Color Atlas of Neurology

Nonepileptic Seizures

Psychogenic seizure	Eyes closed; patient squeezes
(with arc de cercle)	eyes shut when examiner
	attempts to open them

Panic attack (hyperventilation, psychomotor restlessness)

Central Nervous System

203

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Central Nervous System

204

Nonepileptic Seizures

! Drop Attacks

Sudden, unprovoked, and unheralded falls without loss of consciousness are most common in patients over 65 years of age. Some 10–15% of these drop attacks cause serious injury, particularly fractures. The patient may not be able to get up after a fall. The common causes of recurrent falls in each age group are listed in Table 26 (p. 374). Those associated with loss of consciousness are described on pages 192 ff and 200.

! Hyperventilation Syndrome (Tetany)

The clinical manifestations include paresthesiae (perioral, distal symmetrical or unilateral), generalized weakness, palpitations, tachycardia, dry mouth, dysphagia, dyspnea, yawning, pressure sensation in the chest, visual disturbances, tinnitus, dizziness, unsteady gait, muscle stiffness, and carpopedal spasms. The patients report feelings of restlessness, panic, unreality, or confusion. Psychological causes include anxiety, hysteria, and inner conflict. Metabolic causes include hypocalcemia (due to hypoparathyroidism, vitamin D deficiency, malabsorption, or pancreatitis) and a wide range of other disturbances including hypercalcemia, hypomagnesemia, prolonged vomiting, pulmonary embolism, salicylate intoxication, acute myocardial infarction, severe pain, high fever due to septicemia, pneumothorax, stroke, and neurogenic pulmonary edema. Chronic hyperventilation syndromes are more common than acute syndromes, but also more difficult to diagnose.

! Tonic Spasms

! Acute Dystonic Reaction

Acute dystonic reactions can occur within a few hours to one week of starting treatment with dopamine receptor antagonists, e. g., neuroleptics (benperidol, fluphenazine, haloperidol, triflupromazine, perphenazine), antiemetics (metoclopramide, bromopride), and calcium antagonists (flunarizine, cinnarizine). Symptoms and signs: focal or segmental dystonia (p. 64), sometimes painful, marked by oculogyric crisis, blepharospasm, pharyngospasm with glossospasm and laryngospasm, or oromandibular dystonia with tonic jaw and tongue movements. Generalized reactions are also seen on occasion (p. 66).

These are unilateral muscular spasms (often painful) that are not accompanied by loss of consciousness; they last seconds to minutes, and occur up to 30 or more times a day. They are most commonly seen in multiple sclerosis, less commonly in cerebrovascular disorders. These spasms are often triggered by movement. Some patients have paresthesiae (tingling, burning) contralateral to the affected side before the muscle spasm sets in. The underlying lesion may be in the brain stem (pons) or internal capsule.

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Drop attack

Nonepileptic Seizures

Central Nervous System

Hyperventilation

Tonic spasms	Acute dystonic reaction	205
(muscular spasms on left)	(oculogyric crisis, oromandibular/pharyngeal dystonia)

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Central Nervous System

206

Parkinson Disease: Clinical Features

The diagnosis of Parkinson disease (PD; sometimes termed idiopathic Parkinson disease, to distinguish it from symptomatic forms of parkinsonism, and from other primary forms) is mainly based on the typical neurological findings, their evolution over the course of the disease, and their responsiveness to levodopa (L- dopa). Longitudinal observation may be necessary before a definitive diagnosis of PD can be given. PD is characterized by a number of disturbances of motor function (cardinal manifestations) and by other accompanying manifestations of different kinds and variable severity.

