Color Atlas of Neurology

Basilar impression: Dens > 5 mm over Chamberlain’s line and > 7 mm over McGregor’s line

Angle between root of nose and clivus (enlarged in platybasia)

Foramen magnum (anterior and posterior margins)

Palato-occipital Hard palate (Chamberlain’s)

Dens

line

Basal (McGregor’s) line

Lines for assessment of platybasia and basilar impression

Short neck, abnormal neck posture

Klippel-Feil syndrome

! Symptoms and Signs

Early stage. Memory impairment develops gradually and almost imperceptibly, barely differing at first from that of benign senile forgetfulness (p. 136). Ultimately, however, the cognitive deficits of AD produce noticeable changes of behavior, e. g., when the patient is working, shopping, running errands, or taking care of finances, or operating such devices as a telephone, stove, television, or computer. The patient may be aware of these deficits and become additionally anxious and depressed because of them. The distinction between AD with depressive features and primary depression with secondary cognitive changes (pseudodementia) has major implications for treatment (Table 42, p. 383).

Intermediate stage. The patient is too confused and disoriented to carry out previous occupational and social activities (p. 132) and needs help and supervision in almost all activities, but may still be able to perform habitual daily routines, carry on a simple conversation, and abide by the basic rules of etiquette. Aphasia (e. g., impaired comprehension of speech, word-finding difficulty, cf. p. 126) and apraxia (p. 128) are often present. The patient cannot do simple arithmetic or tell time. Visual agnosia is rare at this stage.

Late stage. The increasing cognitive impairment and loss of reasoning and judgment make it impossible for the patients to plan their activities. The patient’s aimless wandering, undirected motor activity, and inability to recognize people—even close relatives and friends— complicate the caregiver’s job, along with changes in the patient’s circadian rhythm (quiet or apathetic by day, restless by night), impulsive behavior (packing suitcases or running away), delusions, hallucinations, paranoid suspicion of close relatives and friends, aggressive behavior, and neglect of personal hygiene. Patients with advanced AD need help with the simplest activities of daily living (eating, dressing, going to the toilet). They may become incontinent of urine and stool, bedridden, akinetic, and mute. Pathological reflexes (sucking and grasping) can be elicited. Auditory and tactile stimuli may trigger epileptic seizures and myoclonus (for differentiation from

Creutzfeldt–Jakob disease, see p. 252). Death is caused by secondary complications such as pneumonia and heart failure.

! Pathogenesis

PET and SPECT studies in early AD reveal bilateral metabolic disturbances in the parietotemporal cortex and decreased neurotransmitter activity in cortical cholinergic fibers (acetylcholine, choline acetyltransferase, nicotinic acetylcholine receptors nucleus basalis, medial septal region), serotonergic fibers (raphe nuclei), and noradrenergic fibers (locus coeruleus). There is probably a reduction of cortical glutamatergic activity (excitatory) with a preponderance of GABAergic activity (inhibitory). Neuropathology: Changes such as neuronal death, neuritic (senile) plaques (NPs), and intraneuronal neurofibrillary tangles (NFTs) are seen mainly in the entorhinal cortex, hippocampus, temporal cortex, primary/secondary visual cortex, and nucleus basalis. NPs consist of a central core containing amyloid-A", apolipoprotein E (Apo E), α1-antichymotrypsin, synuclein, and other proteins, surrounded by dead neurons, activated glial cells, macrophages, and other inflammatory cells. NFTs consist of paired helical filaments (PHFs) composed of tau proteins, which are normally an important stabilizing component of the microtubular (neurofibrillary) cytoskeleton. Increased phosphorylation of tau proteins leads to the formation of NFTs. Amy- loid-A" (normal function unknown) is formed by proteolysis of the transmembrane amyloid precursor protein (APP), to which neurotrophic and neuroprotective properties have been ascribed. A point mutation in APP on chromosome 21q has been implicated in familial AD; patients over 40 years of age with Down syndrome (trisomy 21) also have neuropathological changes similar to those of AD. Accumulation of amyloid-A" in arterial walls is the basic abnormality in amyloid angiopathy (p. 178). The gene for Apo E (a lipoprotein involved in cholesterol transport) is found on chromosome 19q and has three alleles, designated ε2, ε3, and ε4; ε4 is strongly associated with both sporadic and familial AD. Other familial forms of AD have been traced to mutations of the presenilin-1 gene (PS1 14q24.3 protein S182) and the pre- senilin-2 gene (PS2 1q31-42 STM2 protein).

