equina. Medulloblastoma is treated by resection followed by radiotherapy or chemotherapy. The prognosis after radical removal is not unfavorable, but often no more than an incomplete removal can be achieved, in which case tumor recurrence is the rule.

Oligodendroglioma is usually found in the cerebral hemispheres, particularly the frontal lobes. It tends to arise between the ages of 40 and 50 and is usually a relatively well-differentiated tumor that grows slowly over the years and often becomes calcified. It usually presents with epileptic seizures; recurrent seizures affect 70% of patients with this type of tumor. Oligodendroglioma is mostly radioresistant and is best treated by radical resection. If this can be achieved, radiotherapy is usually not given. Nonetheless, apparently radical resection can be followed by tumor recurrence, which may not take place until years after surgery.

Image

Gliomas of the optic nerve and chiasm are found almost exclusively in children, often in the setting of neurofibromatosis.

Meningiomas arise from the dura mater and are nearly always benign, well-demarcated lesions that displace rather than invade the adjacent neural tissue as they grow. These mesodermal tumors most often become clinically evident between the ages of 40 and 50. They are diagnosed by MRI or CT scanning (Fig. 6.8), which reveals marked, homogeneous contrast enhancement. Meningiomas tend to appear in certain classic locations with corresponding typical neurological manifestations, as listed in Table 6.10. They often grow very slowly and are not uncommonly discovered as an incidental radiological finding. The indications for treatment must then be carefully considered: resection may be desirable in younger patients, but unnecessary in older ones.

Pituitary tumors usually arise from the cells of the anterior pituitary lobe. Depending on their cells origin, they can produce hormones in excess or cause hormone deficiency. Thus, they present clinically with endocrine disturbances and/or compressive effects on the adjacent neural tissue (see below). They most commonly present between the ages of 30 and 50. The rare eosinophil adenomas produce excessive growth hormone, causing acromegaly, while basophil adenomas produce excessive ACTH, causing Cushingsyndrome (which, when caused by a pituitary tumor, constitutes Cushing disease).Prolactinomas produce galactorrhea and secondary amenorrheain women and impotence in men. Although basophil adenomas and prolactinomas rarely cause mass effect, eosinophil adenomas and, above all, the hormonally inactive chromophobe adenomas tend to grow quite large, causing compression and dysfunction of the normal pituitary tissue, clinically evident as hypopituitarism (multiple pituitary hormone deficiencies, including hypothyroidism and secondary hypogonadism). Chromophobe adenomas can also compress the optic chiasm, causing a visual field defect, usually bitemporal upper quadrantanopsia or bitemporal hemianopsia. Compression of the optic nerves themselves may impair visual acuity. Prompt neurosurgical removal of the tumor can often reverse these visual difficulties if they are still incomplete at the time of surgery. Most pituitary tumors do not present with signs of mass effect (only one in 10 enlarges the sella turcica visibly on plain films of the skull). Tumors that do cause mass effect should be neurosurgically removed, preferably by the transsphenoidal route. Hormonally active microadenomas can sometimes be treated with medication alone (e. g., prolactinoma can be treated with inhibitors of prolactin secretion, such as bromocriptine and lisuride).

Image

Fig. 6.8 Meningioma of the left cerebral convexity as seen by MRI after the intravenous administration of gadolinium. Marked mass effect deforms the ventricles and shifts the midline structures rightward. There are cystic cavities at the tumor–brain interface. Blood vessels supplying the tumor are seen entering it from its “navel” on the outer surface.

Malformations and hamartomatous tumors include craniopharyngioma, dermoid and epidermoid tumors, and cavernoma. Craniopharyngioma arises in or above the pituitary fossa, often growing upward toward the diencephalon and third ventricle. This is a cystic tumor derived from epithelial remnants in Rathke's pouch, generally containing calcifications as well as cholesterol crystals. It presents with hypopituitarism (see above), diencephalic manifestations (diabetes insipidus), and visual disturbances. Like a pituitary tumor, it can cause hemi- or quadrantanopsia and impair visual acuity; it can also cause occlusive hydrocephalus. Craniopharyngioma is the most common suprasellar tumor in children and adolescents. It is best treated by complete resection.

Cavernoma (also called cavernous angioma or cavernous malformation) consists of a well-demarcated agglomeration of blood vessels. Cavernomas can be multiple and familial (genetic locus on chromosome 7). They present with epileptic seizures and hemorrhage.

Epidermoid tumors are found at the base of the brain, are often calcified, and cause focal deficits or epileptic seizures. Their peak incidence is between the ages of 25 and 45.

Neurinomas (schwannomas) are benign neoplasms arising from Schwann cells. The most common type affects the eighth cranial nerve and is usually (though incorrectly) designated acoustic neuroma. This tumor of the cerebellopontine angle presents initially with eighth nerve dysfunction: progressive hearing loss, tinnitus, and disequilibrium. As it grows, it impinges on the other cranial nerves of the cerebellopontine angle, causing facial palsy and trigeminal sensory deficits. Further growth leads to compression of the cerebellum and brainstem, causing cerebellar signs (esp. ataxia) and possibly pyramidal tract signs. Acoustic neuroma typically markedly elevates the CSF protein concentration. Until recently, the optimal treatment in all patients was complete resection of the tumor. Now many smaller acoustic neuromas can be treated safely and effectively with stereotactic radiosurgery.

Brain metastases account for about 15% of malignant brain tumors. The most common source of a brain metastasis is bronchial carcinoma in men and carcinoma of the breast in women, followed in both sexes by melanoma and renal cell carcinoma. Brain metastases sometimes produce symptoms before the primary tumor does; in such cases, multiple brain metastases are usually already present, even if only a single one is apparent on the neuroimaging study. Generally speaking, surgical resection makes sense only for solitary metastases and the surgical indication should always be carefully considered in the light of the extent of disease. Only about 20% of patients so treated live more than five years after the operation and postoperative radiotherapy, if they have not already died of the effects of their primary tumor. Brain metastases usually produce extensive peritumoral edema and often cause epileptic seizures; thus, corticosteroids and antiepileptic drugs can be given for palliation. This usually brings a substantial, if only temporary, clinical improvement.

Image  Circulatory Disorders of the Brain and Nontraumatic Intracranial Hemorrhage

The term “stroke” encompasses both ischemic and hemorrhagic disturbances of the cerebral circulation producing central neurological deficits of acute or subacute onset. Ischemia accounts for 80 to 85% of stroke, hemorrhage for 15 to 20%.

Cerebral Ischemia

Ischemia causes critical hypoperfusion in an area of the brain. Depending on its extent and duration, hypoperfusion can induce neurological deficits that may be either transient (TIA, RIND) or permanent(completed stroke, infarction). The more common causes of ischemia are blockage of the arterial blood supply by arteriosclerotic processes of both larger and smaller blood vessels (macroangiopathic and microangiopathic processes) and embolic events (arterio-arterial and cardiogenic embolization). A less common cause is obstruction of venous outflow (e.g., venous sinus thrombosis). Every ischemic event should prompt thorough diagnostic evaluation to identify its etiology, so that effective measures can be taken to prevent a recurrence.

Nontraumatic Intracranial Hemorrhage

Regulation of cerebral perfusion. Glucose is the brain's nearly exclusive source of energy. The brain accounts for only about 2% of body weight, but it receives about 15% of the cardiac output. Regulatory mechanisms ensure that the cerebral perfusion remains constant despite fluctuations in the arterial blood pressure, as long as the latter remains within a certain range. Thus, if the arterial blood pressure should fall, a compensatory dilatation of the cerebral arteries occurs to maintain cerebral perfusion, which is significantly reduced only when the systolic blood pressure falls below 70 mmHg (or below 70% of the baseline value in hypertensive individuals). Hyperventilation and elevated intracranial pressure reduce cerebral perfusion, while hypoventilation (i.e., an elevated partial pressure of CO2) increases it.

Consequences of ischemia. Normal cerebral perfusion is ca. 58 mL per 100 g brain tissue per minute. Signs and symptoms of ischemia begin to appear when perfusion falls below 22 mL per 100 g per min. In this stage of relative ischemia, the functional metabolism of the affected brain tissue is impaired, but the infarction threshold has not yet been reached and the tissue can regain its normal function as soon as the perfusion renormalizes. The longer relative ischemia lasts, however, the less likely it is that normal function will be regained. The zone of tissue in which the local cerebral perfusion lies between the functional threshold and the infarction threshold is called the ischemic penumbra (“partial shadow”).

Total ischemia causes irreversible structural damage of the affected region of the brain. If the blood supply of the entire brain is cut off, unconsciousness ensues in 10 to 12 seconds and cerebral electrical activity, as demonstrated by EEG, ceases in 30 to 40 seconds (Fig. 6.9). Cellular metabolism collapses, the sodium/potassium pump ceases to function, and interstitial fluid—i.e., sodium and water—flows into the cells. The resulting cellular swelling is called cytotoxic cerebral edema. Later, when the blood–CSF barrier collapses, further plasma components, including osmotically active substances, enter the brain tissue; a net flow of fluid from the intravascular space into the intercellular and intracellular spaces then produces vasogenic cerebral edema. In a vicious circle, these two varieties of edema lead to additional compression of brain tissue, thereby impairing the cerebral perfusion still further.

Dynamic time course of cerebral ischemia. Cerebral perfusion can cause a wide variety of clinical manifestations. In clinical practice, these are often classified by their temporal course and their degree of reversibility or irreversibility (Table 6.11). Although classification in this way is useful, it says nothing about the underlying etiology of the ischemic events. Moreover, the boundaries between the listed entities (e.g., TIA and RIND) are not sharp.

Arterial blood supply of the brain. To understand how the localization and extent of cerebral infarcts depends on the particular artery that is occluded, one must know the anatomy of the territories of the individual vessels, as well as their numerous anastomoses. The anastomotic arterial circle of Willis, at the base of the brain, provides a connection between the carotid and vertebral circulations and between the blood supplies of the right and left cerebral hemispheres (Fig. 6.10). The territories of the major cerebral arteries are shown in Fig. 6.11.

Image

Fig. 6.9 Time course of cerebral ischemia. Diagram of the effect of sudden total deprivation of blood supply to the brain on tissue metabolism, consciousness, the EEG, neuronal morphology, and tissue glucose concentration.

Table 6.11 Classification of cerebral ischemia by temporal course

Designation

Duration of deficits

Remarks

TIA = transient ischemic attack

usually 2–15 minutes, sometimes as long as 24 hours

transient focal neurological and/or neuropsychological deficit (e. g., aphasia); a TIA in the distribution of the ophthalmic a. presents as amaurosis fugax

RIND = reversible ischemic neurological deficit

up to 7 days

mostly minor neurological deficits

stroke in evolution, progressive stroke

stroke with neurological deficits that continue to worsen for hours or days after onset

 

completed stroke

established neurological deficit that is irreversible or only partly reversible

 

Image

Fig. 6.10 Arteries of the base of the skull (after Baehr M. and M. Frotscher: Duus' Topical Diagnosis in Neurology, 4th edn, Thieme, Stuttgart 2005).

Image

Fig. 6.11 Territories supplied by the individual arteries of the brain.

Ischemic Stroke

Ischemic stroke occurs when persistent ischemia or a complete interruption of the blood supply to a particular area of the brain produces irreversible destruction of brain tissue. The resulting neurological deficits usually arise quite suddenly (whence the term “stroke”) but can sometimes progress over a longer period of time (“stroke in evolution”). They are irreversible, or at most only partly reversible.

Etiology. Ischemic stroke has many causes. Embolic events and vascular stenosis due to atherosclerosis play important roles, as do hypertensive atherosclerotic changes of medium-caliber or small cerebral arteries.

Image The most important risk factor for stroke is arterial hypertension.

The major etiologies of ischemic stroke are summarized in Table 6.12. The acute symptoms are sometimes produced by a sudden drop in blood pressure. The major risk factors for atherosclerosis and ischemic stroke are listed in Table 6.13.

Types of infarct. There are three basic types of brain infarct, distinguished from each other by the caliber of the occluded arteries:

Territorial infarcts are mainly produced by occlusions of the main trunks or major branches of cerebral arteries (cerebral macroangiopathy), which may be due to thrombosis, embolism, or other causes. The infarct includes both cortex and subcortical white matter and sometimes the basal ganglia and thalamus (Fig. 6.12). It is usually possible to infer which vessel has been occluded from the pattern of neurological deficits that are produced.

Table 6.12 Classification of ischemic stroke by etiology

I. Atherosclerosis of large extra- and intracranial vessels, leading to:

Image thrombosis in the region of an atherosclerotic plaque,

Image hemodynamic insufficiency in the poststenotic circulation, or

Image arterio-arterial embolism

II. Cardiogenic and aortogenic embolism

III. Cerebral small vessel disease/arteriolosclerosis, usually due to hypertension

IV. Other etiologies, e. g.:

Image vasculopathies

Image coagulopathies

V. Undetermined etiology

Table 6.13 Risk factors for atherosclerosis and ischemic stroke

Positive family history of early onset of atherosclerotic disease (<55 years of age)

Arterial hypertension

Cigarette smoking

Truncal obesity, hypercholesterolemia

Diabetes mellitus

Sleep apnea syndrome

Past history of cardio- or cerebrovascular disease or occlusive peripheral vascular disease

Watershed infarcts (border zone infarcts) are infarcts of hemodynamic origin that are likewise due to microangiopathic processes. Narrowing of small vessels impairs perfusion in the vulnerable regions at the borders between the territories of two or more arteries (Fig. 6.13). If the perfusion pressure is inadequate, infarction ensues.

Image

Fig. 6.12 Infarct in the territory of the left middle cerebral a. in a 60-year-old man with acute right hemiplegia, a The left carotid angiogram (a–p view) reveals occlusion of the main stem of the middle cerebral a. at its origin. Only the anterior cerebral artery is visualized, b The lateral view shows only the pericallosal artery, with its branches, and the posterior cerebral a., while the middle cerebral a. and its branches are not seen (cf. normal carotid angiogram, p. 51). c ACT scan obtained 2 days after the onset of symptoms reveals massive infarction in the territory of the middle cerebral a., extending from the cortex to the basal ganglia.

Image

Fig. 6.13 Watershed infarct. A 58-year-old man with an infarct in the watershed zone between the right anterior and middle cerebral a. territories, caused by occlusion of the right internal carotid a. The vascular territories are shown in Fig. 6.10 (p. 100). The infarct is well seen in the T2-weighted spin-echo-image (arrow in a), and still better in the diffusion-weighted image (b), as a longitudinal signal abnormality in the watershed zone between the two arterial territories. The internal cerebral a. is occluded below the siphon, as the MR angiogram shows (c). 1, middle cerebral a.; 2, basilar a.; 3, right internal carotid a.

Lacunar infarcts are caused by microangiopathy (usually atherosclerosis of small vessels due to hypertension). The infarcts (lacunes) are less than 1.5 cm in diameter and often multiple. They are found mainly in the basal ganglia, thalamus, and brainstem, and sometimes in the cerebral cortex and subcortical white matter (Fig. 6.13). Their clinical presentation depends on their number and localization. Multiple subcortical infarcts due to hypertension are the hallmark of subcortical arteriosclerotic encephalopathy, also called Binswanger disease (Fig. 6.14).

Signs and Symptoms of Ischemic Stroke. The neurological deficits produced by ischemic stroke depend on the area of the brain that is ischemic or infarcted. We will now briefly summarize the clinical manifestations of the major cerebrovascular syndromes and the typical deficits produced by ischemia in circumscribed areas of the brain.

Ophthalmic a. Transient ischemia in the territory of this vessel produces amaurosis fugax (transient monocular blindness), while longer-lasting ischemia causes retinal infarction. Retinal ischemia is often due to embolism of cholesterol crystals from ulcerating plaques in the internal carotid a. into the ophthalmic a. Embolized crystals within the arteries of the retina can occasionally be seen by ophthalmoscopy.

Internal carotid a. Stenosis or occlusion of this vessel can cause simultaneous ischemia of the eye with monocular visual loss (see above) and contralateral hemiparesis, in combination with neuropsychological deficits. This oculocerebral syndrome is rare, however, as ischemia in the territory of the internal carotid a. usually presents with either monocular visual loss or variably severe hemiparesis and neuropsychological deficits.

Middle cerebral a. (MCA). The site of occlusion (main trunk vs. branch of the middle cerebral a.) determines the clinical manifestations. As a rule, a mainly brachiofacial hemiparesis and hemisensory deficit are found, often accompanied by homonymous hemi- or quadrantanopsia and, in the initial phase, a horizontal gaze palsy toward the side of the hemiparesis. An MCA occlusion on the language-dominant (usually left) side additionally produces aphasia and apraxia, while one on the nondominant side produces impairment of spatial orientation. An occlusion of the main stem of the MCA causes ischemia not only of the cortex, but also of the basal ganglia and internal capsule, producing a more severe contralateral hemiparesis. If the hemiparesis fails to improve over time, or does so only partially, a typical, permanent impairment of gait results: circumduction of the spastically extended lower limb, flexion of the paretic upper limb at the wrist and elbow, and absence of arm swing on the affected side (Wernicke–Mann gait) (Fig. 6.15).

Image

Fig. 6.14 Binswanger disease (cerebral microangiopathy) with lacunar infarct (arrowhead) and severe white matter changes. MR images in a 70-year-old man. The microangiopathic lesions are seen on the T2-weighted images as multifocal signal abnormalities in the white matter. The most severe changes are typically found in the periventricular zones abutting the frontal and occipital horns of the lateral ventricles.

