6.11 Cerebellar Diseases and Other Conditions Causing Ataxia

Key Point

Cerebellar disturbances present clinically with disequilibrium, truncal and/or appendicular ataxia, impaired coordination, and diminished muscle tone (see also section ▶ 5.5.6).

6.11.1 Overview

Classification The different clinical types of ataxia can be classified in several ways:

• By the affected neural structure(s):

  • Cortical cerebellar ataxia.

  • Olivopontocerebellar ataxia.

  • Spinocerebellar ataxia.

• By etiology (see also ▶ Table 6.37, ▶ Table 6.38):

  • Hereditary (autosomal recessive, autosomal dominant, x-chromosomal) or sporadic.

  • Acquired (= symptomatic).

Clinical features Ataxia is characterized by impaired coordination of movement and a dysfunctional interplay of agonist and antagonist muscles. Thus, it typically manifests itself as poorly controlled movements that tend to overshoot their target. The additional manifestations of the individual diseases causing ataxia depend on their etiology and the particular neural structure involved.

Note

Ataxia can be caused not only by cerebellar disease, but also by disease of the afferent and efferent pathways leading to and from the cerebellum, or of any afferent somatosensory or special sensory pathways. The underlying lesion may be in the cerebellum, but it may also be in the brainstem, spinal cord, peripheral nerves, sensory cortex, or thalamus.

An initial, clinically based classification of ataxia distinguishes symmetric from focal, asymmetric types ( ▶ Table 6.36). The table can serve as an overview and guide to the differential diagnosis of ataxia.

Table 6.36 The differential diagnosis of symmetric and focal asymmetric ataxias

Symmetric ataxia	Focal asymmetric ataxia
Acute or chronic intoxication Electrolyte disturbance Acute viral cerebellitis Miller Fisher syndrome Postinfectious, ADEM Alcoholic-nutritional cerebellar damage Vitamin B1 deficiency Vitamin B12 deficiency Paraneoplastic cerebellar disease Antigliadin antibody syndrome Hypothyroidism Creutzfeldt–Jakob disease Hereditary cerebellar degeneration Familial episodic ataxia Multisystem atrophy Tabes dorsalis Psychogenic ataxia	Ischemic stroke Cerebellar hemorrhage Subdural hematoma Abscess Neoplasia (primary brain tumor, metastasis) Demyelinating plaque, multiple sclerosis Arteriovenous malformation, arteriovenous fistula Arnold–Chiari or Dandy–Walker malformation Psychogenic ataxia
Abbreviation: ADEM, acute disseminated encephalomyelitis.

Diagnostic evaluation When ataxia is suspected, the age at onset and the family history are diagnostically relevant:

• If ataxia arises in childhood or adolescence in a patient with a positive family history, the diagnosis is probably an autosomal recessive ataxia. The most common of these is Friedreich ataxia.

• If a parent is similarly affected, then the diagnosis is probably an autosomal dominant ataxia, for example, spinocerebellar ataxia.

• Ataxia arising after age 40 years is less likely to be hereditary and may be an acquired ataxia, for example, of toxic origin (such as alcohol-induced cerebellar degeneration).

Individual types of ataxia can be diagnosed by molecular-genetic testing, imaging studies, or laboratory analysis.

Treatment The symptom complex called “ataxia” has no specific treatment, although coordination may be improved by physiotherapy. Certain types of ataxia of known cause can be correspondingly treated: examples include vitamin E administration in ataxia due to vitamin E deficiency and in Aβ-lipoproteinemia, a diet that is low in phytanic acid in Refsum disease, and a low-copper diet combined with chelators or zinc in Wilson disease.

6.11.2 Selected Types of Ataxia

Key Point

Disturbances of the cerebellum, like those of the cerebral hemispheres, 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.

A thorough description of each ataxia syndrome would be beyond the scope of this textbook, and we therefore discuss only the more important ones briefly. Friedreich ataxia is described in greater detail in a later chapter (section ▶ 7.6.2) among the other hereditary diseases of the spinal pathways.