Huntington Disease (HD)

The first symptoms of HD typically appear between the ages of 35 and 45 years. HD appearing before age 20 (the Westphal variant of HD) is characterized by akinesia, bradykinesia, epileptic seizures, action tremor, and myoclonus. Onset before age 10 or after age 70 is rare. HD patients require total nursing care 10–15 years after the onset of this inexorably progressive, and ultimately fatal degenerative disease.

! Symptoms and Signs

Early stage. In cases of earlier onset, akinesia and cognitive impairment tend to be more prominent than choreiform movements, while, in cases of later onset, the reverse is true. Behavioral changes such as depression, suicidal tendencies, paranoia, querulousness, irritability, impulsiveness, emotional outbursts, aggressive behavior, poor hygiene, loss of initiative, and inappropriate sexual behavior impair familial and social relationships and may even lead to criminal charges. Other changes include cognitive slowing, diminished tolerance for stress, and impairment of memory and concentration. The patient becomes obviously unable to perform his or her usual tasks at work or at home. Chorea (p. 66; Table 43, p. 383) may initially be misdiagnosed as “nervous” agitation or fidgeting. Even severe chorea disappears during sleep. Chorea may be accompanied by akinesia, dystonia, and decreased voluntary motor control. The patient’s gait is impaired by poor balance and loss of postural motor control. Oculomotor disturbances are also common.

Intermediate stage. Progressive dementia (p. 136) is accompanied by loss of drive, generalized choreiform, dystonic, and bradykinetic movements, and frequent falls.

Late stage. Many patients become cachectic, with muscular atrophy ( interosseous muscles of hands) and weight loss despite an adequate caloric intake. Chorea is largely replaced by akinesia in late HD. General motor control is greatly impaired. Urinary incontinence is not uncommon. These patients need full nursing care.

! Pathogenesis (for abbreviations, see p. 211)

HD is characterized by generalized cerebral atrophy, especially of the dorsal striatum

(p. 210), and, neurochemically, by a marked deficiency of GABA and of glutamate decarboxylase (an enzyme involved in GABA synthesis). HD is transmitted in an autosomal dominant pattern with complete penetrance, that is, all persons bearing the gene eventually develop the disease. The gene for HD (IT15) is on the end of the short arm of chromosome 4 (4p16.3), which contains CAG repeats (the trinucleotide sequence CAG codes for glutamine; cf. p. 288). Healthy subjects have 11–34 CAG repeats at this locus, while persons with HD have more than 40. Paternal inheritance is associated with anticipation (increasingly early onset in subsequent generations), but maternal inheritance is not. The gene product is referred to as huntingtin. The pathophysiological mechanism of HD remains obscure; increased glutamatergic transmission at NMDA receptors is thought to produce neurodegenerative changes (excitotoxicity). There is now a direct gene test that can be performed on a peripheral blood sample to detect HD before the onset of symptoms. It may only be performed with the informed consent of a patient above the legal age of majority, after the potential social and psychiatric implications of a positive result have been explained.

Neuroacanthocytosis

Acanthocytes (crenated erythrocytes with thorny processes) make up more than 3% of all erythrocytes in fresh blood smears obtained from patients with the following neurological diseases: abetalipoproteinemia (Bassen–Korn- zweig syndrome, p. 280, 307; cholesterol and triglycerides), McLeod syndrome (X-linked recessive myopathy; absence of Kell precursor protein), and neuroacanthocytosis (normal lipoprotein concentrations). The mode of inheritance of neuroacanthocytosis is unknown. Its major features, orofacial dyskinesia (tonguebiting and lip-biting) and chorea, usually appear between the ages of 20 and 30 years.

Behavioral changes

Chorea

Dementia

Nursing dependence

Thalamus

GL GL

ACh

GABA GABA

GL

DA GABA

GLGABA

Normal functions

NMDA receptor

Chromosome 4

Stimulation of glutamate receptors

Activity of thalamocortical projection (hyperkinesia)

CN

Ventral lateral nucleus of thalamus

Putamen

GPe

Activity (direct striatonigral system)

Functional disturbances in

Huntington disease