Cardinal Manifestations

Bradykinesia, hypokinesia, and akinesia. Motor disturbances include slow initiation of movement (akinesia), sluggishness of movement (bradykinesia) and diminished spontaneous movement (hypokinesia); these terms are often used nearly interchangeably, as these disturbances all tend to occur together. Spontaneous fluctuations of mobility are not uncommon. The motor disturbances are often more pronounced on one side of the body, especially in the early stages of disease. They affect the craniofacial musculature to produce a masklike facies (hypomimia), defective mouth closure, reduced blinking, dysphagia, salivation (drooling), and speech that is diminished in volume (hypophonia), hoarse, poorly enunciated, and monotonous in pitch (dysarthrophonia). The patient may find it hard to initiate speech, or may repeat syllables; there may be an involuntary acceleration of speech toward the end of a sentence (festination). Postural changes include stooped posture, a mildly flexed and adducted posture of the arms, and postural instability. Gait disturbances appear in the early stages of disease and typically consist of a small-stepped gait, shuffling, and limping, with reduced arm swing. Difficulty initiating gait comes about in the later stages of disease, along with episodes of “freez- ing”—complete arrest of gait when the patient is confronted by doorway or a narrow path between pieces of furniture. It becomes difficult for the patient to stand up from a seated position, or to turn over in bed. Impairment of fine motor control impairs activities of daily living such as fastening buttons, writing (micro-

graphia), eating with knife and fork, shaving, and hair-combing. It becomes difficult to perform two activities simultaneously, such as walking and talking.

Tremor. Only about half of all PD patients have tremor early in the course of the disease; the rest usually develop it as the disease progresses. It is typically most pronounced in the hands (pill-rolling tremor) and is seen mainly when the affected limbs are at rest, improving or disappearing with voluntary movement. Its frequency is ca. 5 Hz, it is often asymmetrical, and it can be exacerbated by even mild stress (mental calculations, etc.).

Rigidity. Elevated muscle tone is felt by the patient as muscle tension or spasm and by the examiner as increased resistance to passive movement across the joints. Examination may reveal cogwheel rigidity, i.e., repeated, ratchetlike oscillations of resistance to passive movement across the wrist, elbow, or other joints, which may be brought out by alternating passive flexion and extension.

Postural instability (loss of balance). Propulsion and retropulsion arise in the early stages of Parkinson disease because of generalized impairment of the postural reflexes that maintain the bipedal stance. Related phenomena include involuntary acceleration of the gait (festination), difficulty in stopping walking, gait instability, and frequent falls.

Accompanying Manifestations

! Behavioral Changes

Depression. The range of depressive manifestations includes worry, anxiety, avoidance of social contact, general unhappiness, listlessness, querulousness, brooding, somatoform disturbances, and (rarely) suicidal ideation.

Anxiety. Tension, worry, mental agitation, lack of concentration, and dizziness are relatively common complaints.

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Parkinson Disease: Clinical Features

Hypomimia	Drooling
	Facial expression

	Postural change	Gait impairment (postural instability, propulsion, festination)
	(hypokinesia-left)

Micrographia

Resting tremor

Rigidity (cogwheel phenomenon)

Central Nervous System

207

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Parkinson Disease: Clinical Features

		Dementia. Impairment of memory and concen-
		tration in early PD-associated dementia may be
		difficult to distinguish from depressive manife-
		stations. The side effects of pharmacotherapy
		(p. 212) must be kept in mind before treatment
		is initiated for patients suffering from disorien-
		tation, confusion, suspiciousness, and other
		emotional changes. Impaired memory is usually
		not a major feature of PD; as the disease pro-
		gresses, about 20% of patients develop
		decreased flexibility of thought and action, per-
	System	severation, and increasing difficulty in planning
		future activities. The development of dementia
		in PD is correlated with an increase in the num-
		ber of Lewy bodies (pp. 210).
	Nervous	Hallucinations. A state of excessive suspicious-
		ness, vivid dreams, and increasing anxiety may
		evolve into one of severe confusion with visual
		hallucinations. Frank psychosis (e. g., paranoid
	Central	delusions,	ideas of	reference, or	delusional
		jealousy) may be due to other causes than PD,
		particularly an adverse effect of antiparkin-
		sonian medication. Dementia with Lewy bodies
		(a syndrome in which the clinical features of
		Parkinson disease are found together with
		dementia, fluctuating level of consciousness,
		visual hallucinations, and frequent falls) is
		another possible cause, especially in patients
		who are unusually sensitive to low doses of neu-
		roleptics ( exacerbation of parkinsonism,
		delirium,	malignant	neuroleptic	syndrome,
		p. 347).