Cerebellar Heredoataxias

Cerebellar heredoataxias are of genetic origin. The enzymatic defects and pathophysiologic mechanisms underlying each have not yet been determined, except in a few cases. The main types are listed in ▶ Table 6.37. Spinocerebellar ataxias involve both the cerebellum and the spinal cord and are associated with cognitive deficits as well (see sections ▶ 7.6.1 and ▶ 7.6.2).

Table 6.37 Types of cerebellar ataxia

Disease	Clinical features	Remarks
Autosomal recessive hereditary ataxias
Friedreich ataxia	Lumbering, broad-based, unsteady gait, progressive from the first or second decade onward Later, clumsiness of the hands, explosive speech Typical Friedreich foot (see ▶ Fig. 7.15) Scoliosis, hypotonia	GAA triplet expansion on chromosome 9; impaired synthesis of the protein frataxin
Refsum disease (heredopathia atactica polyneuritiformis)	Ataxia of gait and limbs beginning in childhood or adulthood Polyneuropathy with areflexia and sensory loss Hearing impairment Retinitis pigmentosa Mental abnormalities	Lack of phytanic acid α-dehydrogenase
Aβ-lipoproteinemia (Bassen–Kornzweig syndrome)	Progressive ataxia, nystagmus, ophthalmoplegia, polyneuropathy Acanthocytosis, low cholesterol and triglyceride levels, vitamin E deficiency	Low serum lipoprotein, cholesterol, and triglyceride levels
Ataxia telangiectasia (Louis–Bar syndrome)	Onset in infancy with ataxia and choreoathetosis Frequent lung, ear, nose, and throat infections Slow eye movements Telangiectases in conjunctiva and joint creases	One of the chromosomal fragility syndromes
Spinocerebellar ataxia (different varieties, e.g., deficiencies of hexosaminidase, glutamate dehydrogenase, pyruvate dehydrogenase, ornithine transcarbamylase, or vitamin E)	Onset usually before age 10 y Ataxia with variable accompanying deficits, e.g., intellectual disability, visual or hearing impairment, polyneuritis, myoclonus Speech may be loud, deep, and harsh (“lion’s voice”) If hereditary, generally autosomal recessive
Autosomal dominant hereditary cerebellar ataxias (ADCA)
Cerebellar cortical atrophy (Holmes type = Harding type III)	Onset at age 20 y or later Cerebellar signs	Genetically heterogeneous, SCA 5 and SCA 6
Olivopontocerebellar atrophy (Menzel type = Harding type I)	Onset at age 20 y or later Cerebellar and noncerebellar signs including optic nerve atrophy, basal ganglionic dysfunction, pyramidal tract signs, muscle atrophy, sensory deficits, and sometimes dementia	Genetically heterogeneous, SCA 1–SCA 4; SCA 3 = Machado–Joseph disease
Cerebellar atrophy (Harding type II)	Onset after age 20 y with cerebellar signs and retinal degeneration	Corresponds to SCA 7
Autosomal dominant hereditary episodic ataxias
Familial periodic paroxysmal ataxia	Degenerative cerebellar ataxia with onset in childhood Manifests itself in attacks (paroxysms)	Gene defect on chromosome 19p Responds to acetazolamide
Sporadic, nonhereditary ataxias
“Atrophie cérébelleuse tardive à prédominance corticale”	Onset in late adulthood with slowly progressive gait and truncal ataxia, later arm ataxia Rarely, nystagmus, muscle hypotonia, and pyramidal tract signs	Symmetric degeneration of Purkinje cells, predominantly in the vermis; alcohol may be a precipitating factor in persons with an underlying genetic predisposition
Abbreviation: SCA, spinocerebellar ataxia.

Note

The most common hereditary ataxia is Friedreich ataxia, an autosomal disorder with onset usually in the first or second decade of life that generally leads to death between the ages of 30 and 40 years. Its typical manifestations are the following:

• Unsteady gait, particularly with eyes closed; areflexia, pyramidal tract signs.

• Dysphagia, cerebellar dysarthria, oculomotor disturbances (gaze-evoked nystagmus, square-wave jerks, abnormal suppression of the vestibulo-ocular reflex, ▶ Fig. 12.6).