Anterior choroidal a. Ischemia in the territory of this vessel causes a homonymous visual field defect, a hemisensory deficit, and, less commonly, hemiparesis. The clinical manifestations resemble those of occlusion of the lenticulostriate aa. (branches of the middle cerebral a. supplying the basal ganglia and internal capsule). There may also be extrapyramidal motor signs, such as hemiballism.

Anterior cerebral a. An infarct in the territory of this artery causes contralateral hemiparesis mainly affecting the lower limb, sometimes accompanied by contralateral ataxia and, if the lesion is left-sided, by apraxia. Occasionally there may be apathy, abulia (pathological lack of drive and motivation), and urinary incontinence.

Posterior cerebral a. Occlusion of this artery can produce infarction in the cerebral peduncle, the thalamus, mediobasal portions of the temporal lobe, and the occipital lobe. The most prominent clinical sign of a distal occlusion (beyond the origin of the posterior communicating a.) is contralateral homonymous hemianopsia, possibly combined with neuropsychological deficits.

Basilar a. Occlusion of the main stem or of a branch of the basilar a. causes brainstem, cerebellar, and thalamic signs (see below). Main stem thrombosis can produce locked-in syndrome and is often fatal (p. 77).

Thalamic infarction results from occlusion of one of the arteries supplying the thalamus. It usually presents with a contralateral hemisensory deficit, in addition to mild paresis and hemiataxia. The patient's memory, too, is often impaired.

Image

Fig. 6.15 Typical gait disturbance of a hemiplegic patient. Circumduction of the spastically paretic leg with predominant extensor tone, and flexion of the spastically paretic arm at the elbow because of predominant flexor tone.

Brainstem infarcts are usually lacunar. They arise in the territory of one or more small perforating arteries that branch off the basilar trunk. Their clinical presentation depends on the particular brainstem nuclei and fiber tracts that they affect. Brainstem stroke therefore takes many different clinical forms, corresponding to the wide variety of functions served by brainstem structures. As a rule, brainstem stroke causes ipsilateral cranial nerve deficits and a contralateral hemisensory defect and/or hemiparesis (cf. Table 6.14).

The large number of brainstem vascular syndromes that have been described and given eponymous names are only rarely seen in “pure” form in clinical practice. The most important among them is Wallenberg syndrome, which results from occlusion of the posterior inferior cerebellar a. (PICA). Some of the more common vascular syndromes affecting different parts of the brainstem are summarized in Table 6.14.

Image

Image

Fig. 6.16 Acute infarct in the left cerebellar hemisphere, revealed by MRI. The infarct involves the territory of the superior cerebellar a. There are also two small ischemic foci in the left cerebral hemisphere.

Cerebellar infarction presents with vertigo, nausea, unsteady gait, dysarthria, and often acute headache and progressive impairment of consciousness. The neurological examination reveals ataxia, dysmetria, and nystagmus.Often, simultaneous infarction of part of the brainstem produces additional brainstem signs. Not uncommonly, edema in and around the infarcted area rapidly leads to a life-threatening elevation of intracranial pressure in the posterior fossa. A typical MR image of cerebellar stroke is presented in Fig. 6.16.

Diagnostic Evaluation of Ischemic Stroke. Diagnostic evaluation in the acute phase is focused on the determination of the anatomic site and extent of cerebral ischemia and, above all, its etiology.

Acute diagnostic evaluation. In pursuit of these goals, the initial work-up should always begin with the following:

Image precise history taking concerning not only the present illness, but also the past medical history, with special attention to risk factors and systemic illnesses;

Image a thorough clinical neurological examination enabling localization of the lesion (see above); and

Image examination of the cardiovascular system (measurement of pulse and blood pressure and auscultation ofthe heart, the carotid aa., and perhaps other vessels, depending on the clinical situation; particular attention should be paid to bruits and to any irregularitiesof the pulse that suggest arrhythmia).

Ancillary testing in the acute phase. The following ancillary tests should also be performed on all stroke patients in the acute phase:

Image Laboratory tests, mainly for the identification of risk factors, infectious/inflammatory disorders, and coagulopathies (erythrocyte sedimentation rate, blood sugar, lipid profile, complete blood count and hemoglobin, coagulation profile, and sometimes protein C, antiphospholipid antibodies, syphilis serology, etc.).

Image Imaging studies. Even before these are performed, any central neurological deficit of acute onset is very likely to be due to a cerebrovascular accident, of which ischemic stroke is the most common type; yet neuroimaging is still indicated for definitive confirmation of the diagnosis. Any patient thought to be suffering from acute ischemic stroke should undergo CT as soon as possible, as this will have important implications for the course of treatment, even though areas of ischemia usually cannot be seen by CT till several hours after the onset of symptoms. Early CT does, however, reveal acute brain hemorrhage, if present. MRI can also be performed, if available. MRI reveals the infarct zone and perifocal edema as soon as the patient begins to experience symptoms and it displays brainstem and cerebellar infarcts more clearly than CT.

Image Doppler ultrasonography of the extra- and intracranial vessels to detect vascular stenosis, occlusion, and vascular collateralization.

Image An electrocardiogram (arrhythmia pointing to a likely cardioembolic event? Old or acute myocardial infarction? Evidence of regional cardiac wall motion abnormalities, creating a danger of intracardiac thrombosis and embolism?).

Image When an ischemic stroke is suspected, the most important immediate question in the differential diagnosis is whether the patient is not, in fact, suffering from an intracerebral hemorrhage, rather than from cerebral ischemia. The history and physical examination alone cannot provide a reliable answer; therefore, a neuroimaging study must be performed.

Further diagnostic tests after the acute phase. Depending on the clinical situation, the following tests can also be performed after the acute phase:

Image angio-MRI to reveal stenosis of the carotid or vertebral a. (Fig. 6.17);

Image transthoracic or transesophageal echocardiography to reveal potential sources of emboli in the heart and aortic arch, as well as any dysfunction of the heart valves;

Image cerebral angiography to reveal stenosis or occlusion of the cerebral blood vessels (also performed in the acute phase as a part of thrombolytic treatment); and

Image SPECT to demonstrate impaired perfusion (cf. Fig.4.13, p. Image).

Treatment of Ischemic Stroke. Once the diagnosis of ischemic stroke has been made and an intracerebral hemorrhage has been excluded, the initial goal of treatment is to minimize the amount of brain tissue that will be irreversibly damaged. Brain tissue in the zone of relative ischemia (the ischemic penumbra, p. 99) can be “salvaged” by prompt restoration of its obstructed blood supply.

Image Patients with suspected stroke should be immediately transported to an acute care hospital and admitted. Inpatient treatment markedly improves prognosis.

In parallel with the acute measures already discussed, a further treatment strategy should also be settled upon for long-term prevention of recurrent stroke. The appropriate strategy depends on the etiology of the infarct.

General treatment strategies for ischemic stroke are as follows:

Image keeping the blood pressure relatively high (values up to 200–220 mmHg systolic and 110 mmHg diastolic are tolerable);

Image stabilization of cardiovascular function (adequate hydration, treatment of heart failure and/or arrhythmia, if present);

Image

Fig. 6.17 High-grade stenosis of the right common carotid a. in a 72-year-old woman. The MR angiogram, obtained after the injection of contrast medium, reveals high-grade narrowing at the carotid bifurcation (arrow).

Image treatment of cerebral edema, if present (p. 93); and

Image in some patients, intravenous thrombolysis within three hours of the onset of symptoms, or intra-arterial thrombolysis within six hours; if thrombolysis is contraindicated, aspirin is the drug of choice.

Optimization of oxygen and substrate delivery to the ischemic zone:

Image monitoring of respiratory function (with blood gas analyses, if necessary, and prophylaxis and treatment of pneumonia);

Image treatment of pathological metabolic processes that elevate the demand for oxygen and energy (e.g., treatment of fever, suppression of epileptic seizures); and

Image optimal blood sugar management, with prevention and, if necessary, treatment of hyper- or hypoglycemia.

Further therapeutic measures include rehabilitation and prophylactic measures against recurrent stroke:

Image Early rehabilitation: mobilization (decubitus prophylaxis), physical and occupational therapy, and, ifneeded, speech therapy.

Prevention of recurrent stroke:

Image General medical treatment: minimization of vascular risk profile (optimal treatment of hypertension, diabetes mellitus, hypercholesterolemia, or sleep apnea syndrome, if present, and cessation of smoking); treatment of heart failure and/or arrhythmia.

Image Antithrombotic therapy: the type to be given depends on the etiology of the initial stroke. The following options are available:

Image inhibition of platelet aggregation (mainly aspirin, but also clopidogrel or aspirin with dipyridamole);

Image full heparinization and oral anticoagulation (mainly after cardio- or aortoembolic stroke, basilar artery thrombosis, stroke in evolution, venous thrombosis, or venous sinus thrombosis (see below); there is no consensus on other potential indications);

Image surgical therapy: endarterectomy for high-grade carotid stenosis, or insertion of an intravascular stent.

Image

Fig. 6.18 Thrombosis of the superior sagittal sinus, a In this angiogram (venous phase) of a 43-year-old male patient, only the posterior portion of the sinus is filled with contrast medium, while the anterior segment (black arrows) and the veins draining into it are not seen. The cavernous sinus is well visualized (white arrow). b Another patient with superior sagittal sinus thrombosis: a number of cerebral cortical veins and bridging veins are seen in this angio-MRI, but the superior sagittal sinus is not seen, as it contains no flowing blood, c The thrombus is revealed in the sagittal section as an irregular, crescent-shaped structure lying between the dura mater and the arachnoid.

Venous Thrombosis and Venous Sinus Thrombosis

Besides the much more common arterial disorders just discussed, obstruction to venous flow can also cause cerebral ischemia. Venous obstruction is usually due to thrombosis of the large venous channels draining the brain (venous sinus thrombosis) and of the veins that empty into them (cerebral venous thrombosis). Damming of blood behind a venous obstruction leads to a secondary reduction of arterial inflow and thus to hypoperfusion and infarction. Smaller or larger diapedetic hemorrhages can also occur in the infarcted area (hemorrhagic infarction).

Etiology and frequency. Thromboses of the cerebral veins and venous sinuses are somewhat more common in women than in men; they account for no more than 1% of all cerebral ischemic events. The superior sagittal sinus is most commonly affected, the other sinuses and the cortical veins less commonly. These thromboses are usually bland, i. e., no specific etiology can be identified. A minority of cases are due to infection, either systemic or in the immediate vicinity of the sinus (e.g., chronic otitis); other causes include hypercoagulability states and systemic diseases (e.g., Behçet disease).

Clinical manifestations. The common signs and symptoms are headache, focal or generalized epileptic seizures, papilledema, and sensory and motor deficits, depending on the site of the thrombosis.

Diagnostic evaluation. Imaging studies reveal unilateral or bilateral hemorrhagic infarction; the thrombosis itself can usually be seen by MRI, or by CT after the administration of contrast medium. In a minority of cases, it is revealed only by angiography (Fig. 6.18). The diagnostic method of choice is MRI.

Treatment consists of anticoagulation (heparin followed by oral anticoagulation), usually for a few months.

Nontraumatic Intracranial Hemorrhage

Nontraumatic intracranial hemorrhage is defined as a spontaneous hemorrhage into the brain parenchyma (intracerebral hemorrhage) or the cerebrospinal fluid space (subarachnoid hemorrhage). Intracerebral hemorrhages cause acute signs and symptoms resembling those of cerebral ischemia and account for about 10% of strokes. One of the more common forms of intracerebral hemorrhage is hypertensive hemorrhage. The main symptom of subarachnoid hemorrhage is headache; its most common source is a ruptured aneurysm.

General manifestations of intracranial hemorrhage. Though the manifestations of intracranial hemorrhage and cerebral ischemia are similar, generally speaking (sudden onset of focal neurological deficits), there are a number of clinical signs and symptoms that are more characteristic of hemorrhage than of ischemia. These include:

Image acute headache, often accompanied by vomiting;

Image rapidly or very rapidly progressive neurological deficits (whose type depends on the site of hemorrhage);

Image progressive impairment of consciousness, perhaps leading to coma;

Image in many patients, epileptic seizures.

If these manifestations are present, an intracranial hemorrhage is the probable cause. The definitive diagnosis, however, can only be made with neuroradiological methods.

Intracerebral Hemorrhage

Etiology. Most cases of intracerebral hemorrhage are due to the rupture of vascular lesions of hypertensive origin (“rhexis hemorrhages” of pseudoaneurysms of lipohyalinotic arterioles), aneurysms, or arteriovenous malformations (Figs. 6.196.20). Intracerebral hemorrhage may also be a complication of therapeutic (over-) anticoagulation. Smaller hemorrhages, particularly those that are near the cortical surface, are often due to amyloid angiopathy. There can also be bleeding into an infarct, a primary brain tumor, a metastasis, or a cavernoma. The more common etiologies of intracerebral hemorrhage are listed in Table 6.15.

Image

Fig. 6.19a Arteriovenous malformation in the left temporal lobe of a 68-year-old man with epileptic seizures, b Cavernoma in the right hippocampus of another patient (T2-weighted image).

Image

Fig. 6.20 Arteriovenous malformation. a The T2-weighted spin-echo image reveals the feeding and draining vessels as signal-free areas (“flow voids”). b Analogous finding in a sagittal image, c The right carotid angiogram shows that the malformation is fed by branches of the right middle cerebral and pericallosal aa. d The left carotid angiogram shows that it also derives part of its blood supply across the midline from the left pericallosal a.

Table 6.15 Causes of nontraumatic cerebral hemorrhage

Chronic arterial hypertension

Aneurysm rupture

Hemorrhage into a preexisting lesion (infarct, tumor)

Vascular malformation (cavernoma, arteriovenous malformation)

Vascular fragility due to vasculopathy, e. g., cranial arteritis, amyloid angiopathy

Bleeding diathesis due to hematologic disease or therapeutic anticoagulation

Cerebral venous thrombosis and venous sinus thrombosis

Rarely, in the setting of a hypertensive crisis or drug abuse (e. g., cocaine)

Image

Fig. 6.21 Acute left thalamic hemorrhage as seen by CT in a 76-year-old man with a right-sided hemisensory deficit of acute onset.

Clinical manifestations. The clinical picture mainly depends on the site and extent of the hemorrhage and to a much lesser extent on etiological factors. Certain aspects of the clinical course can, however, suggest that one etiology is more likely than another:

Image Chronic arterial hypertension and advanced age (typically 60–70) make a rhexis hemorrhage more likely. These hemorrhages are ultimately caused by hypertension and are usually very large. Common sites are the pallidum, the putamen, and the internal capsule, with the corresponding clinical manifestations: contralateral usually dense, hemiparesis or hemiplegia, horizontal gaze palsy, and initially, in many cases, déviation conjuguée and deviation of the head to the side of the lesion. Less common sites are the subcortical white matter, brainstem, thalamus (Fig. 6.21), and cerebellum. Very large hemorrhages, particularly if located in the posterior fossa, can rapidly elevate the intracranial pressure, causing brainstem compression and, in turn, impairment of consciousness and coma.

Image Acute worsening of more or less severe, preexisting signs and symptoms, perhaps accompanied by additional impairment of consciousness, suggests hemorrhage into an infarct or tumor.

Image Focal or generalized epileptic seizures preceding theonset of the acute event point toward a tumor, vascular malformation, or other structural lesion of thebrain as the likely cause of hemorrhage.

Diagnostic evaluation. The diagnosis of intracranial hemorrhage is suggested by the characteristic clinical findings (p. 106) and then definitively confirmed by the demonstration of blood on CT or MRI.When performed in the acute phase, these studies may fail to reveal an underlying vascular malformation, if present, which may be obscured by the hemorrhage; angiography may be necessary to complete the diagnostic work-up. The obtaining of a complete coagulation profile is indicated in some patients.

Treatment and prognosis. Patients suffering from an acute intracerebral hemorrhage require close clinical observation; in particular, signs of intracranial hypertension (vomiting, progressive impairment of consciousness, and sometimes anisocoria and papilledema) must be vigilantly watched for. Intracranial hypertension may be due to recurrent hemorrhage or to progressive brain swelling; in either case, it must be promptly detected and treated (for treatment measures, cf. p. 93). In addition, stabilization of vital functions and the treatment of epileptic seizures, if present, are essential. In each case, the possible indication for neurosurgical removal of the hematoma should be carefully considered, in light of the neurological manifestations, site of the hemorrhage, and age and general condition of the patient. Cerebellar hemorrhage with mass effect generally confers a risk of impending brainstem compression and death and is often an indication for life-saving emergency surgery.

Although about one-third of all patients with an intracerebral hemorrhage will die of it, while others go on to enjoy a more or less complete spontaneous recovery.

Subarachnoid Hemorrhage (SAH)

Nontraumatic subarachnoid hemorrhage, defined as spontaneous hemorrhage into the subarachnoid space, accounts for about 7% of all “strokes.” It can occur at any age, with peak incidence around age 50. Children are very rarely affected.

Etiology. Subarachnoid hemorrhage is usually due to the spontaneous rupture of a saccular aneurysm on an artery at the base of the brain, usually one of the arteries forming the circle of Willis. Common sites of saccular aneurysms are shown in Fig. 6.22. Less frequent causes of subarachnoid hemorrhage include arteriovenous malformations, vasculopathies, coagulopathies, and preceding trauma.