! Autonomic Dysfunction

Blood pressure changes. Hypotension is a common side effect of antiparkinsonian medications (levodopa, dopamine agonists). Marked orthostatic hypotension, if present, suggests the possible diagnosis of multisystem atrophy.

Constipation may be caused by autonomic dysfunction, as a manifestation of the disease, or as a side effect of medication (anticholinergic agents).

Bladder disorders. Polyuria, urinary urgency, and urinary incontinence occur mainly at night and in patients with severe akinesia (who have difficulty getting to the toilet). PD only rarely causes severe bladder dysfunction.

208Sleep disorders. PD commonly causes disturbances of the sleep–wake cycle, including diffi-

culty falling asleep, nocturnal breathing prob-

lems similar to sleep apnea syndrome, and shortening of the sleep cycle. Sleep may also be interrupted by nocturnal akinesia, which makes it difficult for the patient to turn over in bed.

Sexual dysfunction. Spontaneous complaints of diminished libido or impotence are rare. Increased libido is a known side effect of levodopa and dopamine agonists.

Hyperhidrosis. Mainly occurs as generalized, irregular, sudden episodes of sweating. Seborrhea. Mainly on the forehead, nose, and scalp (greasy face, seborrheic dermatitis).

Leg edema is often the result of physical inactivity.

! Sensory Manifestations

Pain in the arm or shoulder, sometimes accompanied by fatigue and weakness, may be present for years before the cardinal manifestations arise and enable a diagnosis of PD. Back pain and nuchal cramps are frequent secondary effects of parkinsonian rigidity and abnormal posture. Dystonia may also come to attention because of the pain it produces.

Dysesthesia. Heat, burning or cold sensations may be felt in various parts of the body. For restless legs syndrome, see p. 114.

! Other Motor Manifestations

Dystonia. Tonic dorsiflexion of the big toe with extension or flexion of the other toes may occur in the early morning hours or during walking. Dystonia may be drug-induced (e. g., by levodopa) or due to the disease itself. The differential diagnosis includes dopa-responsive dystonia (a disorder of autosomal dominant inheritance) and Wilson disease (p. 307), two predominantly dystonic motor disorders with onset in childhood and adolescence.

Visual disturbances are caused by impairment of eye movement. Vertical gaze palsy is suggestive of progressive supranuclear palsy (p. 302). The reduced blinking rate of PD may lead to a burning sensation on the cornea, or to conjunctivitis.

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Parkinson Disease: Clinical Features

Seborrhea

Orthostatic hypotension

Constipation

Urinary dysfunction, impotence

Behavioral changes

Edema

(depression, anxiety, dementia)

Autonomic dysfunction

Dystonia (of foot)

Sleep disorders

(increased rigidity at night, ”mental pillow”)

Pain

Central Nervous System

209

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Parkinson Disease: Pathogenesis

		Basal ganglia. The basal ganglia consist of the
		caudate nucleus (CN), putamen, globus pallidus
		(= pallidum; GPe = external segment, GPi = in-
		ternal segment; putamen + pallidum = lentiform
		nucleus), claustrum, substantia nigra (SN; SNc =
		pars compacta, SNr = pars reticularis), and the
		subthalamic nucleus (STN). CN + putamen =
		(dorsal) striatum; nucleus accumbens + portions
		of olfactory tubercle + anterior portion of puta-
		men + CN = limbic (ventral) striatum. Substantia
		nigra (SN): The SNr (ventral portion of SN) con-
	System	tains small amounts of dopamine and iron,
		giving it a reddish color, while the SNc (dorsal
		portion) contains large quantities of dopamine
		and melanin, making it black (whence the
	Nervous	name, substantia nigra).
		gated) neural pathways (circuits). Each circuit
		Connections. The basal ganglia are part of a
		number of parallel and largely distinct (segre-
	Central	originates in a cortical area that is specialized
		for a specific function (skeletal motor, oculomo-
		tor, associative-cognitive, or emotional-moti-
		vational control), passes through several relay
		stations in the basal ganglia, and travels by way
		of the thalamus back to the cerebral cortex. Cor-
		tical projection fibers enter the basal ganglia at
		the striatum (input station) and exit from the
		GPi and SNr (output station). Input from the
		thalamus and brain stem also arrives at the stri-
		atum. Within the basal ganglia, there are two
		circuits subserving motor function, the so-called
		direct and indirect pathways. The direct path-
		way runs from the putamen to the GPi and SNr,
		while the indirect pathway takes the following
		trajectory: putamen GPe STN GPi SNr.
		The GPi and SNr project to the thalamus and
		brain stem.