• Optic nerve atrophy.

• Early loss of proprioception and vibration sense.

• Distal muscle atrophy, typical foot deformity (pes cavus), kyphoscoliosis.

• Cardiac manifestations (conduction abnormalities, cardiomyopathy), diabetes mellitus.

• Cognitive disturbances.

• Dementia.

Symptomatic Types of Ataxia and Cerebellar Degeneration

Aside from hereditary and idiopathic types of ataxia and cerebellar degeneration, there are also types that reflect particular underlying illnesses, including a wide variety of cerebellar and systemic diseases ( ▶ Table 6.38). The clinical manifestations vary depending on the cause. Other systems and organs are often involved.

Table 6.38 Causes of symptomatic ataxia and cerebellar degeneration

Cause or precipitating factor	Examples and remarks
Local disease: mass lesion or ischemia	Malformation, cerebellar tumor, infarct, hemorrhage, inflammation, trauma or other physical causes
Infection	Often in the aftermath of an infectious disease, e.g., mononucleosis 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 preschool-aged child. Unsteady gait, ataxia, tremor, and nystagmus are the characteristic signs; they usually resolve spontaneously in a few weeks. Acute cerebellitis is similar to the foregoing and affects both children and adults. In older patients, the manifestations can persist
Systemic diseases	For example, multiple sclerosis, macroglobulinemias
Toxic conditions	Tardive cerebellar atrophy in chronic alcoholism, other toxic causes (diphenylhydantoin, lithium, organic mercury, piperazine, methotrexate, 5-fluorouracil, DDT)
Metabolic and hormone-associated conditions	Familial AVED (an autosomal recessive condition that clinically resembles Friedreich ataxia), vitamin B deficiency Hypothyroidism and myxedema Malresorption syndrome, gluten intolerance (gluten-induced ataxia with or without gastrointestinal manifestations)
Paraneoplastic conditions	Subacute cerebellar cortical atrophy
Further causes	Heatstroke Miller Fisher syndrome (see section ▶ 11.2.3) Cranial polyradiculitis (see section ▶ 11.2.3) Creutzfeldt–Jakob disease (see section ▶ 6.7.9): ataxia is sometimes the first sign of this disease
Abbreviations: AVED, ataxia with vitamin E deficiency; DDT, dichlorodiphenyltrichloroethane.

Additional Information

Intermittent cerebellar manifestations are found mainly in the following diseases:

• Pyruvate dehydrogenase deficiency.

• Hartnup disease.

• Familial periodic paroxysmal ataxia.

• Multiple sclerosis.

The differential diagnosis of cerebellar ataxia must also include disease processes that cause ataxia but do not involve the cerebellum:

• (Contralateral) frontal lobe lesions.

• Paresis of any cause.

• Lesions of the afferent sensory pathways (e.g., polyneuropathy or posterior column lesion).

• Lesions of the parietal sensory cortex.

A prolonged beridden state (“bed ataxia”) and psychogenic mechanisms are further possible causes.

6.12 Dementia

Key Point

Unlike the terms “intellectual disability” and “oligophrenia,” which refer to congenital disturbances, the term “dementia” refers to an acquired degeneration of intellectual and cognitive abilities that 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 neurologic (particularly motor) deficits. Reactive changes, including insomnia, agitation, and depression, are common.

In this chapter, we will first provide an overview of the general aspects of the dementia syndrome and then describe the main types of degenerative brain disease that cause dementia in greater detail.

6.12.1 Overview: The Dementia Syndrome

Etiology and classification

Unlike the various types of neuropsychological disturbance caused by focal brain lesions, the dementia syndrome is caused by a diffuse loss of functional brain tissue. Neuroimaging usually discloses extensive brain atrophy or multifocal brain lesions.

Primary brain atrophy The loss of functional tissue is often due to primary (degenerative) brain atrophy, which mainly 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 pathologic process. Primary brain atrophy characterizes dementing diseases in the narrow sense of the term:

• Alzheimer disease.

• Lewy body disease.

• Focal cortical atrophies.