Clinical manifestations of subarachnoid hemorrhage are:

Image sudden, extremely intense headache, often described as the “worst headache of my life;” the headache may have been preceded by an earlier, transientepisode of headache or other minor symptoms (“premonitory headache” “warning leak”) it is most commonly diffuse or bioccipital;

Image

Fig. 6.22 Common locations of saccular aneurysms and their relations to the cranial nerves. Aneurysms are typically found at vascular bifurcations.

Image often, at first, a brief and transient impairment of consciousness, which may be followed, at some point in the following hours or days, by a recurrent impairment of consciousness or coma;

Image often, nausea and vomiting;

Image rarely, cranial nerve palsies (caused by aneurysms at particular sites) or other focal neurological deficits, caused, e. g., by additional hemorrhage into the brain parenchyma (see below).

Diagnostic evaluation. Physical evaluation reveals:

Image as the most prominent physical finding, meningism; and sometimes other clinical signs that may be useful for the localization of the lesion, e.g.:

Image oculomotor nerve palsy with aneurysms of the terminal segment of the internal carotid a. or the posterior communicating a.;

Image abulia with an aneurysm of the anterior communicating a.;

Image hemiplegia with an aneurysm of the middle cerebral a.;

Image brainstem and cerebellar signs with aneurysms of the basilar a.

Whenever subarachnoid hemorrhage is suspected on clinical grounds, neuroimaging studies should be performed immediately. CT or MRI with FLAIR sequences can often demonstrate the presence of blood in the cerebrospinal fluid spaces on the day of the hemorrhage (Fig. 6.23). These studies can sometimes also reveal the source of hemorrhage (aneurysm or other), though they often will not. If CT and MRI fail to demonstrate any hemorrhage in the face of clinical suspicion, a lumbar puncture must be performed. Bloody CSF is found in patients with acute subarachnoid hemorrhage, xanthochromic CSF in patients whose hemorrhage occurred a few hours of more before the LP (Fig. 6.24).

Image

Fig. 6.23 Aneurysmal subarachnoid hemorrhage, a The nonenhanced CT reveals blood in the subarachnoid space, particularly along the course of the middle cerebral a. The aneurysm (arrow) is also seen. b The lumen of the aneurysm, dark in a, turns bright after the administration of intravascular contrast (arrow), c Carotid angiography shows the aneurysm at the bifurcation of the internal carotid a. into the anterior and middle cerebral aa.

Image

Fig. 6.24 Aneurysm of the internal carotid a. a The sagittal image shows a large, blood-filled aneurysm in the region of the terminal segment of the internal carotid a. The dome of the aneurysm protrudes upward into the frontobasal cortex. This was an incidental finding in a patient with no apparent neurological deficit, b The angio-MRI reveals the aneurysm of the terminal ICA segment; it is the size of a fingertip.

Image A negative CT or MRI does not rule out subarachnoid hemorrhage. If clinical suspicion remains, a lumbar puncture must be performed.

Once the diagnosis of subarachnoid hemorrhage is confirmed by imaging or lumbar puncture, cerebral angiography should be performed as soon as possible to determine the source of the hemorrhage, usually an aneurysm. Angiography is only indicated, however, if the patient is clinically stable enough to undergo an operation (unless interventional neuroradiological treatment is available—see below).

Blood coming into contact with the outer walls of arteries that course through the subarachnoid space causes vasospasm, which can be detected with transcranial Doppler or duplex ultrasonography.

Treatment. Patients with aneurysmal subarachnoid hemorrhage must be immediately admitted or transferred to a hospital with a neurosurgical department. The goal of treatment is exclusion of the aneurysm from the circulation as soon as possible to prevent a potentially fatal recurrent hemorrhage. This is done either with neurosurgical clipping or, less often, with interventional neuroradiological techniques (“coiling” and others).

In addition, general measures including strict bed rest, stabilization of cardiovascular functions, fluid and electrolyte administration, analgesia, sedation, and the administration of a calcium-channel blocker (nimodipine) to prevent vasospasm (see above) are indicated. The performance of transcranial ultrasonography at regular intervals enables prompt detection of vasospasm, which may require treatment.

Clinical course and long-term prognosis. The clinical course of subarachnoid hemorrhage is often dramatic. Recurrent hemorrhage after the initial bleed is particularly worrisome and often fatal. Without treatment, about 25% of patients die in the first 24 hours and 40% in the first three months. The course is often further complicated by vasospasm arising three to 14 days after the initial hemorrhage (usually in the first three to five days). This may cause transient ischemia or infarction in the distribution of the spastic artery. Vasospasm may not resolve until three or four weeks later. Another potential complication is malresorptive hydrocephalus (p. 92), presumably caused by adhesions of the arachnoid villi obstructing the outflow of CSF. Patients who survive an initial aneurysmal subarachnoid hemorrhage without further treatment of the aneurysm have a long-term risk of recurrent hemorrhage of about 3% per year.

Image  Infectious Diseases of the Brain and Meninges

The intracranial structures, like the rest of the body, can be infected by bacteria, viruses, parasites, and other microorganisms. Different organisms tend to infect either the meninges or the brain substance itself. Thus, there are two main forms of intracranial infection, meningitis and encephalitis (cf. Fig. 6.25). Mixed forms also occur: a meningeal infection can spread to the brain (and/or spinal cord), or vice versa, causing meningo-(myelo)encephalitis.The latter term is only used if the patient unequivocally manifests clinical signs of both meningeal and cerebral involvement.

Infectious diseases of the central nervous system can be classified, broadly speaking, into three basic clinical situations: a predominantly meningitic syndrome, which can be either acute or subacute to chronic, and a predominantly encephalitic syndrome. These three syndromes, and the organisms that cause each, will be discussed individually in this section.

In addition, focal infections of the brain parenchyma can lead to the formation of brain abscesses, which will also be discussed below.

Image

Fig. 6.25 Sites and nomenclature of intracranial (a) and spinal (b) infections.

Infections Mainly Involving the Meninges

General manifestations of a meningitic syndrome

Image reheadache;

Image fever (though elderly and immune-deficient patients are often afebrile);

Image nausea and vomiting due to intracranial hypertension;

Image meningism, which, in severe cases, may be evident as a spontaneous extended posture of the neck, or opisthotonus;

Image positive meningeal signs with neck extension, i.e., the Lasègue, Brudzinski, and Kernig signs (p. 16).

The clinical aspects of individual types of meningitis depend on the inciting organism and the immune state of the host.

Acute Meningitis

Acute Bacterial Meningitis

Acute bacterial meningitis is caused by bacteria that can reach the meninges by any of three routes: hematogenous spread (e. g., from a focus of infection in the nasopharynx), continuous extension (e.g., from the middle ear or paranasal sinuses), or direct contamination (through an open wound or CSF fistula). The clinical onset of purulent meningitis is usually acute or subacute and patients very quickly become severely ill. The initiation of antibiotic therapy as rapidly as possible is essential for a good outcome.

Etiology. The organisms that most commonly cause acute, purulent meningitis are:

Image in neonatesEscherichia coli, group B streptococci, and Listeria monocytogenes;

Image in childrenHemophilus influenzae, pneumococci, and meningococci (Neisseria meningitidis);

Image in adults, pneumococci, meningococci, and, less commonly, staphylococci and gram-negative entero-bacteria.

Clinical manifestations. The course of purulent meningitis is characterized by the meningitic signs and symptoms listed above, as well as by:

Image myalgia, back pain;

Image photophobia;

Image if the infection is mainly located over the cerebral convexity, with irritation of the underlying brain parenchyma, epileptic seizures (40%);

Image cranial nerve deficits (10 to 20%, sometimes permanent deafness, particularly after pneumococcal infection);

Image variably severe impairment of consciousness;

Image in infection with Neisseria meningitidis, there may be petechial cutaneous hemorrhages and hemorrhagic necrosis of the adrenal cortex due to endotoxic shock (Waterhouse–Friderichsen syndrome).

Diagnostic evaluation. The most important and most urgent component of the diagnostic evaluation is lumbar puncture. Whenever acute meningitis is suspected, alumbar puncture should be performed at once, as soon as papilledema (a sign of intracranial hypertension) has been ruled out by ophthalmoscopy. The CSF is typically turbid, with 1000 to several thousand cells/mm3 (mainly granulocytes), the protein concentration markedly elevated (positive Pandy test), and the glucose concentration diminished. CSF examination enables confirmation of the diagnosis of meningitis and, in two-thirds of patients, demonstration of bacteria by Gram stain and identification of the causative organism by CSF culture.

Treatment begins with antibiotic therapy, with a single drug, or multiple drugs, chosen for their effectiveness against the most likely causative organisms in the given clinical setting. Once the organism has been identified by CSF culture and its antibiotic sensitivity spectrum has been determined, the antibiotic treatment can be tailored for maximum effectiveness against this organism.

Image The antibiotic treatment of bacterial meningitis must be started immediately after the lumbar puncture, without waiting, e. g, for a CT or MRI to be performed (if these or other tests are planned). The elapsed time between the clinical presentation and the beginning of treatment is the most important prognostic factor!

Acute Viral Meningitis

A number of viruses can cause so-called aseptic or lymphocytic meningitis, which usually presents acutely (less commonly, subacutely) after a nonspecific prodromal stage with flulike or gastrointestinal symptoms. The more common causative viruses are enteroviruses (polio- and Coxsackie viruses), arboviruses, and HIV; other, rarer ones include lymphocytic choriomeningitis virus (LCV), cytomegalovirus, type II herpesvirus, and the mumps, Epstein–Barr, and influenza viruses. The main clinical manifestations are headache, fever, meningism (often mild), and general symptoms such as fatigue and myalgia. The causative virus is identified by serologic testing. The natural course of aseptic meningitis is usually favorable, provided the brain is not involved (i. e., provided there is no encephalitic component). Antiviral treatment is given if the causative virus is found to be one for which an effective treatment exists. Residual neurological deficits, such as deafness, are rare.

Chronic Meningitis

Chronic meningitis is caused by different organisms from the pus-forming bacteria that cause acute meningitis and therefore takes a less acute and dramatic course, at least initially: the meningitic symptoms arise gradually, often fluctuate, and, depending on the causative organism, may progressively worsen over a long period of time. Fever and other clinical and laboratory signs of infection (elevated ESR and CRP, blood count abnormalities, general symptoms such as fatigue and myalgia) are common but may be absent. There may be variably severe neurological deficits. The spectrum of causative organisms is very wide.

Image

Fig. 6.26 Tuberculous meningitis, a Typical contrast enhancement surrounding the brainstem, b This T1-weighted MR image shows the typical meningeal contrast enhancement along the course of the middle cerebral a. (arrows).

Tuberculous Meningitis

Etiology. Mycobacterium tuberculosis bacilli reach the meninges by hematogenous spread, either directly from a primary complex (early generalization), or else from a focus of tuberculosis in an internal organ (late generalization). The site of origin may be clinically silent.

Clinical manifestations. Meningitic symptoms usually develop gradually. Febrile bouts and general symptoms (see above) are often but not always present. Because the infectious process typically centers on the base of the brain (so-called basal meningitis [Fig. 6.26], in contrast to bacterial meningitis, which is typically located around the cerebral convexities), cranial nerve palsies are common, particularly of the nerves of eye movement and the facial n. Moreover, arteritis of the cerebral vasculature may result in focal brain infarction. The protein concentration in CSF is typically markedly elevated and gelatinous exudates in the subarachnoid space, including the basal cisterns, cause progressive hardening of the meninges and malresorptive hydrocephalus.

Diagnostic evaluation. The most important part of the evaluation is the detection of the causative organism in the CSF or other bodily fluids (sputum, tracheal secretions, gastric juice, urine). In the past, the detection of mycobacteria in the CSF often required weeks of culture; at present, it can be done relatively quickly with PCR. Occasionally, a Ziehl–Neelsen stain of the CSF will directly and immediately reveal acid-fast bacilli (mycobacteria).

Treatment generally begins with a combination of four tuberculostatic drugs (isoniazid, rifampicin, pyrazinamide, and myambutol), followed by a combination of three drugs, and then of two, for at least 12 months. Untreated tuberculous meningitis is lethal.

Other Causes of Chronic Meningitis. A number of other organisms can rarely cause chronic meningitis, usually accompanied by variably severe encephalitis.

Image

Fig. 6.27 Sarcoidosis. This MR image of a 31 -year-old woman with sarcoidosis shows infiltration of the basal meninges. There is marked signal abnormality in the basal ambient cistern.

Fungal meningitis mainly affects immune-deficient patients, though not exclusively; the causative species include Cryptococcus neoformans, Candida albicans, and aspergilli. Further causative organisms include protozoa (Toxoplasma gondii) and parasites (cysticerci, echinococci).

The noninfectious causes of the chronic meningitic syndrome include sarcoidosis, which, like tuberculous meningitis, is mainly found around the base of the brain (Fig. 6.27), and seeding of the meninges with metastatic carcinoma or sarcoma (carcinomatous or sarcomatous meningitis).

Infections Mainly Involving the Brain

Infections with a predominantly encephalitic, rather than meningitic, syndrome typically cause focal neurological and neuropsychological deficits as well as a variably severe impairment of consciousness. Encephalitis, like meningitis, can be of viral, bacterial, fungal, protozoal, or parasitic origin. Prion diseases are a special category of encephalitis.

These infectious processes often involve other structures in the nervous system simultaneously with the brain (e.g., the peripheral nerves and plexuses, nerve roots, spinal cord, and meninges). In particular, the three important clinical varieties of spirochetal infection (syphilis, borreliosis, and leptospirosis) often present initially with meningitic or polyradiculitic and polyneuritic manifestations.

General signs and symptoms of an encephalitic syndrome are:

Image fever,

Image headache,

Image impairment of consciousness,

Image personality changes and neuropsychological abnormalities,

Image epileptic seizures,

Image focal neurological deficits.

Viral Encephalitis

Herpes Simplex Encephalitis

Herpes simplex encephalitis is a serious infectious condition caused by the herpes simplex virus, type I.

Pathogenesis. This viral disease is characterized by hemorrhagic–necrotic inflammation of the basal portions of the frontal and temporal lobes, combined with severe cerebral edema. The inflammatory foci are found in both hemispheres, but one is usually more strongly affected than the other.

Clinical manifestations. After a nonspecific prodromal phase with fever, headache, and other general symptoms, the disease presents with progressive impairment of consciousness, epileptic seizures (usually of complex partial type, with or without secondary generalization, because of the temporal localization of the disease), and focal neurological and neuropsychological deficits, particularly impairment of memory and orientation. Aphasia and hemiplegia may ensue.

Diagnostic evaluation. CSF examination reveals up to 500 cells/mm3, mainly lymphocytes but also granulocytes; the CSF is sometimes bloody or xanthochromic. Viral DNA can be identified in the CSF by the polymerase chain reaction (PCR) in the first few days of illness and, two weeks later, IgG specific for herpes simplex virus can be identified in the CSF as well. The EEG, in addition to nonspecific changes, may reveal characteristic focal findings over one or both temporal lobes. The CT scan is usually normal at first but, within a few days, reveals temporal or frontal hypodense areas, which may contain foci of hemorrhage (Fig. 6.28). MRI may reveal corresponding signal changes even earlier.

Image

Fig. 6.28 Herpes simplex encephalitis affecting both temporal lobes.

Treatment. Acyclovir is given intravenously. Corticosteroids are given to combat cerebral edema and antiepileptic drugs to prevent seizures.

Image If there is good reason to suspect herpes simplex encephalitis (progressive impairment of consciousness, aphasia, epileptic seizures [particularly of the complex partial type], an inflammatory CSF profile, focal EEG abnormalities), intravenous acyclovir therapy must be started immediately.

Early Summer Meningoencephalitis (ESME)

This disease is caused by an arbovirus and transmitted by tick bites. In endemic areas (e.g., Austria and southern Germany), it affects one in every 100 to 1000 tick-bite victims. After an incubation period of one to four weeks, in which there are nonspecific prodromal manifestations such as fever and flulike or gastrointestinal symptoms, about 20% of patients develop headache, meningism, and focal neurological deficits referable to the brain and spinal cord. Peripheral nerve deficits may also appear some time later. When the patient has recovered from the acute illness, residual paresis and, less commonly, neuropsychological deficits may remain. The essential diagnostic test is the demonstration of virus-specific IgM antibodies. ESME can be effectively prevented by exposure prophylaxis (adequate clothing in endemic forest areas) and active immunization. Immune serum given within 48 hours of a tick bite is protective.

HIV Encephalitis and Opportunistic Infections in HIV-positive Persons

Nearly 50% of persons infected with HIV have a clinically evident infection of the brain or other parts of the nervous system at some point in the course of their illness. The nervous system can be infected with HIV itself, other, opportunistic pathogens, or both. In severe cases, patients may suffer from encephalitis, myelopathy, mono- and polyneuropathy, and/or myopathy. Encephalitis presents with neuropsychological abnormalities including delirium, personality change, and dementia.

Other Types of Viral Encephalitis

Herpes zoster encephalitis is accompanied by a segmental vesicular rash in the territory of a peripheral nerve (cranial nerve). CSF examination reveals lymphocytic pleocytosis up to 200 cells/mm3. The disease may appear in particularly severe form after a generalized herpes zoster infection.

Rarer types. Other, rarer viruses causing meningoencephalitis, some of which are specific to particular regions, are listed in Table 6.16 in addition to those already discussed. Fig. 6.29 concerns one such virus (papova-virus encephalitis in an HIV-positive man).