Neurotransmitters. Glutamate mediates excitatory impulses from the cortex, amygdala, and hippocampus to the striatum. Synapses from STN fibers onto cells of the GPi and SNr are also glutamatergic. Both the excitatory and the inhibitory projections of the SNc to the basal ganglia are dopaminergic. In the striatum, dopamine acts on neurons bearing D1 and D2 receptors, of which there are various subtypes (D1 group: d1, d5; D2 group: d2, d3, d4). D1 receptors predominate in the direct pathway, D2 receptors in the indirect path-

210way. Cholinergic interneurons in the striatum form a relay station within the basal ganglia

(transmitter: acetylcholine). Medium spiny-type

neurons (MSN) in the striatum have inhibitory projections to the GPe, GPi, and SNr (transmitters: GABA, substance P/SP, enkephalin/Enk). Other inhibitory GABAergic projections run from the GPi to the STN, from the GPi to the thalamus (ventrolateral and ventroanterior nucleus), and from the SN to the thalamus. The thalamocortical projections are excitatory.

Motor function. The direct pathway is activated by cortical and dopaminergic projections to the striatum. The projection from the striatum in turn inhibits the GPi, diminishing its inhibitory output to the thalamic nuclei (i.e., causing net thalamic activation). Thalamocortical drive thus facilitates movement initiated in the cerebral cortex (voluntary movement). In the indirect pathway, the striatum, under the influence of afferent cortical and dopaminergic projections, exerts an inhibitory effect on the GPe and STN. The result is a diminished excitatory influence of the STN on the GPi and SNr, ultimately leading to facilitation of cortically initiated voluntary movement and inhibition of involuntary movement.

! Pathophysiology

The cause of Parkinson disease is unknown. Its structural pathological correlate is a loss of neurons in the caudal and anterolateral parts of the SNc, with reactive gliosis and formation of Lewy bodies (eosinophilic intracytoplasmic inclusions in neurons) and Lewy neurites (abnormally phosphorylated neurofilaments) containing α- synuclein. Loss of pigment in the substantia nigra can be seen macroscopically. The most prominent neurochemical abnormality is a deficiency of dopamine in the striatum, whose extent is directly correlated with the severity of PD. The physiological effect of the lack of (mostly inhibitory) dopamine neurotransmission in the striatum is a relative increase in striatal activity, in turn causing functional disinhibition of the subthalamic nucleus via the indirect pathway. Meanwhile, in the direct pathway, decreased striatal inhibition of the GPi enhances the inhibitory influence of the GPi on the thalamus, leading to reduced activity in the thalamocortical projection. These changes in neural activity manifest themselves in the clinically observable akinesia, rigidity, and postural instability. For tremor, see p. 62.

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					Parkinson Disease: Pathogenesis
Cerebral cortex			Thalamocortical projections
Thalamus
CN				Indirect		Melanin
				pathway
						pigment
				Putamen
STN				GPe
				GPi			System
SN					Neuron	Lewy
				Nucleus
						body
				accumbens
			Direct pathway				Nervous
		Cerebral peduncle
Superior			Pons	Thalamus	Ventral lateral nucleus, ventral
colliculus	Red					anterior nucleus	Central
	nucleus					(thalamus)
Basal ganglia			GL GL			Putamen
					CN
						MSN
		ACh
			GABA,Enk GABA
			GABA
			GL
		DA			GPi
			GABA,SP		GPe
				STN
			GL
				GABA
Direct pathway
					SNr
Neurotransmitters:					SNc
GL: Glutamate
ACh: Acetylcholine						Connections:
DA: Dopamine
						Red: Excitatory
						Blue: Inhibitory
						Green: Excitatory and	211
	Functional organization (left, normal; right, Parkinson disease)					inhibitory