Symptomatic dementia In principle, however, any disease that damages the structure or function of the brain can produce the dementia syndrome. Dementia, in such cases, is often a possible but not universal accompaniment of the main features of the disease in question, and is generally not the only manifestation. 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. The timely diagnosis and treatment of such patients is crucial for the prevention of further deterioration.

Cortical and subcortical dementia In cortical types of dementia, dementia is the main manifestation of the disease (classic example: Alzheimer disease). In contrast, movement disorders are typically prominent in patients with subcortical dementia.

Overview of causes ▶ Table 6.39 contains an overview of the causes of dementia, with an indication of which among these conditions are irreversible and which are at least partly treatable.

Table 6.39 Causes of dementia

Type	Treatability	Diseases
Degenerative diseases of the nervous system	Partly treatablea	Alzheimer disease Parkinson disease Progressive supranuclear palsy Progressive myoclonus epilepsy
	Irreversible	Frontotemporal dementia (Pick disease) Frontal lobe degeneration Pantothenate kinase–associated neurodegeneration Heredoataxias Lewy body disease Corticobasal degeneration Fragile-X syndrome
Cerebrovascular diseases	Partly treatablea	Multi-infarct syndrome “Strategically placed” infarcts or hemorrhages Subcortical arteriosclerotic encephalopathy (previously called Binswanger disease)
	Irreversible	Amyloid angiopathy CADASIL
Infectious dementias	Treatableb	Syphilis (progressive paralysis) Brain abscesses Whipple disease (intestinal lipodystrophy)
	Partly treatablea	HIV, AIDS-dementia complex Other viral encephalitides and postviral encephalopathies
	Irreversible	Prion diseases: Kuru Creutzfeldt–Jakob disease Gerstmann–Sträussler–Scheinker syndrome Familial fatal insomnia Familial progressive subcortical gliosis
Metabolic disorders affecting the brain	Treatableb	Wilson disease (hepatolenticular degeneration)
	Partly treatablea	Disorders of lipid, protein, urea, and carbohydrate metabolism
	Irreversible	Leukodystrophies Polyglucosan body disease
Neoplasia	Partly treatable	Primary brain tumors, metastases
	Irreversible	Status post radio- and chemotherapy for brain tumor
Autoimmune encephalopathies	Treatableb	Hashimoto encephalopathy
	Partly treatablea	Paraneoplastic encephalopathies Limbic encephalitis Primary CNS vasculitis
Epilepsy	Treatableb	Status epilepticus
	Partly treatablea	Progressive myoclonus epilepsy Frequent seizures
Mental illnesses	Treatableb	Depression Schizophrenia Hysteria
Hydrocephalus	Treatableb	Occlusive hydrocephalus Malresorptive hydrocephalus
Trauma	Partly treatablea	Closed head trauma with contusion or subcortical shearing injury Dementia pugilistica (chronic traumatic encephalopathy of boxers)
	Irreversible	Open head trauma with destruction of brain tissue
Demyelination	Partly treatablea	Multiple sclerosis
Abbreviations: AIDS, acquired immunodeficiency syndrome; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS, central nervous system; HIV, human immunodeficiency virus. aFor example, preventable, occasionally curable, or amenable to symptomatic treatment in some cases. bUsually curable or responsive to treatment.

Note

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 older than 85 years, 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., multi-infarct) dementia (15%); the third most common cause is alcoholism.

General clinical features

The dementia syndrome is characterized by neuropsychological deficits, personality changes, and behavioral abnormalities. In particular, the following are seen:

• Impairment of short-term and long-term memory:

  • For new content (faulty generation of engrams), and/or

  • For old content (faulty recall).

• Impairment of thinking, particularly with respect to:

  • Judgment.

  • Problem-solving.

  • Symbol comprehension.

• Impairment of visuospatial and spatial-constructive functions.

• Aphasia and apraxia.

• Impairment of attention and concentration.

• Reduced drive, initiative, and motivation; easy fatigability.

• Affect lability and impaired affect control.

• Impairment of emotionality and social behavior.

• In some patients, confusion and impairment of consciousness.