Image

Image

Image

Fig. 6.29 Asymmetrical encephalitis, probably due to papova-virus, in a 42-year-old, HIV-positive man. MRI reveals involvement of the occipital lobes bilaterally.

Fungal, Parasitic, and Protozoal Encephalitis

Some of the fungi mentioned above as causes of meningitis can also cause encephalitis. In persons with normal immune competence, encephalitis can be caused by Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis. Persons with reduced immune competence due to disease or pharmacotherapy may develop encephalitis due to any of these or to Candida, Aspergillus, or Zygomycetes. Parasites,particularly Toxoplasma gondii, and protozoa (amebae, Plasmodia, trypanosomes, cysticerci, and echinococci) can also infect the brain.

Spirochetal (Meningo-)encephalitis

Neurosyphilis

Etiology. Syphilis is caused by the sexually transmitted spirochete, Treponema pallidum.

Clinical manifestations. Hematogenous spread of treponemes in the secondary phase of syphilis may lead to meningeal irritation or early syphilitic meningitis with cranial nerve palsies (basal meningitis).

In the tertiary phase (usually one or two years after the primary infection and secondary seeding of treponemes), cerebrospinal syphilis mainly affects the mesenchymal structures (blood vessels, meninges) of the brain and, often, the spinal cord. Inflammatory changes of vascular walls, particularly in the arteries of the skull base and the middle cerebral a., cause stenoses and multiple ischemic strokes. Meningitis,mainly in the region of the skull base, presents with fluctuating headache and cranial nerve palsies. Occasionally, tertiary syphilis gives rise to polyneuropathic and polyradicular manifestations. In the rare gummous variant of tertiary syphilis, large granulomatous masses may form within the cranial cavity, producing mass effect and intracranial hypertension.

In the quaternary phase of syphilis, the inflammatory process extends into the parenchyma of the brain and spinal cord, producing tabes dorsalis (spinal cord involvement) and/or progressive paralysis (chronic meningoencephalitis).

Tabes dorsalis appears in 7% of untreated syphilitics eight to 12 years after the primary infection. It is characterized, above all, by progressive degeneration of the posterior columns and posterior roots. Its clinical manifestations include progressively severe ataxia, lancinating pains, bladder dysfunction, diminished reflexes, loss of pupillary reactivity (p. 193), diminished sensitivity to pain, hypotonia of the musculature, and joint deformities.

Progressive paralysis appears 10–15 years after the primary infection and is caused by parenchymal meningoencephalitis with formation of caseating granulomas. Its major clinical sign is progressive dementia, with typical features including impaired judgment, lack of social inhibition, and, in some patients, expansive agitation (megalomania, nonsensical and delusional ideas). In other cases, patients may develop flattening of drive and affect, become depressed, or manifest schizophreniform phenomena (hallucinations, paranoia).

The two late forms of neurosyphilis can also be present in combination.

Diagnostic evaluation. The diagnosis of neurosyphilis is established by various serologic tests: the TPHA and FTA–ABS tests for the demonstration of previous contact with Treponema pallidum, the VDRL test for the assessment of current disease activity (though this test is not specific for Treponema pallidum), and the 19-S-IgM–FTA–ABS test for the demonstration of treponeme-specific IgM antibodies, which indicate an active or florid infection. Neurosyphilis also causes an inflammatory CSF picture with elevated leukocyte count and protein concentration, a positive VDRL test in the CSF, and an elevated CSF concentration of treponeme-specific IgG.

Treatment. All forms of neurosyphilis are treated with penicillin G; if the patient is allergic to penicillin, tetracycline or erythromycin can be given instead. The success of treatment depends on the time at which it is begun: improvement is less likely if the brain and spinal cord parenchyma have already sustained considerable damage.

Prognosis. The prognosis of early syphilitic meningitis is good. In the other phases of neurosyphilis, progression can be prevented by appropriate treatment, but residual deficits are common.

Neuroborreliosis

Etiology. Borreliosis is caused by Borrelia burgdorferi, a spirochete transmitted by bites of the tick Ixodes ricinus.

Clinical manifestations. Borrelia burgdorferi can attack the nervous system, joints, cardiovascular system, liver, and skin. Its clinical manifestations are equally varied: after transfer of the organism by a tick bite, one-quarter of patients locally develop erythema chronicum migrans, a red, annular rash that expands centrifugally around the site of the tick bite, clearing in the central area as it grows outward. If the spirochetes are then disseminated systemically, headache, fever, arthralgia, and sometimes generalized lymphadenopathy will follow.

Fifteen percent of patients who reach this stage without treatment go on to develop neurological manifestations, typically lymphocytic meningitis combined with radiculoneuritis, causing weakness, very unpleasant, often burning, dysesthesia, and severe pain in the distribution of the affected nerve roots (Bannwarth syndrome). Cranial nerve involvement is also common and may cause facial diplegia, a condition that should always arouse suspicion of borreliosis. Less commonly, plexus neuritis, encephalitis, or myelitis can develop at this stage or later.

Other possible complications of advanced borreliosis are vasculitis of the cerebral vessels and, outside the central nervous system, myopericarditis, acrodermatitis chronica atrophicans, arthralgia, and liver involvement.

In the United States, borreliosis is commonly known as “Lyme disease,” after the town of Lyme, Connecticut, in which an outbreak was described.

Diagnostic evaluation. A clinical suspicion of neuroborreliosis can be supported, though not definitively confirmed, by the demonstration of specific IgG and, above all, IgM antibodies in the serum and cerebrospinal fluid.

Image Serologic testing for Borrelia is positive in at least 10% of asymptomatic individuals. Thus, the demonstration of antibodies against Borrelia is no reason to ascribe an unclear neurological condition to florid borreliosis.

The diagnosis of neuroborreliosis can only be made if there is an inflammatory CSF profile (elevated cell count and protein concentration, positive Borrelia titer in the CSF). A normal CSF profile makes the diagnosis questionable, even if the serologic tests are positive.

Treatment. If a borrelial infection is suspected after a tick bite (overt erythema chronicum migrans, flulike symptoms), doxycycline is given orally. In all later stages of the disease, third-generation cephalosporins (ceftriaxone, cefotaxime) are given intravenously.

Leptospirosis

Leptospirosis in its initial stage often causes acute lymphocytic meningitis. In a more advanced stage, there may be signs of encephalitis (epileptic seizures, delirious psychosis) or myelitis. The brain can also be damaged by vasculitis of the cerebral vessels. Outside the nervous system, leptospirosis can affect the liver (causing jaundice) and kidneys and cause a bleeding diathesis.

Encephalitis in Prion Diseases

Prions are infectious particles composed of protein that replicate within the body's cells even though they possess no genetic material (nucleic acids) of their own. They can arise in situ by mutation of the host's genetic material or reach the body from outside and incorporate themselves into its cells, where they replicate.

Neurons in the brain that have been infected by prions may die after a latency period of years or even decades. The typical pathological findings in prion infection are vacuolization and the formation of amyloid plaques (spongiform encephalopathy, SEP). The main prion diseases are Creutzfeldt–Jakob disease, kuru, Gerstmann–Strdussler–Scheinker syndrome, familial progressive subcortical gliosis, and familial fatal insomnia.

Image

Fig. 6.30 The progression of EEG changes over time in Creutzfeldt–Jakob disease. The diagnosis of CJD in this 57-year-old woman was later confirmed by autopsy. 6 weeks after the onset of the prodromal phase (10.1.79), only a hint of periodic activity is seen. It is fully developed 1 month later (11.1.79) and slowly declines in amplitude in the ensuing months.

Creutzfeldt–Jakob disease, the most common prion disease in Europe and North America, is nevertheless rare, with an incidence of about one case per million individuals per year. It presents initially with mental abnormalities, insomnia, and fatigability. Soon, progressive dementia develops, along with pyramidal tract signs, cerebellar signs, abnormalities of muscle tone, fasciculations, and myoclonus. In about two-thirds of patients, the EEG reveals characteristic, periodic triphasic and tetraphasic theta and delta waves (Fig. 6.30). The disease progresses rapidly, leading to a decorticate state and death within months of onset. A variant of Creutzfeldt–Jakob disease has attracted considerable attention in the past decade, particularly in the United Kingdom, because it is contracted by eating beef derived from cows with bovine spongiform encephalopathy (BSE, “mad cow disease”).

Slow virus diseases

The slow virus diseases are characterized by extremely long incubation periods, a protracted, chronically progressive course, and little or no response to treatment. SSPE is the most common slow virus disease.

Subacute sclerosing panencephalitis (SSPE) usually arises in children who had measles in their infancy. The virus persists in the central nervous system and, years later, gives rise to a disease of insidious onset and chronically progressive course, leading to death in two to three years. The initial presentation is with mental abnormalities such as irritability, fatigability, and impaired cognitive performance. Involuntary movements and noise-induced myoclonus appear a few weeks later. Finally, the child develops generalized spasticity and severe, progressive dementia. The EEG reveals periodic, high-amplitude slow waves. The illness is always fatal.

Other illnesses whose pathogenetic mechanisms are probably similar are progressive rubella panencephalitis and the various types of encephalitis arising a few days or weeks after an infectious illness (measles, mumps, chickenpox, rubella).

Postvaccinal encephalitis. It has been hypothesized, but never proved, that encephalitis can rarely arise as a complication of vaccination against measles, rubella, or smallpox.

Intracranial Abscesses

Brain abscesses are produced by focal infection of the brain parenchyma leading to tissue destruction and pus formation. They can be solitary or multiple. A special form is focal encephalitis, in which systemic sepsis or the embolization of infectious material into the central nervous system gives rise to multilocular, disseminated microabscesses.

Brain Abscess

Etiology. Brain abscesses are caused by one or more pathogens, mainly streptococci and staphylococci and, less commonly, Pseudomonas, Actinomyces, and fungi. Like the organisms that cause bacterial meningitis, these pathogens can reach the brain through local extension of infection (especially mastoiditis, sinusitis, and otitis), hematogenous dissemination from a distant infectious focus (usually pulmonary infections or endocarditis), or direct contamination (open brain injury). Immunocompromised patients are at increased risk.

Clinical manifestations. A large brain abscess exerts mass effect and typically causes fever, leukocytosis, and rapidly progressive intracranial hypertension. Marked perifocal edema generally adds to the mass effect.

Alternatively, there may be a subdural empyema between the dura mater and the arachnoid, or an epidural abscess between the dura mater and the inner table of the skull. These processes usually arise as a complication of sinusitis or otitis, less commonly after trauma. Fever, headache, and meningism, accompanied by neurological deficits, are their clinical hallmarks. The course of subdural empyema is often fulminant and life-threatening, that of epidural abscess usually more protracted.

Diagnostic evaluation. The diagnosis is suspected on the basis of the typical clinical findings (intracranial hypertension with papilledema, impaired consciousness, sometimes hemiparesis or other focal neurological deficits), accompanying signs of infection (fever, elevated laboratory parameters of inflammation), and relevant aspects of the past medical history (such as traumatic brain injuries, known lung or heart disease, and immune suppression or diseases of the immune system). CSF examination may reveal inflammatory changes (predominantly granulocytic pleocytosis, elevation of total protein), and the CT or MRI scan shows a ring-shaped area of contrast enhancement (abscess wall) surrounding the hypodense interior of the abscess.

Treatment. Operative removal of the abscess is the preferred form of treatment in most patients, accompanied by antibiotic therapy, which is initiated before surgery and continued thereafter for at least six weeks.

Focal Encephalitis

Etiology. Focal encephalitis consists of multilocularfoci of infection in the brain parenchyma (Fig. 6.31), produced either by the seeding of the brain with bacteria in generalized sepsis {metastatic focal encephalitis) or by the embolization of multiple infectious microthrombi into the cerebral vasculature (embolicfocal encephalitis). The latter is usually a complication of subacute bacterial endocarditis, which, in turn, is most often caused by Streptococcus viridans. In contrast, the septic form may be secondary to purulent infection in practically any area of the body. Streptococcal and staphylococcal infections are the usual causes.

Image

Fig. 6.31 Embolic focal encephalitis and brain abscesses (T1-weighted MRI after the administration of contrast medium).

Clinical manifestations. The typical findings include signs of a generalized septic illness (high fever, rigors) combined with focal brain signs, impaired consciousness, and, not uncommonly, psychosis. The neurological and psycho-organic signs fluctuate in severity. They manifest themselves in bouts, with remissions in between.

Image A septic illness accompanied by fluctuating mental status on neurological abnormalities should raise suspicion of focal encephalitis.

Diagnostic evaluation. The diagnosis is suspected from the clinical findings and, possibly, inflammatory CSF changes, and confirmed by a CT and/or MRI scan demonstrating multiple small lesions in the brain. A heart murmur should always be listened for. Blood should be drawn for culture during the upward phase of the fever curve, and during rigors; blood culture may reveal the responsible pathogen.

Treatment. Antibiotic therapy is indicated and should be tailored to the sensitivity profile of the responsible organism, if it can be identified.

Image  Metabolic Disorders and Systemic Illnesses Affecting the Nervous System

The intense metabolic activity of the nervous system (both central and peripheral) makes it vulnerable to damage by a wide variety of metabolic disorders, both congenital (inborn errors of metabolism, i. e., metabolic diseases in the narrower sense of the term) and acquired (e.g., toxic). These disorders manifest themselves clinically as metabolic encephalopathy and metabolic neuropathy, of which there are many different types. Involvement of the nervous system by general medical illnesses (e.g., endocrinopathy or vasculitis) and paraneoplastic syndromes affecting the nervous system can present in similar ways.

Congenital Metabolic Disorders

Metabolic diseases are caused by hereditary enzyme defects. They usually present in early childhood but sometimes not until many years later. They can be roughly divided into disorders of lipid, amino acid, and carbohydrate metabolism. Wilson disease is due to a disturbance of copper metabolism.

General clinical manifestations. The following findings in children and adolescents suggest the presence of a metabolic disease:

Image delayed motor and cognitive development,

Image a slowly worsening course,

Image progressive spasticity,

Image progressive dementia,

Image optic nerve involvement,

Image epileptic seizures,

Image accompanying polyneuropathy and myopathy,

Image a positive family history of similar manifestations.

Diagnostic evaluation. In general, the diagnostic workup includes:

Image the taking of a comprehensive family and personal history,

Image a clinical neurological (neuropediatric) examination,

Image amino acid screening of the urine,

Image measurement of the serum concentration of glucose, ammonia, lactate, and pyruvate and screening for the lysosomal enzymes arylsulfatase A, hexosaminidase, and α-galactosidase,

Image light- and electron-microscopic examination of biopsied tissue samples, with routine and special stains,

Image radiologic examination of the skeleton,

Image MRI of the brain.

Disorders of Lipid Metabolism

Lipid storage diseases are caused by faulty enzymatic degradation of individual lipid substances, leading to deposition of the intermediate products of lipid metabolism in various internal organs (liver, spleen, bone marrow) and in the nervous system. Disorders in which these nondegradable metabolites accumulate mainly in the neurons of the brain are characterized by degeneration of the cerebral cortex or of the subcortical nuclear areas (lipidoses); disorders in which they accumulate mainly in white matter are characterized by demyelination of the cerebral white matter and/or peripheral nerve sheaths (leukodystrophies). The lipid storage diseases affecting the nervous system are listed in Table 6.17. Two examples of the radiologic appearance of the brain in the leukodystrophies are shown in Fig. 6.32.

Disorders of Amino Acid and Uric Acid Metabolism

The more common disorders of these types include phenylketonuria (an autosomal recessive disorder of amino acid metabolism), maple syrup urine disease, Hartnup disease, and homocysteinuria (Table 6.18).

Disorders of Carbohydrate Metabolism

These disorders include the monosaccharidoses (e.g., galactosemia), the glycogenoses, and the mucopolysaccharidoses (Table 6.19). Myoclonus epilepsy, a type of mucopolysaccharidosis, is characterized by generalized epileptic seizures, myoclonus, and dementia.

Disorders of Copper Metabolism

A disturbance of copper metabolism causes hepatolenticular degeneration (Wilson disease), an autosomal recessive disorder whose genetic locus lies on the long arm of chromosome 13. The concentration of the copper transport protein ceruloplasmin is abnormally low and, as a result, the serum free copper concentration is high and an abnormally large amount of copper is eliminated in the urine. Free copper is deposited in the liver, the edge of the cornea (producing the typical Kayser–Fleischer ring), and the brain. Hepatopathy dominates the clinical picture in childhood and the neurological manifestations come later; the most impressive of these is a coarse postural and intention tremor of the extremities (recognizable on extension of the arms to both sides, for example, as a “flapping tremor”). Dysarthria, dystonia, and rigidity are common, as are mental abnormalities (depression, personality changes, or even psychotic episodes). The Kayser–Fleischer ring, a brown ring around the periphery of the cornea, helps to establish the diagnosis. MRI reveals cortical atrophy, enlarged ventricles, and signal abnormalities in the basal ganglia. This disorder is treated with D-penicillamine or zinc sulfate.

Image

Fig. 6.32 Leukodystrophies (T2-weighted MRI images), a MRI in an 8-year-old boy: symmetrical, diffuse signal abnormalities in the white matter of the occipital and parietal lobes. b MRI in a 43-year-old man: symmetrical signal abnormalities in white matter.

