Dementing Diseases 137

The differential diagnosis must include all noncerebellar 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 confine-

ment 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.

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 diseases in 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.

!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 dis-

ease, 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., multiinfarct) dementia (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:

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,

and symbol comprehension;

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

impairment of attention;

reduced drive, initiative, and motivation;

impaired concentration;

mild fatigability;

affect lability and impaired affect control;

impairment of emotionality and social behavior;

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:

nonpathological diminution of cognitive ability in old age;

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6

Diseases of the Brain and Meninges

138	6		Diseases of the Brain and Meninges
		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		Epilepsy:
		as their principal manifestation:		—	progressive myoclonus epilepsy1
		—	Alzheimer disease1	—	frequent seizures, status epilepticus2
		—	Pick disease	—	diseases causing both dementia and epilepsy1
		—	frontal lobe degeneration	Demyelinating diseases:
		—	Lewy body disease
				—	multiple sclerosis1
		Other degenerative diseases causing dementia:		Systemic diseases, endocrine disorders, and deficiency states:
		—	Parkinson disease1
				— hypothyroidism, Hashimoto thyroiditis2
		— progressive supranuclear palsy1
				—	hypopituitarism2
		— pantetheine kinase-associated neurodegeneration (formerly
				—	hepatic encephalopathy1
			Hallervorden−Spatz disease)
				—	uremic encephalopathy2
		—	hereditary ataxias
				—	hypoxic brain injury
		— progressive myoclonus epilepsy1
				—	hypoglycemia1
		Cerebrovascular diseases:		—	electrolyte disorders1
		—	multi-infarct syndrome1	—	hypercalcemia, hyperparathyroidism2
		—	“strategic” infarcts1	—	vasculitis, connective tissue disease2
		—	Binswanger disease (subcortical arteriosclerotic encephalopa-	—	vitamin B12 deficiency2
			thy)1	—	pellagra2
		Infectious diseases:		—	Wernicke encephalopathy1
				— jejuno-ileal bypass2
		—	HIV, AIDS−dementia complex1
		—	other viral encephalitides and postviral encephalopathies1	Toxic conditions:
		—	prion diseases	—	alcoholism2
			kuru	—	heavy metal poisoning2
			Creutzfeldt−Jakob disease	—	carbon monoxide poisoning
			Gerstmann−Sträussler−Scheinker syndrome	—	organic solvent poisoning1
			familial fatal insomnia	—	medication toxicity2
			familial progressive subcortical gliosis	Mental illnesses:
		— syphilis (progressive paralysis)2
				—	depression2
		—	brain abscesses2
				—	schizophrenia2
		—	Whipple disease2
				—	hysteria2
		Metabolic disorders affecting the brain:		Hydrocephalus:
		—	Wilson disease2
				—	obstructive hydrocephalus2
		— disorders of lipid, protein, urea. and carbohydrate metabolism1
				—	malresorptive hydrocephalus2
		—	leukodystrophies

Neoplasia:

Trauma:

— primary brain tumors, metastases1

— open trauma with destruction of brain tissue

— paraneoplastic encephalopathies1

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

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

2usually curable or, at least, largely treatable

	depression with severely reduced drive (so-called	cluding depression, delusions, insomnia, and agitation.
	depressive pseudodementia);	Training of the remaining cognitive abilities is also advis-
	an isolated neuropsychological disturbance (espe-	able in order to keep the patient functionally independ-
	cially aphasia, apraxia, and/or agnosia);	ent for as long as possible. In advanced stages, patients
congenital mental retardation (oligophrenia);		often require home nursing visits, or care in a suitable
	cognitive impairment by medications or drugs of	day clinic; removal from the home to a permanent care
	abuse;	facility should be deferred for as long as this is practi-
	status epilepticus with partial complex seizures or	cally achievable. The patient’s family is thus the most im-
	absences;	portant component of treatment. Family members
cognitive impairment due to endogenous psychosis.		should receive early and thorough information about
General aspects of treatment. If the dementia syn-		the patient’s disease and, where appropriate, counseling
		in the ways they can help care for the patient.
drome is found to be due to a treatable condition, causa-		The common degenerative diseases of the brain
tive treatment can be instituted, resulting in cure or, at		whose major clinical manifestation is dementia are de-
least, the prevention of further progression of dementia.		scribed in greater detail in the next section, and vascular
In all other cases, however, dementia responds poorly to		dementia in the section immediately following.
treatment, if at all. The current medications for
Alzheimer disease provide only modest clinical benefit,
often at the cost of side effects. Various symptoms ac-
companying dementia can be treated individually, with
major benefit to the patient and his or her family, in-

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Dementing Diseases

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 21q, 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.

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 highdose 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.

139

6

Diseases of the Brain and Meninges

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140 6 Diseases of the Brain and Meninges

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				Fig. 6.37 Vascular encephalopathy as seen by MRI. There are
					multiple focal signal abnormalities in the deep white matter, the
	SAE-Associated Dementia and Multi-infarct				subcortical region, and the cerebral cortex. The ventricles and sub-
	Dementia				arachnoid space are dilated (“hydrocephalus ex vacuo”).
	Etiology. Vascular dementia, the second most common
	etiologic category of dementia, is caused either by mul-
	tiple subcortical lacunar infarcts due to cerebral micro-
	angiopathy	(subcortical	arteriosclerotic	en-	The psychopathological abnormalities in patients with
	cephalopathy, SAE: more common type) or by multiple				predominantly subcortical lesions include apathy, de-
	cortical and subcortical infarcts due to macroangiopathy				pression, and slowness. Patients can recall old informa-
	or recurrent embolic stroke (multi-infarct dementia: less				tion more easily than they can store new information.
	common type). The two types often appear together.				Diagnostic evaluation. Neuroimaging reveals brain
	The sites and extent of the infarcts determine the sever-
	ity and progression of the dementia syndrome.				atrophy and evidence of multiple focal lesions (usually
	Clinical manifestations.		Vascular dementia	often	in the subcortical white matter; see Fig. 6.37).
					Course. Vascular dementia is, in principle, a progressive
	strikes patients with preexisting arterial hypertension
	and/or other vascular risk factors. There may be a his-				illness, but the speed of progression is variable, as it de-
	tory of transient neurological deficits in the past.				pends on the type and extent of the underlying arteri-
	Dementia can arise suddenly or progress in spurts. There				opathy.
	may be accompanying neuropsychological deficits, such				Treatment. The intermediate goal of treatment is
	as aphasia, as well as marked incontinence of affect: in-
	voluntary laughing and crying are common. The neuro-				vascular risk reduction (treatment of arterial hyperten-
	logical findings include enhanced perioral reflexes, signs				sion, cardiac arrhythmias, and diabetes mellitus, if pre-
	of pseudobulbar palsy (e. g., dysarthria and dysphagia),				sent; inhibition of platelet aggregation with aspirin and/
	a tripping, small-stepped gait (old person’s gait,				or other drugs). Generally speaking, the treatment is the
	“marche à petits pas”), and, sometimes, pyramidal and				same as that discussed above for the prevention of
	extrapyramidal signs.				ischemic stroke (p. 105).

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