General diagnostic evaluation

The diagnosis of the dementia syndrome is based on thorough history-taking from the patient and family members, a comprehensive general medical and neurologic examination, and neuropsychological testing.

Screening tests The following can be used as screening tests for dementia, although they are not very informative or specific:

• Mini-Mental State Examination ( ▶ Table 3.1).

• Clock test (the patient is asked to draw a clock face indicating a particular time).

• Montreal Cognitive Assessment (MoCA) test: this test simultaneously assesses various cognitive skills with a sequence of simple tasks that can be scored on a point system. It takes approximately 10 minutes to administer. See www.mocatest.org.

Imaging studies and electrophysiology Neuroimaging (usually MRI) should be performed in every case as part of the search for the underlying etiology. PET, SPECT, and EEG can be performed as well.

Laboratory tests Depending on the specific clinical situation and the suspected causes, targeted laboratory testing should be performed, including, for example, complete blood count, electrolytes, hepatic and renal function tests, thyroid hormones, vitamin B₁₂, folic acid, TPHA test, HIV serology, and CSF examination.

Differential Diagnosis at the Syndrome Level

The dementia syndrome may be hard to differentiate from certain other psychopathologic states, especially the following:

• Nonpathologic cognitive decline in old age (can be diagnosed on the basis of history obtained from family members and clinical testing).

• Depression with severely reduced drive, so-called depressive pseudodementia (neuropsychological and psychiatric examination).

• An isolated neuropsychological disturbance, especially aphasia, apraxia, and/or agnosia (clinical testing, neuropsychological examination).

• Congenital intellectual disability, that is, oligophrenia (history).

• Cognitive impairment by medications or drugs of abuse (history, general physical examination, laboratory testing).

• Status epilepticus with partial complex seizures or absences (EEG).

• Cognitive impairment due to endogenous psychosis (neuropsychological and psychiatric examination).

General Aspects of Treatment

Cause-directed treatment If the dementia syndrome is found to be due to a treatable condition, cause-directed treatment can be given, leading to a cure or, at least, the prevention of further progression. 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.

Accompanying manifestations Various manifestations that accompany dementia can be treated symptomatically, with major benefit to the patient and his or her family, including depression, delusions, insomnia, and agitation. Training of (temporarily) preserved cognitive abilities is also advisable to keep the patient functionally independent for as long as possible.

Nursing care In advanced stages of disease, 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 an 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.

6.12.2 Alzheimer Disease (Senile Dementia of Alzheimer Type)

Note

Alzheimer disease is the paradigmatic example of cortical (as opposed to subcortical) dementia, with dementia itself as the main clinical manifestation. It is the most common cause of dementia in the elderly.

Synonyms

Senile dementia of Alzheimer type; Alzheimer dementia.

Epidemiology Women are more commonly affected than men, and the prevalence rises with age. The mean age at the onset of Alzheimer disease is 78 years. Persons under age 65 with the disease are said to have “presenile dementia.”

Etiology and genetics

Genetic factors are clearly contributory, as first-degree relatives of Alzheimer patients are much more likely to develop the disease than persons with no family history of it. Yet, as most affected persons have no such history, environmental factors must also play a role. It seems that the likelihood of developing the disease is higher in persons of low educational attainment and those whose intellectual abilities are not regularly put to use; hypercholesterolemia, diabetes mellitus, and other brain diseases also increase the risk.

Genetics Hereditary cases of Alzheimer disease (which are often early-onset cases) are associated with defects in:

• Chromosome 21q, which contains the amyloid precursor protein (APP) gene.

• Chromosome 14: mutation of the presenilin-1 gene.

• Chromosome 1: mutation of the presenilin-2 gene.

Familial clustering of Alzheimer disease is associated with defects in:

• Chromosome 19q: mutation of the apolipoprotein E locus (ApoE-4).

Persons with trisomy 21 (Down syndrome) are generally demented after age 30 years.