Table 6.17 Lipidoses and leukodystrophies affecting the nervous system

Diseases

Clinical features

Remarks

 

Lipidoses

GM1 -gangliosidoses
 and

GM2-gangliosidoses

infantile progressive encephalopathy, progressive myopathy in adults; possibly myoclonus, convulsions, visual impairment, progressive spasticity and dementia; muscle atrophy and progressive weakness

galactosidase deficiency in GM1-gangliosidoses; hexosaminidase deficiency in GM2-gangliosidoses, including Tay–Sachs disease and Sandhoff disease, with characteristic cherry-red spot

Fabry disease (angiokeratoma corporis diffusum)

onset of symptoms in childhood or adolescence; burning pain in the limbs, particularly in warm surroundings; deficient sweating; maculopapular, purplish-red skin changes; renal failure; frequent cerebrovascular accidents

X-linked inheritance; α-galactosidase deficiency with intracellular accumulation of trihexosylceramides

Gaucher disease juvenile and adult forms

diverse neurological manifestations, gaze paresis, bulbar signs, spasticity, polyneuropathy, psychosis, dementia, myoclonus, epileptic seizures

autosomal recessive inheritance, glucocerebrosidase deficiency; foam cells in bone marrow

Niemann–Pick disease

progressive developmental delay beginning in the first year of life; juvenile forms with encephalopathy or hepatomegaly, progressive dementia, spasticity, and ataxia as well as epileptic seizures and psychosis

autosomal recessive inheritance; genetic defect in Ashkenazi Jews

Refsum disease (heredopathia atactica polyneuritiformis)

onset of symptoms in middle age; night blindness due to retinitis pigmentosa, hearing loss, polyneuropathy with areflexia and gait ataxia; mental abnormalities

lack of phytanic acid α-dehydrogenase, accumulation of phytanic acid in the body (liver, kidneys, nervous system); a low-phytanic-acid diet and plasmapheresis are effective treatments

Cerebrotendinous xanthomatosis(cholestanol storage disease)

onset of symptoms in adolescence or later; mental retardation; juvenile cataracts, progressive spasticity and ataxia; xanthomas, particularly on extensor tendons and Achilles' tendons; polyneuropathy and muscle atrophy

autosomal recessive inheritance; impaired synthesis of bile acids; accumulation of cholestanol in plasma and brain, tendon xanthomas

Neuronal ceroid lipofuscinosis(Batten–Kufs disease)

presentation in infancy and early childhood (Spielmeyer–Vogt type) or in adulthood (Kufs disease); ataxia, myoclonus, epileptic seizures, progressive visual loss and mental deterioration

 
 

Leukodystrophies: Metachromatic leukodystrophy

late infantile type: from the age of 1 year onward, spastic weakness progressing toward quadriplegia, loss of mental function, areflexia, bulbar and pseudobulbar signs, optic atrophy;

juvenile type: presentation at age 2–10 years, elevated CSF protein, white matter hypodense in CT and hyperintense in T2-MRI

autosomal recessive inheritance; lack of arylsulfatase A; accumulation of sulfatide in the brain, peripheral nerves, and other tissues; demonstration of arylsulfatase A deficiency in leukocytes and urine

Globoid cell leukodystrophy (Krabbe disease)

infantile, juvenile, and adult types; spasticity, optic atrophy, and polyneuropathy

lack of galactocerebrosidase

Table 6.18 Disorders of amino acid and urate metabolism

Disease

Clinial features

Remarks

 

Phenylketonuria

clinical manifestations from the age of 6 months onward, if untreated: mental retardation, epileptic seizures, spasticity, tremor, hypopigmentation

autosomal recessive inheritance; lack of hydroxylation of phenylalanine to tyrosine; treated with a low-phenylalanine diet; neonatal screening (Guthrie test)

Maple syrup urine disease

presentation in the neonatal period: impaired alertness, diminished muscle tone, mental retardation

impaired degradation of branched amino acids; sweet-smelling urine (like maple syrup)

Hartnup disease

bouts of pellagralike dermatitis, accompanied by episodes of ataxia, nystagmus, and gait unsteadiness, progressive dementia, and spasticity

impaired tubular and intestinal resorption of tryptophan; aminoaciduria

Homocysteinuria

arterial and venous thromboembolism, lens ectopy mental retardation

impairment of methionine metabolism

Table 6.19 Disorders of carbohydrate metabolism

Disease

Clinial features

Remarks

 

Galactosemia

onset in infancy: failure to thrive, retardation, jaundice, cataracts

impaired enzymatic degradation of galactose; accumulation of the phosphorylated form in the liver, kidneys, lenses, and brain

Glycogenoses, types I–XI

accumulation of glycogen in the liver, kidneys, muscles, and brain; clinically, hepatic dysfunction, possibly myopathy, mental retardation, epileptic seizures

impaired enzymatic degradation of glycogen

Mucopolysaccharidoses

Pfaundler–Hurler syndrome:

onset in infancy, corneal opacification, joint swelling, dwarfism, mental retardation, possibly quadriparesis due to spinal cord compression

Scheie syndrome:

juvenile type, with slow progression

Progressive myoclonus epilepsy (Lafora type): generalized epileptic seizures, myoclonus, progressive dementia, psychosis

deposition of acidic mucopolysaccharides in various tissues, due to hydrolase deficiency deposition of mucopolysaccharides in the form of Lafora bodies in the brain, muscles, and liver

Other Metabolic Disorders

A number of other metabolic disorders must be mentioned here for completeness, some of which are of as yet unknown causes. Adrenoleukodystrophy is due to an inherited defect of the X chromosome, which causes a deficiency of lignoceroyl coenzyme A synthetase. Most patients are male. In the first or second decade of life, they develop spastic gait disturbances, visual impairment, and mental changes. Affected adults may develop adrenal insufficiency. In adrenomyeloneuropathy, the same manifestations are present, with polyneuropathy in addition. Reye syndrome is probably of multifactorial origin. A few days after a viral illness, the patient becomes progressively somnolent, with nausea, delirium, and cerebral edema. In the various types of α-lipo-proteinemia, the serum cholesterol and triglyceride levels are abnormally low. These disorders are clinically characterized by ataxia, nystagmus, disturbances of eye movement, and polyneuropathy, in combination with retinitis pigmentosa. These manifestations are often accompanied by acanthocytosis (Bassen–Kornzweig). Intoxications of the nervous system are classified according to their clinical presentation in Table 6.20, which also includes iatrogenic intoxications.

Acquired Metabolic Disorders

Intoxications

Medications, recreationally used substances, drugs of abuse, industrial toxins, and numerous other substances can exert a toxic influence on the nervous system.

Alcohol-induced Disorders of the Nervous System

Because of their importance in clinical practice, the effects of alcohol on the nervous system are listed in detail in a separate table (Table 6.21).

Table 6.20 Neurological manifestations of toxic or iatrogenic origin

Neurological signs and syndromes

Causes

 

Headache

nearly all headache preparations when overused; withdrawal of caffeine, ergotamine, or amphetamine; oral contraceptives and other hormone preparations (pseudotumor cerebri); nitrates, aminophylline, tetracycline, sympathomimetics, IV immunoglobulins, tamoxifen, H2-antagonists

Ischemic stroke

oral contraceptives and other hormone preparations, antihypertensive agents, ergotamine, amphetamine, cocaine, sympathomimetics, intra-arterial methotrexate, angiography, interventional intra-arterial procedures, cardiovascular surgery, radiotherapy, fat injection (“liposculpturing”), chiropractic manipulation

Hemorrhage (intracerebral, extracerebral, spinal)

anticoagulants, fibrinolytic agents, inhibitors of platelet aggregation, amphetamine, cocaine, sympathomimetics; femoral nerve palsy due to psoas hematoma

Epileptic seizures

antibiotics (penicillin, isoniazid), general and local anaesthetics (e.g., lidocaine), insulin, radiological contrast media, withdrawal of benzodiazepines or other sedatives, anticonvulsant withdrawal, phenytoin overdose, antidepressants, aminophylline and theophylline, phenothiazines, pentazocine, tripelennamine, cocaine, meperidine, cyclosporine, antineoplastic agents, other

Coma

insulin, barbiturates, benzodiazepines and other sedatives, analgesics, other

Neurasthenic symptoms, acute and chronic encephalopathy

heavy metals, lithium, aluminum, heroin pyrolysate, cyclosporine, anticholinergics, dopamine agonists, benzodiazepines and other sedatives, antihistamines, antibiotics, anticonvulsants, corticosteroids, H2-antagonists, disulfiram, methotrexate, organic solvents, hallucinogens, radiotherapy, dehydration, water intoxication, dialysis encephalopathy, other

Extrapyramidal movement disorders (acute dystonia, dyskinesia, akathisia, drug-induced parkinsonism, tardive dyskinesia)

neuroleptics (phenothiazines, thioxanthenes, butyrophenones, dibenzapines), antiemetics containing metoclopramide or phenothiazines, dopamine agonists, levodopa, antihypertensive agents (e. g., reserpine, captopril), flunarizine, cinnarizine, MPTP

Cerebellar ataxia

phenytoin, carbamazepine, barbiturates, lithium, organic solvents, heavy metals, acrylamide, 5-fluorouracil, cytosine arabinoside, procarbazine, hexamethylmelamine, vincristine, cyclosporine, ciguatera fish poisoning

Central pontine myelinolysis

too rapid correction of hyponatremia

Malignant neuroleptic syndrome

neuroleptics

Malignant hyperthermia

succinylcholine, halothane, other general anaesthetics

Polyneuropathy

see p. 176 ff.

Optic neuropathy

tobacco, ethanol, methanol, myambutol

Deafness

aminoglycosides, cytostatic agents

Disorders of neuromuscular transmission

penicillamine, muscle relaxants, procainamide, magnesium, quinine, aminoglycosides, α-interferon

Myopathy and rhabdomyolysis

ethanol, cocaine, heroin and other opiates, pentazocine, benzene, corticosteroids, thyroxine, antimalarial agents, colchicine, antilipid agents (fibrates and statins), zidovudine, cyclosporine, diuretics (via hypokalemia), ipecac

Table 6.21 Effects of alcohol on the nervous system

Clinical condition

Features

Remarks

Acute alcohol intoxication

euphoria, dysphoria, disinhibition, ataxia, somnolence, stupor

respiratory arrest may cause death

Alcohol withdrawal syndrome, delirium tremens

diaphoresis, tachycardia, insomnia, tremor, hallucinations, epileptic seizures, psychomotor agitation, possibly delirium

when the patient's alcohol intake is cut off, the blood alcohol level falls and the patient passes through the stages of alcohol withdrawal syndrome, from mild autonomic symptoms to predelirium and delirium; full delirium (delirium tremens) is the most severe form of the alcohol withdrawal syndrome; treated with clomethiazole

Alcoholic dementia

chronic alcohol abuse with systemic effects on the liver and peripheral nervous system

brain atrophy, visible in CT and MRI, reversible with abstinence

Wernicke encephalopathy

memory impairment, confusion, oculomotor dysfunction (abducens palsy, nystagmus, conjugate gaze palsy), ataxia, dysarthria

signal abnormalities around the cerebral aqueduct and third ventricle in T2-weighted MRI; caused by thiamine deficiency and malnutrition; often combined with Korsakoff psychosis

Korsakoff syndrome

acute amnestic syndrome with anterograde and retrograde amnesia, confabulation, reduced drive, and reckless behavior

thiamine deficiency; seen also in nonalcoholics

Marchiafava–Bignami syndrome

acute confusion, epileptic seizures, impairment of consciousness; demyelination of corpus callosum and centrum semiovale; patients who survive the acute phase are often abulic and demented

predominantly seen in Italian drinkers of red wine

Alcoholic cerebellar degeneration

progressive limb ataxia mainly affecting the lower limbs, with impairment of gait

 

Central pontine myelinolysis

confusion, followed within a few days by dysphagia, dysarthria, quadriparesis with pyramidal tract signs, and oculomotor disturbances (bilateral abducens palsy or horizontal conjugate gaze palsy); progressive impairment of consciousness, later development of the locked-in syndrome

seen in malnourished chronic alcoholics, also as an iatrogenic process after excessively rapid correction of hyponatremia; also in liver disease

Alcoholic polyneuropathy

predominantly sensory polyneuropathy, often painful; distal sensory deficit in the lower limbs, loss of reflexes

 

Fetal alcohol syndrome (alcohol embryopathy)

caused by maternal alcoholism; short stature, psychomotor retardation, microcephaly, facial dysmorphism (stub nose, thin lips, micrognathism)

 

Endocrine Diseases

Neurological manifestations often accompany dysfunction of the endocrine glands, particularly the thyroid gland, the parathyroid glands, the pancreatic islet cells, and the adrenal gland.

Hypothyroidism causes cretinism in infants, mental retardation and short stature in children. In adults, it can cause ataxia, dysarthria, and nystagmus, a predominantly sensory polyneuropathy, and muscle weakness, with characteristically delayed relaxation of muscle fibers after elicitation of the deep tendon reflexes. Mental abnormalities may also be present (apathy, depression, dementia, delirium).

Table 6.22 Clinical manifestations of hypoglycemia

Autonomic manifestations

Dizziness, diaphoresis, nausea, pallor, palpitations, precordial pressure, abdominal pain, hunger, anxiety, headache

Cerebral manifestations

Image paresthesiae, blurred vision, diplopia, tremor, unusual or abnormal behavior

Image epileptic seizures: simple partial, complex partial, or generalized

Image impairment of consciousness ranging from somnolence to coma

Image focal neurological deficits, e. g., hemiparesis, hemianopsia, aphasia, apraxia

Permanent neurological deficits (after prolonged or repeated episodes of hypoglycemia)

Image cognitive deficits, dementia

Image cognitive deficits of focal type, focal neurological deficits

Image mainly distal muscular atrophy due to damage of anterior horn cells and axons

Hyperthyroidism can produce, in addition to its characteristic general manifestations (nervousness, insomnia, tremor, sweating, tachycardia, diarrhea, heat intolerance), a variety of neurological deficits:

Image cerebral manifestations: irritability, psychotic episodes, tremor, choreoathetosis, spastic elevation of muscle tone, pyramidal tract signs;

Image ocular manifestations: diminished frequency of blinking (Stellwag sign), ophthalmoplegia, diplopia, optic neuropathy; in Graves disease, lid retraction (Graefe sign), weakness of convergence (Mobius sign), exophthalmos;

Image muscular manifestations: thyrotoxic myopathy with mainly proximal weakness, myasthenia gravis, and thyrotoxic periodic paralysis;

Image partial and generalized epileptic seizures;

Image rarely, polyneuropathy.

Hypoparathyroidism. A deficiency of parathyroid hormone causes hypocalcemia, leading to tetany, epileptic seizures, intracranial hypertension with headache and papilledema, hypomotor and hypermotor movement disorders, and neurastheniform mental manifestations and delirium.

Hyperparathyroidism. An excess of parathyroid hormone manifests itself clinically mainly through behavioral disturbances (emotional lability, agitation, fatigability, and confusional states) and dementia-like cognitive impairment,in addition to muscle weakness, ataxia, dysarthria, and sometimes spasticity and epileptic seizures.

Disturbances of insulin metabolism. Hyperinsulinism is one of the possible causes of hypoglycemia, which causes the neurological manifestations listed in Table 6.22. The most prominent neurological manifestation of the insulin deficiency of diabetes mellitus is polyneuropathy (see p. 176); in addition, diabetic arteri-opathy may secondarily harm the nervous system (ischemic stroke, mononeuropathies of peripheral or cranial nerves).

Gastrointestinal Diseases

Gastrointestinal diseases can cause toxic damage to the nervous system (e.g., in hepatic dysfunction). The nervous system can also be harmed by secondary nutritional deficiencies and hypovitaminoses(e.g., in stomach diseases and intestinal resorptive disorders).

Neurological manifestations are commonly seen in hepatic diseases, particularly chronic hepatopathy with portal hypertension, and a portacaval shunt. Ammonia and other toxic substances bypass the portal circulation, enter the systemic circulation, and are transported to the brain, where they cause hepatic encephalopathy. This disorder is characterized at first by somnolence and apathy, later by progressive impairment of consciousness and delirium. As in renal insufficiency, asterixis can be seen (see below). In addition, there may be spasticity, with exaggerated deep tendon reflexes and pyramidal tract signs.

Other gastrointestinal diseases. In sprue, impaired intestinal resorption can cause malnutrition, which in turn causes polyneuropathy and cerebellar ataxia (vitamin B12 deficiency). The gliadin antibodies that are present in sprue are also often associated with ataxia. Crohn disease may be accompanied by myelopathy and muscle weakness, while ulcerative colitis may be accompanied by peripheral neuropathy.

Hematologic Diseases

Hematologic diseases can alter the viscosity and coagulability of the blood, putting the patient at risk of thrombosis or hemorrhage. They can also alter its transport properties (quantitative and structural anomalies of the blood cells or plasma proteins). Finally, some hematologic diseases involve malignant neoplasia of certain types of blood cells. All of these phenomena can have damaging effects on the nervous system.

Anemia reduces the oxygen-carrying capacity of the blood and can lead to cerebral hypoxic (ischemic) manifestations. The vitamin B12 deficiency of untreated pernicious anemia causes funicular myelosis (p. 153) and polyneuropathy (cf. Table 10.1p. 176).

Polycythemia vera is associated with headache, dizziness, and paresthesiae, as well as ischemic stroke and extrapyramidal manifestations.

Leukemia often leads to cerebrovascular complications (hemorrhage, infarct, venous sinus thrombosis). One-third of leukemia patients have a meningeal leukemic infiltrate (leukemic meningitis). Leukemic infiltrates can cause various kinds of focal deficits of the central and peripheral nervous system.