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Central Nervous System

212

Parkinson Disease: Treatment

The goal of treatment is improvement of the motor, autonomic, and cognitive symptoms of the disease. The treatment generally consists of medication along with physical, occupational, and speech therapy. Neurosurgical procedures are mostly reserved for intractable cases (see below). Pharmacotherapy is palliative, not curative. It is begun when the patient has trouble carrying out the activities of daily living and is prescribed, not according to a uniform pattern, but in relation to the needs of the individual patient.

! Symptomatic Treatment

Dopaminergic agents. Levodopa is actively absorbed in the small intestine and rapidly distributed throughout the body (especially to skeletal muscle). Amino acids compete with the levodopa transport system at the blood–brain barrier. A decarboxylase inhibitor that does not penetrate the blood–brain barrier (benserazide or carbidopa) is administered together with levodopa to prevent its rapid breakdown in the peripheral circulation. Once it reaches the brain, levodopa is decarboxylated to dopamine, which is used for neurotransmission in the striatum. After it has been released from the presynaptic terminals of dopaminergic neurons in the striatum and exerted its effect on the postsynaptic terminals, it is broken down by two separate enzyme systems (deamination by monoamine oxidase type B, MAO-B; methylation by cate- chol-O-methyltransferase, COMT). Levodopa effectively reduces akinesia and rigidity, but has only a mild effect against tremor. Its long-term use is often complicated by motor fluctuations, dyskinesia, and psychiatric disturbances. Dopamine agonists (DAs) mimic the function of dopamine, binding to dopamine receptors. Their interaction with D1 and D2 receptors is thought to improve motor function, while their interaction with D3 receptors is thought to improve cognition, motivation, and emotion. Long-term use of DAs is less likely to cause unwanted motor side effects than long-term use of levodopa. Commonly used DAs include bromocriptine (mainly a D2 agonist), lisuride (mainly a D2 agonist), and pergolide (a D1, D2, and D3 agonist). Apomorphine, an effective D1 and D2 agonist, can be given by subcutaneous injection, but its effect lasts only about 1 hour. Other, recently in-

troduced dopamine agonists are ropinirol and pramipexol (D2 and D3), cabergoline (D2), and α- dihydroergocryptine (mainly D2).

Selegiline inhibits MAO-B selectively and irreversibly ( reduced dopamine catabolism increase in striatal dopamine concentration). Entacapone increases the bioavailability of levodopa via peripheral inhibition of COMT.

Nondopaminergic agents. Anticholinergic agents

(biperidene, bornaprine, metixene, trihexyphenidyl) act on striatal cholinergic interneurons. Budipine can relieve tremor (risk of ventricular tachycardia ECG monitoring). Glutamate antagonists (amantadine, memantine) counteract increased glutamatergic activity at the N-methyl-D-aspartate (NMDA) glutamate receptor in the indirect pathway.

! Transplant Surgery

Current research on intrastriatal transplantation of stem cells (derived from fetal tissue, from umbilical cord blood, or from bone marrow) seems promising.

!Stereotactic Neurosurgical Procedures, Deep Brain Stimulation (for abbreviations, see

p. 210)

These procedures can be used when PD becomes refractory to medical treatment. Pallidotomy (placement of a destructive lesion in the GPi) derives its rationale from the observed hyperactivity of this structure in PD. Deep brain stimulation requires bilateral placement of stimulating electrodes in the GPi or STN. Highfrequency stimulation by means of a subcutaneously implanted impulse generator can improve rigor, tremor, akinesia, and dyskinesia.

! Genetics of PD

A genetic predisposition for the development of PD has been postulated. Mutations in the genes for α-synuclein (AD), parkin (AR), and ubiquitin C-terminal hydrolase L1 (UCHL1; AD) have been found in pedigrees affected by the rare autosomal dominant (AD) and autosomal recessive (AR) familial forms of PD.

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