Pathogenesis and Pathology

Note

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

Amyloid and tau protein deposition In Alzheimer disease, degradation of the membrane protein APP (amyloid precursor protein) leads to the increased production of a neurotoxic protein called β-amyloid (more precisely, Aβ1–42, which is longer than the physiologic degradation product). This pathologic protein forms perivascular deposits and cortical amyloid plaques. In addition, hyperphosphorylated tau protein also accumulates within neurons in Alzheimer fibrils and tangles. Amyloid and tau protein deposition has multiple consequences:

• Neuron degeneration, mainly temporobasal (hippocampal) and temporoparietal.

• Axon degeneration and loss of synapses.

• A cholinergic deficit in the cerebral cortex.

• In the late stage of the disease, immune reactions of glial cells to plaques, resulting in further cell loss.

Cholinergic deficit Neuron degeneration is regularly seen in the nucleus basalis of Meynert, which sends a diffuse cholinergic projection to the frontal cortex. This and the diminished amount of acetylcholine found in the brain of persons with Alzheimer disease suggest that the cholinergic system plays a role in the pathogenesis of the disease. These observations provide the motivation for treatment with cholinergic drugs (as described later).

Clinical Features, Course, and Diagnostic Evaluation

Clinical features and course The nonspecific early manifestations can include depression, insomnia, agitation, anxiety, and excitability. Early signs of dementia include impairments of memory, word-finding ability, and spatial orientation.

Practical Tip

Persons who have a demonstrable memory deficit that impairs their performance of complex everyday tasks (but not of simpler ones) are said to have “mild cognitive impairment.” This can be an early manifestation of Alzheimer disease.

Within a year, patients manifest gradually worsening forgetfulness, fatigability, poor concentration, and lack of initiative. Nonetheless, motor functioning, including erect body posture, remains normal for a long time, so that the superficial appearance of good health is preserved.

There are often also focal neuropsychological deficits such as aphasia, apraxia, impaired temporal and spatial orientation, and the applause sign (described in section ▶ 5.5.1). The patient loses the ability to think abstractly or grasp complex situations, 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.

Diagnostic evaluation Early recognition and interpretation of the psychopathologic deficits described earlier is crucial for the diagnosis of the disease.

Often, the diagnosis is further supported by typical neuroimaging findings (MRI: cortical brain atrophy, especially in the temporal lobe, and ventriculomegaly; see ▶ Fig. 6.61). Neuroimaging is also mandatory because it can rule out some of the other causes of the dementia syndrome (cf. ▶ Table 6.39).

Further studies (hematologic biochemical, and serologic blood tests, CSF examination, EEG) may be indicated, depending on the specific differential diagnostic considerations in the individual patient.

A differential diagnostic overview of the main clinical and radiologic features of Alzheimer disease and other conditions resembling it is provided in ▶ Table 6.40.

Table 6.40 Distinguishing features of different types of dementia

	Alzheimer dementia	Lewy body dementia	SAE (vascular dementia)	Frontotemporal dementia (Pick disease)
Type of dementia	Cortical	Both cortical and subcortical	Subcortical	Frontal
Main cognitive manifestations	Disturbance of recent memory, visuospatial orientation, word-finding typical: normal “façade”	Combined manifestations of cortical and subcortical dementia	Slowing, forgetfulness, impaired concentration and drive	Personality change, loss of drive, sometimes aphasia
Accompanying neurologic or other bodily manifestations	Sometimes hyposmia, otherwise no particular bodily manifestations at first physical impairment, only in the late stage	Fluctuating attention and wakefulness, visual hallucinations, parkinsonism	Increased muscle tone, hypokinesia, small-stepped and broad-based gait (lower-body parkinsonism), dizziness, falls, sometimes TIAs, urinary incontinence	Early urinary incontinence, sometimes parkinsonism
Mental disturbances	Depression, later restlessness, anxious agitation, paranoia, insomnia	Insomnia, visual hallucinations, delusions	Sometimes depression, irritability, “lazy” speech	Variable; personality change, abnormal behavior, progressively “lazy” speech
Neuroimaging	CT, MRI: cortical brain atrophy, ventriculomegaly	SPECT, PET: low dopaminergic activity in occipital lobes	CT, MRI: marked SAE lesions and multiple lacunar infarcts	CT, SPECT, PET: frontal hypoperfusion and hypometabolism
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; SAE, subcortical arteriosclerotic encephalopathy; SPECT, single-photon emission computed tomography; TIAs, transient ischemic attack.