Collagen Diseases and Immune Diseases

Collagenoses affect not only the skin, joints, and internal organs, but also the nervous system. Secondary damage of nervous tissue (ischemia and/or hemorrhage) occurs because of inflammatory changes of the blood vessels of the brain, spinal cord, and peripheral nerves (vasa nervorum). These vascular changes are mostly produced by autoimmune mechanisms.

In this section, we will merely list the neurological manifestations of the main types of collagen disease. More detailed discussions can be found in textbooks of internal medicine.

Image Though collagen diseases and vasculitic conditions are I only briefly discussed in this book, the clinician must keep them in mind when formulating the differential diagnosis of practically any condition with neurological manifestations.

Collagen diseases are diagnosed by their typical clinical manifestations, the demonstration of specific (auto-)antibodies in the serum, and further evidence derived from angiography or from biopsies of tissue and/or blood vessels.

Periarteritis nodosa. In the nervous system, this disease causes polyneuropathy and mononeuropathies and, less commonly, focal deficits of the central nervous system or epileptic seizures.

Churg–Strauss syndrome. The main clinical manifestations of this disorder, closely related to periarteritis nodosa, are bronchial asthma and eosinophilia; polyneuritis is the main neurological manifestation.

GANS (granulomatous angiitis of the central nervous system) is a vasculitic disorder, restricted to the cerebral vessels, that causes multiple thrombotic strokes.

Temporal arteritis. Intractable headache is the main symptom of this disease. The temporal artery is thickened (at least on one side) and, in advanced disease, no longer pulsates. A more extensive discussion of this disease can be found on page 250.

Wegener granulomatosis is a systemic, necrotizing vasculitis that primarily involves the kidneys and the upper airways, but can also cause mononeuritis (of the cranial nerves as well) and focal manifestations in the central nervous system.

Systemic lupus erythematosus only rarely presents with neurological deficits, but more than half of all patients develop neurological and/or psychiatric manifestations as the disease progresses. The most common types are headache, neuropsychological deficits and behavioral abnormalities, focal neurological deficits, and spinal cord transection syndromes, followed by neuritis and myopathy.

Sarcoidosis (Boeck disease) is characterized by the formation of multiple granulomas in the lungs and other internal organs. Depending on their location, granulomas in the nervous system can cause chronic meningitis (p. 113), encephalitic manifestations (diabetes insipidus, hemiparesis, ataxia), cranial nerve palsies, or mononeuritis multiplex (p. 179).

Renal Failure and Electrolyte Disturbances

Electrolyte disturbances can impair the functioning of the brain (impairment of consciousness and/or cognition, generalized epileptic seizures) and of the neuromuscular junction (overexcitability, e.g., in tetany due to hypocalcemia; underexcitability, e.g., in disorders of potassium metabolism with episodic paralysis, see p. 271). Electrolyte disturbances, particularly those affecting sodium concentration, are often caused by renal failure. In renal disease, the pathological retention of substances normally excreted in the urine has further toxic effects.

Acute renal failure causes uremic encephalopathy, which is characterized by progressive impairment of concentration and short-term memory, followed by impairment of consciousness and delirium. These abnormalities of mental state are often accompanied by dysarthria, gait unsteadiness, and ataxia. Myoclonus and asterixis (bilateral, irregular back-and-forth movements of the fingers when the arms are extended; sometimes, analogous motor phenomena in other parts of the body as well) are seen in nearly all patients.

Chronic renal failure may lead to the development of polyneuropathy and “restless legs syndrome” (p. 261). Patients undergoing dialysis may develop the dialysis disequilibrium syndrome (nausea, agitation, delirium, convulsions). Those who have been treated with dialysis for a long time are at risk for dialysis encephalopathy (dialysis dementia), with dysarthria, ataxia, and convulsions.

Electrolyte disturbances. Disturbances of sodium concentration alter the serum osmolality and are the type of electrolyte disturbance most commonly causing neurological dysfunction. The neurological condition in such cases can be considered a type of metabolic encephalopathy. Hyponatremia and hypo-osmolality cause cerebral edema, which presents clinically with headache, nausea, impaired attention and concentration, epileptic seizures, and a progressive decline of consciousness. Hypernatremia and hyperosmolality lower the water content of the brain and, therefore, also its volume, and cause cognitive impairment and a progressive decline of consciousness. The generalized hyper-coagulable state characterizing these conditions may lead to venous sinus thrombosis. Alternatively, as the brain shrinks from loss of water, bridging veins may be torn, producing a subdural hematoma.

A rapid return of sodium concentration from below normal (hyponatremic) toward normal values is thought to be the cause of central pontine myelinolysis, i. e., bilaterally symmetrical demyelination of the white matter of the base of the pons. Clinically, the disorder presents with impairment of consciousness, dysphagia, dysarthria, and spastic quadriparesis, and sometimes oculomotor dysfunction (horizontal gaze paresis). Severe cases can cause the “locked-in syndrome” (p. 77) or decerebrate rigidity.

Disturbances of potassium, calcium, and magnesium balance, as well as hypophosphatemia, can affect muscular function, sometimes dramatically. Hypokalemia or hyperkalemia can cause flaccid paralysis of peripheral neurogenic type, as well as disturbances of myocardial excitability. Hypocalcemia or Hypomagnesemia causes tetany; hypercalcemia or hypermagnesemia causes metabolic encephalopathy with slowing, confusion, and impairment of consciousness. Hypophosphatemia causes peripheral weakness.

Malignancy

Malignant neoplasia can impair the functioning of the nervous system by direct tumor invasion, metastasis (p. 95), or long-distance humorally mediated effects (paraneoplastic syndromes).

Paraneoplastic effects can, in principle, occur in any type of malignancy, but are especially common in small-cell bronchial carcinoma. Paraneoplastic syndromes often become clinically evident while the primary tumor is still asymptomatic. They can predominantly affect the central nervous system, the spinal nerve roots, the peripheral nerves, or the muscles. They are diagnosed based on their clinical findings, combined with the identification of the responsible tumor; the diagnosis can be confirmed, in many patients, by the demonstration of more or less specific antineuronal antibodies. Nonetheless, paraneoplastic syndromes are still, in general, diagnoses of exclusion. Some of the paraneoplastic syndromes affecting the nervous system are listed in Table 6.23, together with the primary tumors that cause them.

Table 6.23 paraneoplastic syndromes affecting the nervous system

Syndrome/structure affected

Clinical features

Remarks

 

Paraneoplastic encephalomyelitis

affects the cerebral hemispheres, limbic system, brainstem, cerebellum, and spinal cord; limbic system involvement is prominent; confusion, agitation, hallucinations, anxiety, depression, epileptic seizures, pyramidal tract signs

occurs in small-cell bronchial carcinoma, less commonly in carcinoma of the breast, ovary, uterus, and other organs; there are subtypes that preferentially affect individual nervous structures, e.g., paraneoplastic myelitis, paraneoplastic retinopathy, opsoclonus–myoclonus syndrome, and stiff man syndrome

Paraneoplastic cerebellar degeneration

rapidly progressive cerebellar ataxia (weeks), disabling truncal and appendicular ataxia, dysarthria, nystagmus, and sometimes other neurological deficits

the most common paraneoplastic syndrome; actually a subtype of paraneoplastic encephalomyelitis; seen in small-cell bronchial carcinoma, ovarian carcinoma, Hodgkin lymphoma

Paraneoplastic polyneuropathy

sensory or, less commonly, sensorimotor polyneuropathy or mononeuropathy

mainly in lung carcinoma

Paraneoplastic syndromes of the neuromuscular junction: myasthenia gravis and Lambert-Eaton syndrome

myasthenic syndrome preferentially affecting the extraocular and bulbar musculature in myasthenia gravis and the limb muscles in Lambert–Eaton syndrome

thymoma (myasthenia gravis); mainly small-cell bronchial carcinoma (Lambert–Eaton syndrome)

Dermatomyositis, polymyositis

progressive muscle weakness; in dermatomyositis, skin changes also

tumors of the breast, lung, stomach, ovary, and intestine

Image  Diseases of the Basal Ganglia

Fundamentals

In general, diseases of the basal ganglia are characterized by either too much or too little movement impulse, movement automatism, and/or muscle tone (p. 18). The typical signs and symptoms of these diseases include:

Image an abnormality of movement (in all cases of basal ganglionic disease)

Image muscular hyper- or hypotonia (in most patients)

Image involuntary movements (often)

Image neuropsychological deficits (sometimes).

Elevated muscle tone is often combined with paucity of movement, while diminished muscle tone is often combined with an excess of movement. Thus, extrapyramidal syndromes can be broadly classified into:

Image hypertonic–hypokinetic syndromes and

Image hypotonic–hyperkinetic syndromes.

Diseases Causing Hypertonia and Hypokinesia

In hypertonic–hyperkinetic syndromes, elevated muscle tone is typically manifest as rigidity. Paucity of movement, depending on its severity, is termed either hypokinesia (= diminished movement) or akinesia (= complete lack of movement). A third so-called “cardinal manifestation,” tremor, is also commonly present. This clinical triad, called the parkinsonian syndrome (or parkinsonism), is typically found in idiopathic Parkinson disease. This disease, however, is only one possible cause of parkinsonism; there are many others besides, some of which have a clearly identifiable cause. Parkinsonism may be due to an underlying illness or condition other than idiopathic Parkinson disease (symptomatic parkinsonian syndromes). In addition, a number of systemic neurodegenerative diseases cause parkinsonism. These diseases are marked by a loss of neurons not only in the basal ganglia, but also in other areas of the CNS, and thus are clinically characterized not only by extrapyramidal manifestations, but also by neurological deficits localizable to other regions of the brain.

Idiopathic Parkinson Disease

Epidemiology. Parkinson disease has an overall prevalence of 0.15% and a mean age of onset of 55 years. Its age-specific prevalence rises with increasing age, to 1 % in persons over 60 and 3 % in persons over 80.

The etiology of idiopathic Parkinson disease is unknown. There are a number of rare conditions similar to idiopathic Parkinson disease that run in families (so-called hereditary Parkinson disease; one well-known variety is the Parkinson-dementia complex seen on the island of Guam). Though most cases of idiopathic Parkinson disease are sporadic, rather than familial, certain genetic factors do appear to play a role in its causation (above all the chromosome segments 2q, 6q, 4q, and 4p).

The neuropathological hallmark of idiopathic Parkinson disease is degeneration of the dopaminergic neurons of the substantia nigra and the locus ceruleus. Hyaline inclusion bodies, called Lewy bodies, are found within the degenerated neurons.

The loss of dopaminergic neurons leads to a degeneration of the nigrostriatal dopaminergic pathway and, therefore, to dopamine deficiency in the striatum. This, in turn, results in enhanced activity of striatal glutamatergic neurons, which produces the clinical manifestations of the disease.

Clinical manifestations. The clinical picture is typically characterized by:

Image hypokinesia, i. e., slowing of movement,

Image increased muscle tone,

Image abnormal body posture (stooped head and trunk, flexion at the knees),

Image impaired postural reflexes,

Image often tremor,

Image later, neuropsychological deficits, and

Image a number of other manifestations, to be described.

The motor signs (both “plus” and “minus”) are often only unilateral, or more marked on one side, when the disease first appears.

Hypokinesia manifests itself as paucity of facial expression (mask facies), reduced frequency of blinking, and speech disturbances (slow, monotonous, unmodulated speech, repetitions). There is little spontaneous movement, and the normal accessory movements (e. g., of the arms during walking) are diminished or absent. The patient's handwriting becomes progressively smaller (micrographia). Repeated or alternating movements are performed slowly (dysdiadochokinesia). Axial movements, such as turning around in a standing position or turning over in bed, are difficult to perform. Very severe hypokinesia is sometimes called akinesia.

The patient's gait is characterized by a mildly stooped posture, with the head jutting forward, and a small-stepped, often shuffling gait, without accessory arm movements (Fig. 6.33). To turn around in a standing position, the patient makes numerous, small turning steps.

Image

Fig. 6.33 Typical posture of a patient with Parkinson disease while walking.

Increased muscle tone is primarily evident as rigidity (p. 29Fig. 3.22), felt by the examiner during large-amplitude, passive flexion and extension of the joints. Rigidity is sometimes easier to detect when the patient voluntarily contracts the muscles on the opposite side of the body. Often, during passive movement, the examiner may feel a small, brief, periodically recurring diminution of muscle tone, known as the cogwheel phenomenon, which is usually most evident in the radiocarpal joint (Fig. 3.23p. 30). The patient's postural tone, too, is elevated; if, for example, the head is lifted off the bed and let go; it may remain suspended in midair for some time (the classic literature spoke of a “coussin psychique,” i. e., an imaginary pillow).

Tremor is seen eventually in ¾ of patients, most often a distal rest tremor at a frequency of 5 Hz. A pronation-supination (“pill-rolling”) tremor is highly characteristic. The tremor is present at rest and generally disappears on voluntary movement; it is sometimes increased by mental exertion, concentration, or walking. Some patients have postural and intention tremor in addition to rest tremor (p. 29).

An impairment of postural reflexes, combined with hypokinesia, has the consequence that changes of body posture and orientation in space can no longer be compensated for by reflexive, rapid corrective movements. The most obvious manifestations of this problem are pro- and retropulsion. If the patient is pushed while standing still, or stumbles over an obstacle, the movements made to regain balance are too small and too slow, and a fall may result.

Neuropsychological deficits usually appear as the disease progresses. Memory is impaired, cognitive processes are slowed, and there is a tendency toward perseveration: rapid changes in the content of thought are difficult to achieve.

Table 6.24 Simplified scale for evaluating the severity of individual signs of Parkinson disease (Webster, 1968)

1. Bradykinesia of hands, including handwriting

0 = normal

1 = mild slowing

2 = moderate slowing, handwriting severely impaired

3 = severe slowing

2. Rigidity

0 = none

1 = mild

2 = moderate

3 = severe, present despite medication

3. Posture

0 = normal

1 = mildly stooped

2 = arm flexion

3 = severely stooped; arm, hand, and knee flexion

4. Arm swing

0 = good bilaterally

1 = unilaterally impaired

2 = unilaterally absent

3 = bilaterally absent

5. Gait

0 = normal, turns without difficulty

1 = short steps, slow turn

2 = markedly shortened steps, both heels slap on floor

3 = shuffling steps, occasional freezing, very slow turn

6. Tremor

0 = none

1 = amplitude < 2.5 cm

2 = amplitude > 10 cm

3 = amplitude > 10 cm, constant, eating and writing impossible

7. Facial expression

0 = normal

1 = mild hypomimia

2 = marked hypomimia, lips open, marked drooling

3 = masklike facies, mouth open, marked drooling

8. Seborrhea

0 = none

1 = increased sweating

2 = oily skin

3 = marked deposition on face

9. Speech

0 = normal

1 = reduced modulation, good volume

2 = monotonous, not modulated, incipient dysarthria, difficulty being understood

3 = marked difficulty being understood

10. Independence

0 = not impaired

1 = mildly impaired (dressing)

2 = needs help in critical situations, all activities markedly slowed

3 = cannot dress him- or herself, eat or walk unaided

Possible further symptoms and signs include seborrhea, orthostatic hypotension, disturbances of the sense of smell, and constipation.

Classification and quantification. The foregoing clinical manifestations are not all present to equal degrees in every patient. Idiopathic Parkinson disease has the following clinical subtypes:

Image the akinetic-rigid subtype (without tremor),

Image the tremor-dominant subtype (with relatively little hypokinesia and rigidity), and

Image the equivalence or mixed subtype (with equally severe tremor, rigidity, and hypokinesia).

The individual clinical manifestations can be quantified (e. g., for research purposes, or for long-term patient follow-up) with the aid of the Webster Rating Scale (Table 6.24) or the very detailed Unified Parkinson Disease Rating Scale (UPDRS, not presented here).

Physical findings and other diagnostic tests. The diagnosis is made based on the typical clinical manifestations and characteristic findings on neurological examination and further diagnostic testing. In addition to hypokinesia, rigidity, tremor, and propulsion and retropulsion, examination generally reveals a weakness of convergence and a persistent glabellar reflex (i. e., lack of habituation of the reflex after repeated glabellar tapping). Ocular pursuit movements are often saccadic. The intrinsic muscle reflexes are normal, however, as are all modalities of sensory function. CT and MRI of the head reveal no abnormalities; the loss of striatal dopaminergic afferent fibers can be demonstrated with PET or SPECT after the administration of 18fluorodopa.

Idiopathic Parkinson disease is always a diagnosis of exclusion, i.e., all varieties of symptomatic parkinsonism must be ruled out before this diagnosis can be made.

Treatment. Effective therapy alleviates the manifestations of the disease, moving the symptomatic progression curve to the right by some three to five years, but does not affect the disease process as such. The putative early neuroprotective effect of selegiline and similar medications has not yet been confirmed.

Pharmacotherapy replaces the missing dopamine in the striatum. Dopamine agonists (e.g., bromocriptine, lisuride, pergolide, ropinirol, or pramipexol) are preferred for initial treatment in younger patients; the effectiveness of these agents, however, matches that of L-DOPA only in the early stages of the disease. The disease manifestations can sometimes be controlled adequately for a few months, and the need for dopaminergic treatment deferred, by using either amantadine (thought to enhance dopamine release from nerve terminals) or selegiline (an MAO-B inhibitor that slows the degradation of dopamine to homovanillic acid). In older patients, L-DOPA is used from the outset. This agent, unlike dopamine itself, crosses the blood–brain barrier; it is converted to dopamine in the central nervous system. It is always given in combination with a decarboxylase inhibitor to prevent its premature degradation in the periphery. A COMT inhibitor, such as tolcapone or entacapone, can further increase dopamine bioavailability. Tolcapone, however, is occasionally hepatotoxic and is therefore reserved for otherwise intractable cases.