Fig. 6.61 Brain atrophy in dementia. High-grade, symmetric, 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 temporal horns, are markedly dilated, as is the third ventricle. Both external hydrocephalus and internal hydrocephalus are present (“ex vacuo,” i.e., as a result of brain atrophy).

6.12.3 Treatment and Prognosis

Treatment Cholinomimetic drugs (acetylcholinesterase inhibitors: donepezil, galantamine, rivastigmine) and antiglutamatergic NMDA-receptor antagonists (memantine) improve neuropsychological deficits symptomatically but do not halt the progression of dementia.

A possible beneficial effect of acetylsalicylic acid is currently being studied, as patients with Alzheimer disease often have concomitant small-vessel disease as a contributory cause of dementia.

No clear benefit has been shown for high-dose vitamin E, Ginkgo biloba preparations, calcium antagonists, or nootropic drugs (= drugs that putatively improve brain performance), such as piracetam.

The most important aspect of treatment in all patients is the management of the accompanying manifestations:

• Depression (preferably with selective serotonin reuptake inhibitors).

• Psychosis (preferably with clozapine or olanzapine).

• Insomnia, agitation, and aggressiveness (preferably with low-potency 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.

Prognosis Alzheimer disease always progresses. The average life expectancy from the time of diagnosis is 8 to 9 years.

6.12.4 Dementia with Lewy Bodies

Epidemiology Vascular dementia is the second most common type of dementia after Alzheimer disease, but the second most common neurodegenerative dementing disease is Lewy body dementia.

Note

Lewy body disease overlaps with Parkinson disease (section ▶ 6.9) in its neuropathologic and clinical features but differs in having dementia as a prominent early manifestation, appearing at the same time as the motor disturbances or even before them.

Pathology The neuropathologic hallmark of this disease is the presence of Lewy inclusion bodies (deposits of α-synuclein) in the neurons of the cerebral cortex and brainstem.

Clinical features In these patients, progressive dementia (of a combined cortical and subcortical type; cf. ▶ Table 6.38) is accompanied by certain other characteristic findings: there are fluctuating deficits of attention and concentration, as well as frequent, objective visual hallucinations and motor parkinsonism (particularly in patients with early disease onset). Patients often suffer from repeated falls, syncope, brief episodes of unconsciousness, and hallucinatory experiences.

Diagnosis and treatment

• SPECT and PET reveal diminished perfusion and metabolism in the occipital lobes.

• An L-DOPA challenge test may alleviate motor parkinsonism in patients with this disease (although it often does not), while tending to intensify the hallucinations. Neuroleptic drugs make all manifestations worse.

• Acetylcholinesterase inhibitors can improve both dementia and hallucinations.

6.12.5 Frontotemporal Dementia (Pick Disease)

Classification Frontotemporal dementia (Pick disease) is the commonest type of focal cortical atrophy. The dementing diseases belonging to this category, all of them much rarer than Alzheimer disease, are characterized by localized atrophy of circumscribed areas of the cerebral cortex. They are classified among the system atrophies. Histopathologic examination reveals gliosis and spongiform changes.

Additional Information

Aside from frontotemporal dementia, focal cortical atrophy can also be of the following kinds:

• 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 (see section ▶ 5.5.1, ▶ 5.5.1.4).

Frontotemporal dementia is also classified by some authors as a type of frontal lobe degeneration.

Etiology and epidemiology Some cases are hereditary, with an autosomal dominant inheritance pattern. Most patients are less than 65 years old; in this age group, frontotemporal dementia is, in fact, nearly as common as Alzheimer disease. Overall, however, the focal cortical atrophies account for only approximately 5% of all cases of dementia.