Neurosurgical treatment consists of the stereotactic implantation of stimulating electrodes into the thalamus, globus pallidus, or subthalamic nucleus for deep brain stimulation. This method has now largely replaced earlier methods involving the creation of permanent lesions.

In addition to medications and surgery, physical therapy and speech therapy play important roles in patient care, as does adequate psychological support for patients and their families. Self-help groups can be very valuable in this regard.

Medication side effects and complications. Prolonged L-DOPA treatment can cause a number of problems:

Image Fluctuations in drug effect (“on-off” phases, end-of-dose akinesia) can often be improved by the use of sustained-release L-DOPA preparations, division of the daily dose into smaller individual doses at more frequent intervals (perhaps with the use of liquid preparations), and/or the addition of dopamine agonists or COMT inhibitors.

Image Drug-induced dyskinesias, e. g., peak-dose dyskinesia or hyperkinesia (often manifest as choreiform involuntary movements), are seen in 40% of patients after six months of L-DOPA treatment, in 60% after two years, and in 100% after six years. They are usually more disturbing to patients' families than to the patients themselves.

Image Painful foot dystonia can be managed with the use of sustained-release preparations in the evening and perhaps by the subcutaneous injection of 2–5 mg of apomorphine, as needed.

Image “Freezing,” i. e., sudden arrest of movement, is not directly related to the serum concentration of L-DOPA. Various mental techniques can help (carrying a briefcase, etc.).

Image Psychosis may respond to a reduction of the dose or to the addition of an atypical neuroleptic drug (clozapine, risperidone).

Image Akinetic crisis is a prolonged phase of extreme rigidity causing complete immobility and accompanied by hyperthermia, hyperhidrosis, other autonomic disturbances, and dysphagia. It is treated with water-soluble L-DOPA and intravenous amantadine.

Image Malignant L-DOPA withdrawal syndrome, consisting of rigidity, hyperthermia, autonomic disregulation, impairment of consciousness, and elevation of the serum CK, is treated with dopamine agonists and dantrolene.

Prognosis. The tremor-dominant type has a relatively favorable prognosis. L-DOPA treatment can shift the symptomatic progression curve to the right by six to seven years. It is hard to predict which patients will eventually become dependent on nursing care. This tends to occur after about 20 years of illness.

Table 6.25 The differential diagnosis of idiopathic Parkinson disease

Arteriosclerotic parkinsonism

(e. g., in subcortical arteriosclerotic encephalopathy)

Medication-induced parkinsonism

Image neuroleptic agents (most common cause)

Image reserpine

Image flunarizine

Parkinsonism of infectious origin

Image postencephalitic parkinsonism (after encephalitis lethargica)

Image cerebrospinal syphilis

Image AIDS encephalopathy

Normal pressure hydrocephalus

Wilson disease

Repeated blunt trauma to the head (so-called boxer's encephalopathy)

Toxic parkinsonism

Image carbon monoxide poisoning (most common cause)

Image manganese poisoning

Image MPTP

Parkinsonism in the setting of other neurodegenerative diseases Other causes: brain tumor, subdural hematoma, polycythemia vera

Symptomatic Parkinsonism

There are a number of clinical conditions resembling idiopathic Parkinson disease that have another underlying cause or pathophysiological mechanism. The clue to such a condition may be a history of a precipitating event (e. g., intoxication, medication use, trauma, or infection) or a structural abnormality of the basal ganglia or other brain areas (e.g., multiple arteriosclerotic changes, hydrocephalus) revealed by CT or MRI. A further characteristic of symptomatic parkinsonism is its relative resistance to treatment with L-DOPA, in contrast to idiopathic Parkinson disease, which usually responds very well to L-DOPA, at least at first. Moreover, some forms of symptomatic parkinsonism present symmetrically, while idiopathic Parkinson disease often presents asymmetrically. The most important differential diagnoses of idiopathic Parkinson disease are listed in Table 6.25.

Degenerative Systemic Diseases Causing Hypertonia and Hypokinesia

The diseases discussed in this section are other, rarer causes of the parkinsonian syndrome.

Progressive Supranuclear Palsy

This disease is also known as Steele–Richardson–Olszewski syndrome.

The underlying neuropathological lesion consists of cellular degeneration in the substantia nigra, globus pallidus, subthalamic nucleus, periaqueductal area of the midbrain, and other brain nuclei.

Clinical manifestations include:

Image paucity of movement,

Image gait disturbance early in the course of the disease,

Image predominantly axial rigidity,

Image often, a permanently extended cervical spine (head turned upward),

Image frequent falls,

Image tendency to fall backward,

Image progressive dementia,

Image an impairment of vertical gaze movements (particularly downward), with nystagmus.

Course. This disease presents between ages 50 and 70, mainly in men. It progresses rapidly and causes death within a few years.

Multiple System Atrophies (MSA)

This term subsumes a variety of rare diseases that have also been described individually: olivo-ponto-cerebellar atrophy (OPCA), striatonigral degeneration (SND), Shy–Drager syndrome (SDS), and mixed forms of these.

The neuropathological lesion consists of cellular degeneration and gliosis in the substantia nigra, striatum, pons, inferior olive, and cerebellum.

The main clinical manifestations are present to varying extents in the different forms of MSA, each of which has its own characteristic initial presentation:

Image bradykinesia, akinesia, rigidity, and rest tremor (seen early in the course of OPCA and SND),

Image autonomic dysfunction, including orthostatic hypotension, incontinence, and impotence in men (seen early in the course of SDS),

Image ataxia and other cerebellar signs (prominent in OPCA),

Image pyramidal tract signs.

The diagnosis is made from the clinical manifestations. Other findings that are compatible with the diagnosis of MSA may include partial brain atrophy, as revealed by MRI, or a reduction of glucose metabolism or of the concentration of dopamine receptors in the striatum, as revealed by PET or SPECT.

Treatment of MSA is generally not very effective, though dopamine agonists tend to be more effective than L-DOPA. The disease usually leads to severe disability within a few years of onset.

Corticobasal Degeneration

Neuropathological lesion of this disease consists of cellular degeneration and gliosis in the substantia nigra and in the precentral and postcentral gyri. The cerebral peduncles are correspondingly diminished in size.

Clinical manifestations, which are asymmetrically distributed, include:

Image impaired fine motor control of an arm (early in the course of the disease),

Image progressive rigidity and akinesia,

Image weakness,

Image central sensory disturbances,

Image (sometimes) apraxia,

Image (sometimes) dystonia.

Treatment with L-DOPA is generally not very effective and patients usually become severely disabled within a few years of the onset of the disease.

Lewy Body Disease

This disease is described below on p. 139.

Diseases Causing Hyperkinesia

These diseases, unlike Parkinson disease, cause “too much” movement, often in combination with diminished muscle tone. The different clinical varieties of hyperkinesia include chorea, athetosis, ballism and dystonia, and mixed forms. Each of these disturbances of movement may be due to many different causes. The hyperkinetic extrapyramidal diseases are a heterogeneous group with regard to both phenomenology and etiology.

Table 6.26 provides an overview of the extrapyramidal diseases that manifest themselves as hyperkinetic syndromes. The more important members of this group are described in greater detail in this section.

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Diseases Causing Chorea

The neuropathological basis of chorea consists of degeneration of small neurons, mainly in the putamen and caudate nucleus. This lesion is particularly evident in hereditary chorea (see below).

Clinical manifestations. Chorea consists of irregular, sudden, involuntary movements that are usually more pronounced at the distal end of the limbs. In some patients, these movements are of low amplitude and look almost normal, resembling nonpathological “fidgetiness”; in others, they are massive and highly disturbing. They can appear on one side (“hemichorea”) or both (Fig. 6.34). The muscle tone is normal or diminished, there is no weakness or sensory deficit, and pyramidal tract signs are absent. The intrinsic muscle reflexes are normal, except that they may have a second extension phase (Gordon phenomenon) if elicited at the same time as an incipient choreiform movement. Choreiform movements, like other types of hyperkinetic movement (see below), are typically enhanced by goal-directed movement, mental stress, or concentration, and subside in sleep and under general anesthesia.

Individual etiologic forms. Chorea has diverse causes and the prognosis depends on the cause.

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Fig. 6.34 Senile hemichorea. Drawings made from a film recording.

Huntington disease (chorea major) is a genetic disorder of autosomal dominant inheritance due to an unstable CAG trinucleotide repeat expansion on chromosome 4. The clinical manifestations generally arise between the ages of 30 and 50 (earlier in patients who inherited the defective gene from their father). Rigidity and pyramidal tract signs are sometimes present at the outset, but, as a rule, choreiform movements soon dominate the clinical picture, accompanied by progressive dementia. The disease progresses chronically, generally ending in death 10 to 15 years after the onset of symptoms. There is no treatment other than palliative, symptomatic management (see below).

Chorea minor (Sydenham chorea) is the most common etiologic form of chorea. It mainly strikes school-aged girls after an infection with β-hemolytic group A streptococci and is caused by an autoimmune reaction in which antibodies are generated that cross-react with neurons. Within a few days or weeks after an attack of “strep throat,” or within a few weeks or months of an attack of rheumatic fever, the patient develops choreiform motor unrest(mainly in the face, pharynx, and hands), combined with irritability and other mental abnormalities. These manifestations resolve spontaneously in a few weeks or months. The usual treatment is with high-dose penicillin for at least 10 days.

Rare types of chorea include chorea gravidarum (in pregnant women), benign familial chorea, and postapoplectic hemichorea.

Treatment. Choreiform movements can be alleviated by perphenazine, tetrabenazine, tiapride, and other neuroleptic medications.

Athetosis

The neuropathological basis of athetosis is loss of neurons in the striatum, the globus pallidus, and, less commonly, the thalamus.

Clinical manifestations. Athetosis generally consists of slow, irregular movements mainly affecting the distal ends of the limbs, causing extreme flexion and extension at the joints and correspondingly bizarre postures, particularly of the hands (Fig. 6.35). The interphalangeal joints may be hyperextended to the point of subluxation (“bayonet finger”). Athetosis is often found in combination with chorea (“choreoathetosis”).

Individual forms. Congenital and perinatally acquired lesions of the basal ganglia (status marmoratus, status dysmyelinisatus, severe neonatal jaundice = kernicterus) cause bilateral athetosis (athétose double), sometimes in conjunction with other signs of brain damage. Choreoathetosis and dystonia are prominent manifestations of iron deposition in the basal ganglia in pantetheine kinase-associated neurodegeneration. Focal lesions, too, e. g., an infarct, can produce hemiathetosis.

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Fig. 6.35 Hand posture in athetosis.

Ballism

The neuropathological substrate of ballism is a lesion of the contralateral subthalamic nucleus (corpus Luysii) and/or its fiber connections to the thalamus.

Etiology. Ballism is usually due to a focal ischemic process, less commonly to a space-occupying lesion. It may also be the result of severe neonatal jaundice or of a hereditary degenerative disease; it is bilateral in such patients.

Clinical manifestations. Rapid, lightning-like, large-amplitude, unbraked flinging movements of the limbs are seen on one side of the body (hemiballism) or both. Unlike chorea, these movements occur mainly at the proximal joints. The limbs maybe hurled into stationary objects (walls, etc.), causing injury.

Treatment. Haloperidol and chlorpromazine can alleviate ballistic movements. Stereotactic neurosurgical procedures are rarely indicated.

Dystonic Syndromes

Pathology. There are no characteristic neuropathological abnormalities in dystonia. To date, only a few of its etiologic forms have a known pathophysiological basis (e.g., L-DOPA-sensitive dystonia).

Clinical manifestations. Dystonia consists of slow, long-lasting contractions of individual muscles or muscle groups. The trunk, head, and limbs assume uncomfortable or even painful positions and maintain them for long periods of time. The various clinical types of dystonia are classified as either focal, i. e., affecting individual (small) muscle groups, or generalized.

Types of Generalized Dystonia

Torsion dystonias are characterized by slow, forceful, mainly rotatory movements of the trunk and head, usually accompanied by athetotic finger movements. Muscle tone is diminished at the onset of the disease. In some cases, hyperkinesia gradually ceases and gives way to hypertonia with a rigidly maintained dystonic posture (myostatic form). The various types of primary torsion dystonia are mostly of autosomal dominant inheritance, with low penetrance, and have been localized to genes on various chromosomes. The early-onset form is particularly common among Jews of Ashkenazi (Eastern European) ancestry and is due to a genetic defect at the 9p34 locus.

L-DOPA-sensitive dystonia (Segawa disease) is an autosomal recessive disorder due to a genetic defect on chromosome 14q. It usually presents in young girls as a disturbance of gait with dystonic postures or movements of the legs that vary greatly in severity over the course of the day. It is liable to misdiagnosis as a psychogenic disorder. It characteristically responds to low doses of L-DOPA (250 mg, or a little more, daily). A therapeutic test of L-DOPA is worth trying in any young patient with dystonia, including sporadic forms.

Focal Dystonia

Focal dystonia is much more common than generalized dystonia. The abnormal movements are restricted to individual parts of the body or muscle groups. The main types of focal dystonia are the following:

Spasmodic torticollis. In this disorder, slow contraction of individual muscles of the neck and shoulder girdle produce tonic rotation of the head to a certain position. It is usually the contralateral sternocleidomastoid muscle that is most prominently affected. Only one-third of all patients with “wry neck” due to spasmodic torticollis undergo a spontaneous remission; a further third later develop other dystonic manifestations. The etiology usually cannot be determined and is presumably multifactorial.

Blepharospasm consists of bilateral tonic contraction of the orbicularis oculi muscle, often with very prolonged, involuntary eye closure, during which the patient cannot voluntarily open his or her eyes. It tends to affect older patients, mainly women. Eye closure may be forceful, with visible contraction of the orbicularis oculi muscle, or weak, with a relatively normal external appearance. Cases of the latter type are alternatively designated lid-opening apraxia. Misdiagnosis as a psychogenic disturbance is, unfortunately, common.

Dystonia affecting multiple muscles of the head is a subcategory of focal dystonia. The various types of dystonia coming under this heading are not rare when taken together; they include facio-buccolingual dystonia, oromandibular dystonia, and Breughel or Meige syndrome. There may also be a relatively isolated dystonia of the mouth, pharynx, and tongue, particularly in patients who have been treated with neuroleptics. An acute form can appear as a complication of antiemetic agents such as metoclopramide.

Isolated dystonia has been described for practically every muscle group in the body. Dystonia of this type may be idiopathic or may arise in connection with nonphysiological (occupational) overuse of the muscle group in question. Well-known examples include writer's cramp, hand dystonia in musicians, and foot dystonia in certain other occupations. Spastic dysphonia is a focal dystonia of the laryngeal musculature.

Etiology. Precipitating factors for dystonia can be identified in some patients (symptomatic types of dystonia), but the etiology of dystonia usually remains undetermined.

Treatment. Generalized dystonia can be treated with baclofen, carbamazepine, or trihexyphenidyl, as monotherapy or in combination, but the effect of treatment is usually disappointing. A trial of L-DOPA can be rewarding in some patients (see above). Focal dystonia can be successfully treated with injections ofbotulinus toxin A. Stereotactic neurosurgical procedures for dystonia are currently under investigation and seem to hold some degree of promise.

Other Types of Involuntary Movement

Tremor

Types of tremor. The main phenomenological distinction is between rest tremor and action tremor. The latter, in turn, is subdivided into postural tremor, isometric tremor (appearing when a muscle is contracted against constant resistance), and kinetic tremor (appearing only during movement). Intention tremor is a type of kinetic tremor that worsens as the limb approaches its target. Tremor can also be classified etiologically as parkinsonian tremor(discussed above), psychogenic tremor (generally of highly variable severity, coarse, and demonstrative), alcoholic tremor (fine rest and intention tremor, worse after alcohol withdrawal, better after alcohol consumption), or essential tremor. The last named is often misdiagnosed as Parkinson disease.

Essential tremor is the most common type of tremor and often runs in families. It is a predominantly postural and sometimes also kinetic tremor of the hands; a pure intention tremor is seen in 15 % of patients (see p. 29). It may also affect the head in isolation (nodding tremor of the “yes” or “no” type), sometimes including the chin and/or vocal cords. It typically improves after the consumption of a small amount of alcohol and worsens with nervousness or stress. It usually arises between the ages of 35 and 45. Genetic defects causing familial essential tremor have been found on chromosomes 2p22–p25 and 3q. “Essential tremor plus” is a combination of this entity with another neurological disorder (e.g., Parkinson disease, dystonia, myoclonus, polyneuropathy, restless legs syndrome).

Further types of tremor that will not be discussed here in any detail include autonomic (vegetative) tremor, hyperthyroid tremor, and the tremor of Wilson disease.

Treatment. If the tremor is severe enough to interfere with the patient's everyday activities, a beta-blocker such as propranolol can be tried; this agent is particularly effective against essential tremor. Primidone, benzodiazepines, and clozapine are further alternatives. Deep brain stimulation through an electrode that has been stereotactically implanted in the nucleus ven-trointermedius (V.im.) of the thalamus is highly effective but is reserved for severe and medically intractable cases.