Clinical features See also ▶ Table 6.40. Patients with frontotemporal dementia often manifest frontal personality changes and abnormal social conduct (see section ▶ 5.5.1). They may have reduced drive, aphasia, and difficulty initiating speech, as well as an affect disturbance. The type of cognitive deficit depends on the particular area of cerebral cortex that is affected. Patients often develop urinary incontinence early in the course of this disease.

6.12.6 Vascular Dementia: SAE-Associated Dementia and Multi-Infarct Dementia

SAE stands for subcortical arteriosclerotic encephalopathy. On this topic, see also the discussion of lacunar infarction in section ▶ 6.5.6.

Etiology and epidemiology Vascular dementia, the second most common etiologic category of dementia, is caused either by multiple subcortical lacunar infarcts due to cerebral microangiopathy (SAE) or, less commonly, by multiple cortical and subcortical infarcts due to macroangiopathy or recurrent embolic stroke (multi-infarct dementia). These two mechanisms often operate in combination. The site and extent of the infarcts determine the severity and rate of progression of the dementia syndrome.

Clinical features See ▶ Table 6.38. Vascular dementia often strikes patients with preexisting arterial hypertension and/or other vascular risk factors. There may be a history of transient neurologic deficits in the past, due to TIAs or minor strokes. 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 neurologic findings include enhanced perioral reflexes, signs of pseudobulbar palsy (e.g., dysarthria and dysphagia), a tripping, small-stepped gait (old person’s gait, “marche à petits pas”), and, sometimes, pyramidal and extrapyramidal signs. The psychopathology of subcortical vascular dementia includes 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, often old lacunar infarcts; these are usually found in the subcortical white matter ( ▶ Fig. 6.62).

Fig. 6.62 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”).

Treatment The intermediate goal of treatment is vascular risk reduction (treatment of arterial hypertension, cardiac arrhythmias, diabetes mellitus, and hypercholesterolemia, if present; inhibition of platelet aggregation with aspirin and/or other to lower the risk of thrombosis). Generally speaking, the treatment is the same as that discussed earlier for the prevention of ischemic stroke (section ▶ 6.5.9). The symptomatic and supportive measures are the same as for Alzheimer disease: cholinomimetic drugs (donepezil, galantamine, rivastigmine) and the antiglutamatergic drug memantine alleviate the cognitive disturbances.

Course and prognosis Vascular dementia is a progressive illness, typically with stepwise progression. The rate of progression is variable, however, as it depends on the type and extent of the underlying arteriopathy.

6.12.7 Dementia due to Malresorptive Hydrocephalus

Synonym This disorder is often incorrectly called (idiopathic or secondary) normal pressure hydrocephalus.

Epidemiology The peak incidence is between the ages of 50 and 70 years.

Etiology This disorder can arise in the aftermath of meningitis, aneurysmal or traumatic subarachnoid hemorrhage, or venous sinus thrombosis; as a consequence of elevated CSF protein concentration; or spontaneously, that is, without any known risk factor. The common pathophysiologic mechanism is impaired CSF outflow through the arachnoid granulations and nerve root pouches, leading to a buildup of CSF and ventricular dilatation (see ▶ Fig. 6.2).

Clinical features The classic clinical triad of malresorptive hydrocephalus includes a progressively severe gait disturbance, urinary incontinence, and psycho-organic syndrome. Neurologic examination reveals paraparesis, ataxia, impaired memory, and, in advanced stages, dementia. Some patients also have headache.

Diagnostic evaluation CT or MRI characteristically reveals enlarged lateral ventricles, while the subarachnoid space appears tight ( ▶ Fig. 6.2c). The CSF pressure measured via LP is normal or, at most, mildly elevated (hence the alternative name of this condition, “normal pressure hydrocephalus”).

Practical Tip

The removal of CSF via LP can bring about prompt, but transient, improvement of the patient’s gait and memory. The “sticky” and small-stepped gait can suddenly become much more fluid. A good response to CSF removal (the “CSF tap test”) supports the diagnosis of malresorptive hydrocephalus and implies a likely benefit from treatment with a shunt (see later).

Treatment If the patient responds well to the CSF tap test, a ventriculoperitoneal shunt is neurosurgically implanted. This generally leads to an improvement of the symptomatic triad.