Differential diagnosis. Involuntary movements arising from diseases of the basal ganglia must be differentiated from a variety of other movement disorders, which are listed in Table 5.3 (p. 71).

Image  Cerebellar Diseases

Cerebellar disturbances present clinically with disequilibrium, truncal, and/or appendicular ataxia, impaired coordination, and diminished muscle tone (p. 80). Like disturbances of the cerebral hemispheres, they are usually due either to vascular processes (ischemia, hemorrhage) or to tumors. Multiple sclerosis is a further, common cause. In this section, we will also discuss other diseases that may present primarily with cerebellar dysfunction, including infectious, parainfectious, (heredo-)degenerative, toxic, and paraneoplastic conditions, as well as cerebellar involvement in general medical diseases.

The More Common Diseases of the Cerebellum

Acute cerebellar ataxia in childhood arises a few days or weeks after a chickenpox infection, less commonly after another viral illness. The patient is usually a school-aged child. Unsteady gait, ataxia, tremor, and nystagmus are the characteristic signs; they usually resolve spontaneously and completely within a few weeks.

Acute cerebellitis is similar to the foregoing and affects both children and adults. In older patients, the clinical manifestations may persist.

Atrophie cérébelleuse tardive à prédominance corticate is a historic term encompassing a group of disorders that share the neuropathological finding of extensive loss of Purkinje cells, particularly in the vermian cortex. This is expressed clinically as unsteady gait, truncal ataxia, less severe appendicular ataxia, and nystagmus. The underlying disorder may be a cerebellar degeneration of genetic or (to date) unexplained etiology or a symptomatic involvement of the cerebellum, e.g., late cerebellar atrophy in chronic alcoholism or subacute paraneoplastic cerebellar cortical atrophy.

Cerebellar heredoataxias are of genetic origin. The enzymatic defects and pathophysiological mechanisms underlying each have not yet been determined, except in a few patients. These disorders are listed together with sporadic and symptomatic forms of cerebellar ataxia in Table 6.27.

Spinocerebellar ataxias involve not only the cerebellum, but also the spinal cord (cf. p. 153).

Intermittent cerebellar dysfunction has various causes, among which are pyruvate dehydrogenase deficiency, Hartnup disease, and familial periodic paroxysmal ataxia. The last named is a genetic disease, due to a defect on chromosome 19p, which responds to treatment with acetazolamide. Intermittent ataxia is also seen in many cases of multiple sclerosis.

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Cerebellar dysfunction in other diseases is usually manifest as ataxia. Intoxication with diphenylhydantoin, lithium, organic mercury, piperazine, 5-fluorouracil, or DDT is a common cause. Others include infectious diseases, such as mononucleosis, macroglobulinemia, myxedema, vitamin B deficiency, heatstroke, cerebellar tumors, and cranial polyneuritis (p. 175). There is also a form of gluten-induced ataxia, which may or may not be accompanied by gastrointestinal symptoms. Finally, cerebellar dysfunction may be the presenting manifestation of Creutzfeldt–Jakob disease.

The differential diagnosis must include all noncerebel-lar processes that can cause ataxia: (contralateral) frontal lobe lesions, motor pareses, and disorders affecting the afferent sensory pathways (e.g., polyneuropathy and posterior column disorders). Prolonged confinement to bed by illness (“bed ataxia”) and psychogenic mechanisms are further possible causes.

Treatment is possible only when a treatable underlying illness has been identified.

Image  Dementing Diseases

The Dementia Syndrome

Unlike the terms “mental retardation” and “oligophrenia,” both of which refer to congenital disturbances, “dementia” refers to an acquired degeneration of intellectual and cognitive abilities, which persists for at least several months or takes a chronically worsening course, leading to major impairment in the patient's everyday life. The clinical picture is dominated by personality changes as well as neuropsychological and accompanying neurological (particularly motor) deficits. Reactive changes, including insomnia, agitation, and depression, are common.

Causes. Unlike the various types of neuropsychological disturbance that are due to localized brain lesions, dementia is a global syndrome caused by a diffuse loss of functional brain tissue. Neuroimaging usually discloses extensive brain atrophy or multifocal lesions in the brain. The loss of functional tissue is often due to primary (degenerative) brain atrophy, which predominantly affects the cerebral cortex, progresses chronically, and causes irreversible cognitive impairment; in such cases, dementia is the direct consequence and most obvious expression of the causative pathological process (dementing diseasesin the narrow sense of the term: Alzheimer disease, Lewy body disease, focal cortical atrophies). In principle, however, any disease that damages the structure or function of the brain can produce the dementia syndrome (symptomatic dementia, usually accompanied by other manifestations of the underlying disease). It is important to realize that nearly 10% of all cases of dementia are due to diseases that can be reversed, or at least kept from progressing further, by appropriate treatment. Early diagnosis and treatment of such patients is crucial for the prevention of worsening dementia. Table 6.28 contains an overview of the causes of dementia, with an indication of which among these conditions are irreversible, and which are at least partially treatable.

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All patients with dementia deserve a thorough diagnostic evaluation, because a treatable cause may be discovered.

Epidemiology. One percent of persons aged 60 to 64, and more than 30% of persons over age 85, suffer from dementia. The most common cause is Alzheimer disease, which accounts for 40 to 50% of all patients. The second most common cause, and the most common cause of symptomatic dementia, is vascular (i. e., multiinfarctdementia (15%); the third most common cause is alcoholism.

General clinical features of the dementia syndrome include neuropsychological deficits, personality changes, and behavioral abnormalities. In particular, the following are seen:

Image impairment of short-term and long-term memory,

Image for new content (faulty generation of engrams)

Image and/or for old content (faulty recall);

Image impairment of thinking, particularly with respect to

Image judgment,

Image problem solving,

Image and symbol comprehension;

Image impairment of visuospatial and spatial-constructive functions, aphasia, apraxia;

Image impairment of attention;

Image reduced drive, initiative, and motivation;

Image impaired concentration;

Image mild fatigability;

Image affect lability and impaired affect control;

Image impairment of emotionality and social behavior;

Image in some patients, confusion and impairment of consciousness.

General procedure for the diagnostic evaluation of dementia. The diagnosis of the dementia syndrome is based on thorough history-taking from the patient and from the members of his or her family; a comprehensive general medical and neurological examination; and neuropsychological testing. (The MiniMental Status Test described on p. 39 can be used for screening, but is nonspecific and thus of limited diagnostic value.) Neuroimaging (usually MRI) should be performed in every case as part of the search for the underlying etiology, which may also require some or all of the following, depending on the specific clinical situation: laboratory tests (complete blood count, electrolytes, hepatic and renal function tests, thyroid hormones, vitamin B12, folic acid, TPHA test, HIV serology, CSF examination, etc.), EEG, PET, and SPECT.

Differential diagnosis at the syndrome level. It may be hard to differentiate the dementia syndrome from certain other psychopathological states, particularly the following:

Image nonpathological diminution of cognitive ability inold age;

Table 6.28 Causes of dementia (based on the classifications of Whitehouse and of Cummings and Benson)

Degenerative diseases of the nervous system with dementia as their principal manifestation:

— Alzheimer disease1

— Pick disease

— frontal lobe degeneration

— Lewy body disease

Other degenerative diseases causing dementia:

— Parkinson disease1

— progressive supranuclear palsy1

— pantetheine kinase-associated neurodegeneration (formerly Hallervorden-Spatz disease)

— hereditary ataxias

— progressive myoclonus epilepsy1

Cerebrovascular diseases:

— multi-infarct syndrome1

— “strategic” infarcts1

— Binswanger disease (subcortical arteriosclerotic encephalopathy)1

Infectious diseases:

— HIV, AIDS-dementia complex1

— other viral encephalitides and postviral encephalopathies1

— prion diseases

Image kuru

Image Creutzfeldt-Jakob disease

Image Gerstmann-Straussler-Scheinker syndrome

Image familial fatal insomnia

Image familial progressive subcortical gliosis

— syphilis (progressive paralysis)2

— brain abscesses2

— Whipple disease2

Metabolic disorders affecting the brain:

— Wilson disease2

— disorders of lipid, protein, urea, and carbohydrate metabolism1

— leukodystrophies

Neoplasia:

— primary brain tumors, metastases1

— paraneoplastic encephalopathies1

Epilepsy:

— progressive myoclonus epilepsy1

— frequent seizures, status epilepticus2

— diseases causing both dementia and epilepsy1

Demyelinating diseases:

— multiple sclerosis1

Systemic diseases, endocrine disorders, and deficiency states:

— hypothyroidism, Hashimoto thyroiditis2

— hypopituitarism2

— hepatic encephalopathy1

— uremic encephalopathy2

— hypoxic brain injury

— hypoglycemia1

— electrolyte disorders1

— hypercalcemia, hyperparathyroidism2

— vasculitis, connective tissue disease2

— vitamin B12 deficiency2

— pellagra2

— Wernicke encephalopathy1

— jejuno-ileal bypass2

Toxic conditions:

— alcoholism2

— heavy metal poisoning2

— carbon monoxide poisoning

— organic solvent poisoning1

— medication toxicity2

Mental illnesses:

— depression2

— schizophrenia2

— hysteria2

Hydrocephalus:

— obstructive hydrocephalus2

— malresorptive hydrocephalus2

Trauma:

— open trauma with destruction of brain tissue

— closed trauma with brain contusions1 and/or subcortical shear injuries1

1 preventable, (rarely) curable, or treatable to some extent 

2 usually curable or, at least, largely treatable

Image depression with severely reduced drive (so-called depressive pseudodementia);

Image an isolated neuropsychological disturbance (especially aphasia, apraxia, and/or agnosia);

Image congenital mental retardation (oligophrenia);

Image cognitive impairment by medications or drugs of abuse;

Image status epilepticus with partial complex seizures or absences;

Image cognitive impairment due to endogenous psychosis.

General aspects of treatment. If the dementia syndrome is found to be due to a treatable condition, causative treatment can be instituted, resulting in cure or, at least, the prevention of further progression of dementia. In all other cases, however, dementia responds poorly to treatment, if at all. The current medications for Alzheimer disease provide only modest clinical benefit, often at the cost of side effects. Various symptoms accompanying dementia can be treated individually, with major benefit to the patient and his or her family, including depression, delusions, insomnia, and agitation. Training of the remaining cognitive abilities is also advisable in order to keep the patient functionally independent for as long as possible. In advanced stages, patients often require home nursing visits, or care in a suitable day clinic; removal from the home to a permanent care facility should be deferred for as long as this is practically achievable. The patient's family is thus the most important component of treatment. Family members should receive early and thorough information about the patient's disease and, where appropriate, counseling in the ways they can help care for the patient.

The common degenerative diseases of the brain whose major clinical manifestation is dementia are described in greater detail in the next section, and vascular dementia in the section immediately following.

Degenerative Brain Diseases Causing Dementia as Their Most Prominent Manifestation

Alzheimer Disease (Senile Dementia of Alzheimer Type, SDAT)

Alzheimer disease is the paradigmatic example of cortical (as opposed to subcortical) dementia. In cortical dementia, dementia itself is the main clinical manifestation; subcortical dementia is usually seen as an accompaniment to a motor disturbance.

The neuropathological lesion in Alzheimer disease consists of neuronal loss in the cerebral cortex, particularly in the basal temporal lobe (hippocampus) and the temporoparietal region. Histological examination reveals a paucity of cells and an accumulation of neuritic (“senile”) plaques and neurofibrillary tangles. Amyloid angiopathy is often present as well.

Pathogenesis. Genetic factors play a role, but not the only role. Familial cases are associated with a defect in chromosome 21 q, which contains the amyloid precursor gene. Persons with trisomy 21, i. e., Down syndrome, generally become demented by age 30. In other patients, there is a defect in the apolipoprotein E gene on chromosome 19q. The regularly demonstrable loss of neurons in the nucleus basalis of Meynert, which sends a diffuse cholinergic projection to the frontal cortex, and the finding of a diminished amount of acetylcholine in the brain of persons with Alzheimer disease both imply that the cholinergic system plays a role in pathogenesis. These observations provide the motivation for cholinergic treatment (as described below).

Clinical manifestations. The nonspecific early manifestations can include depression, insomnia, agitation, anxiety, and excitability. Within a year, forgetfulness, fatigability, poor concentration, and a lack of initiative appear and slowly worsen, often accompanied by focal neuropsychological deficits such as aphasia, apraxia, and disturbances of temporal and spatial orientation. Thereafter, the patient's capacity for abstract thought deteriorates, complex situations can no longer be grasped, and confusion, lack of interest, and the progressive loss of language ultimately lead to the loss of functional independence and the need for nursing care.

Diagnosis. Early recognition and interpretation of the psychopathological deficits described above is crucial for the diagnosis of the disease, which is often further supported by the typical neuroimaging findings (cortical atrophy, wide ventricles; see Fig. 6.36). Neuroimaging is also mandatory because it can rule out some of the other causes of the dementia syndrome. Further studies (hematological biochemical, and serological blood tests, CSF examination, EEG) may be indicated, depending on the specific differential diagnostic considerations in the individual patient.

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Fig. 6.36 Brain atrophy in dementia. High-grade, symmetrical, mainly frontal atrophy of the cerebral hemispheres in a 64-year-old man. Note the marked atrophy of the temporal lobes as well. The lateral ventricles, including the inferior horns, are markedly dilated, as is the third ventricle. Both external hydrocephalus and internal “hydrocephalus ex vacuo” are present.

Course. Alzheimer disease always progresses. The average life expectancy from the time of diagnosis is eight to nine years.

Treatment. Cholinomimetic agents (donezepil or rivastigmine) improve neuropsychological deficits symptomatically but do not halt the progression of dementia. A possible beneficial effect of nonsteroidal anti-inflammatory drugs, including aspirin, is currently being studied. No clear benefit has been shown for high-dose vitamin E, Ginkgo biloba preparations, calcium antagonists, or nootropic agents such as piracetam. The most important aspect of treatment in all patients is the management of the accompanying symptoms: depression (preferably with selective serotonin reuptake inhibitors), psychosis (preferably with clozapine or olanzapine), insomnia, agitation, and aggressiveness(preferably with mild neuroleptic agents such as pipamperone, melperone, and clomethiazole). Patients with advanced Alzheimer disease, and their families, can benefit from referral to special outpatient and day care facilities.

Dementia with Lewy Bodies

The hallmark of this common dementing disease is the presence of Lewy bodies in the neurons of the cerebral cortex and brainstem. Clinically, progressive dementia in these patients is accompanied by certain other characteristic findings: there are highly variable deficits of attention and concentration, as well as frequent, objective visual hallucinations and parkinsonian manifestations (particularly in patients with early disease onset). Patients often suffer from repeated falls, syncope, brief episodes of unconsciousness, and hallucinatory experiences.

Focal Cortical Atrophies

The dementing diseases belonging to this category, all of them much rarer than Alzheimer disease, are characterized by localized atrophy of particular areas of the brain. Histopathological examination reveals gliosis and spongiform changes. The commonest of these conditions is Pick disease, classified by some authors as a type of frontal lobe degeneration. Patients often manifest frontal personality changes and abnormal social behavior (p. 77) Many cases are familial and of autosomal dominant inheritance. In primary progressive aphasia, the language disturbance may precede the development of generalized dementia by several years. In posterior cortical atrophy, dementia may be accompanied by the specific neuropsychological deficits of Gerstmann syndrome (p. 78).

Vascular Dementia

SAE-Associated Dementia and Multi-infarct Dementia

Etiology. Vascular dementia, the second most common etiologic category of dementia, is caused either by multiple subcortical lacunar infarcts due to cerebral microangiopathy (subcortical arteriosclerotic encephalopathy, SAE: more common type) or by multiple cortical and subcortical infarcts due to macroangiopathy or recurrent embolic stroke (multi-infarct dementia: less common type). The two types often appear together. The sites and extent of the infarcts determine the severity and progression of the dementia syndrome.

Clinical manifestations. Vascular dementia often strikes patients with preexisting arterial hypertension and/or other vascular risk factors. There may be a history of transient neurological deficits in the past. Dementia can arise suddenly or progress in spurts. There may be accompanying neuropsychological deficits, such as aphasia, as well as marked incontinence of affect: involuntary laughing and crying are common. The neurological findings include enhanced perioral reflexes, signs of pseudobulbar palsy (e.g., dysarthria and dysphagia), a tripping, small-stepped gait (old person's gait, “marche a petits pas”), and, sometimes, pyramidal and extrapyramidal signs.

Image

Fig. 6.37 Vascular encephalopathy as seen by MRI. There are multiple focal signal abnormalities in the deep white matter, the subcortical region, and the cerebral cortex. The ventricles and subarachnoid space are dilated (“hydrocephalus ex vacuo”).

The psychopathological abnormalities in patients with predominantly subcortical lesions include apathy, depression, and slowness. Patients can recall old information more easily than they can store new information.

Diagnostic evaluation. Neuroimaging reveals brain atrophy and evidence of multiple focal lesions (usually in the subcortical white matter; see Fig. 6.37).

Course. Vascular dementia is, in principle, a progressive illness, but the speed of progression is variable, as it depends on the type and extent of the underlying arteriopathy.

Treatment. The intermediate goal of treatment is vascular risk reduction (treatment of arterial hypertension, cardiac arrhythmias, and diabetes mellitus, if present; inhibition of platelet aggregation with aspirin and/ or other drugs). Generally speaking, the treatment is the same as that discussed above for the prevention of ischemic stroke (p. 105).