Diseases of the Basal Ganglia 127

Tabelle 6.23 Paraneoplastic syndromes affecting the nervous system

Syndrome/structure	Clinical features	Remarks
affected

Paraneoplastic	affects the cerebral hemispheres, limbic system,
encephalomyelitis	brainstem, cerebellum, and spinal cord; limbic sys-
	tem involvement is prominent; confusion, agita-
	tion, hallucinations, anxiety, depression, epileptic
	seizures, pyramidal tract signs
Paraneoplastic cere-	rapidly progressive cerebellar ataxia (weeks), disa-
bellar degeneration	bling truncal and appendicular ataxia, dysarthria,
	nystagmus, and sometimes other neurological defi-
	cits
Paraneoplastic	sensory or, less commonly, sensorimotor poly-
polyneuropathy	neuropathy or mononeuropathy
Paraneoplastic	myasthenic syndrome preferentially affecting the
syndromes of the	extraocular and bulbar musculature in myasthenia
neuromuscular junc-	gravis and the limb muscles in Lambert−Eaton syn-
tion: myasthenia	drome
gravis and Lambert−
Eaton syndrome
Dermatomyositis,	progressive muscle weakness; in dermatomyositis,
polymyositis	skin changes also

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

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

mainly in lung carcinoma

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

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

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:

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

muscular hyperor hypotonia (in most patients)

involuntary movements (often)

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:

hypertonic−hypokinetic syndromes and

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.

6

Diseases of the Brain and Meninges

blubber blubber

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme All rights reserved. Usage subject to terms and conditions of license.

128 6		Diseases of the Brain and Meninges
Idiopathic Parkinson Disease
Epidemiology. Parkinson disease has an overall preva-
	lence 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 un-
	known. 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, cer-
	tain genetic factors do appear to play a role in its causa-
	tion (above all the chromosome segments 2q, 6q, 4q,
	and 4p).
	The neuropathological hallmark of idiopathic Parkin-
son disease is degeneration of the dopaminergic neu-
	rons of the substantia nigra and the locus ceruleus. Hya-
	line inclusion bodies, called Lewy bodies, are found		Fig. 6.33 Typical posture of a patient with Parkinson disease
	within the degenerated neurons.
			while walking.
		The loss of dopaminergic neurons leads to a
	degeneration of the nigrostriatal dopaminergic pathway		Increased muscle tone is primarily evident as rigidity
	and, therefore, to dopamine deficiency in the striatum.
	This, in turn, results in enhanced activity of striatal glu-		(p. 29, Fig. 3.22), felt by the examiner during large-
	tamatergic neurons, which produces the clinical		amplitude, passive flexion and extension of the joints.
	manifestations of the disease.		Rigidity is sometimes easier to detect when the patient
	Clinical manifestations. The clinical picture is typically		voluntarily contracts the muscles on the opposite side of
			the body. Often, during passive movement, the ex-
	characterized by:		aminer may feel a small, brief, periodically recurring
		hypokinesia, i. e., slowing of movement,	diminution of muscle tone, known as the cogwheel phe-
		increased muscle tone,	nomenon, which is usually most evident in the radiocar-
		abnormal body posture (stooped head and trunk,	pal joint (Fig. 3.23, p. 30). The patient’s postural tone, too,
		flexion at the knees),	is elevated; if, for example, the head is lifted off the bed
		impaired postural reflexes,	and let go; it may remain suspended in midair for some
		often tremor,	time (the classic literature spoke of a “coussin psychi-
		later, neuropsychological deficits, and	que,” i. e., an imaginary pillow).
	a number of other manifestations, to be described.		Tremor is seen eventually in 3/4 of patients, most often a
	The motor signs (both “plus” and “minus”) are often		distal rest tremor at a frequency of 5 Hz. A pronation−
	only unilateral, or more marked on one side, when the		supination (“pill-rolling”) tremor is highly characteris-
	disease first appears.		tic. The tremor is present at rest and generally disap-
Hypokinesia manifests itself as paucity of facial expres-			pears on voluntary movement; it is sometimes in-
			creased by mental exertion, concentration, or walking.
	sion (mask facies), reduced frequency of blinking, and		Some patients have postural and intention tremor in ad-
	speech disturbances (slow, monotonous, unmodulated		dition to rest tremor (p. 29).
speech, repetitions). There is little spontaneous move-			An impairment of postural reflexes, combined with hy-
	ment, and the normal accessory movements (e. g., of the
	arms during walking) are diminished or absent. The		pokinesia, has the consequence that changes of body
	patient’s handwriting becomes progressively smaller		posture and orientation in space can no longer be com-
	(micrographia). Repeated or alternating movements are		pensated for by reflexive, rapid corrective movements.
	performed slowly (dysdiadochokinesia). Axial move-		The most obvious manifestations of this problem are
	ments, such as turning around in a standing position or		proand retropulsion. If the patient is pushed while
	turning over in bed, are difficult to perform. Very severe		standing still, or stumbles over an obstacle, the move-
	hypokinesia is sometimes called akinesia.		ments made to regain balance are too small and too
	The patient’s gait is characterized by a mildly stooped		slow, and a fall may result.
			Neuropsychological deficits usually appear as the dis-
	posture, with the head jutting forward, and a small-
stepped, often shuffling gait, without accessory arm			ease progresses. Memory is impaired, cognitive
	movements (Fig. 6.33). To turn around in a standing		processes are slowed, and there is a tendency toward
	position, the patient makes numerous, small turning		perseveration: rapid changes in the content of thought
steps.			are difficult to achieve.

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Diseases of the Basal Ganglia 129

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

1.	Bradykinesia of hands, including handwriting			6.	Tremor
	0	= normal			0	= none
	1	=	mild slowing		1	=	amplitude 2.5 cm
	2	=	moderate slowing, handwriting severely impaired		2	=	amplitude 10 cm
	3	=	severe slowing		3	= amplitude 10 cm, constant, eating and writing
							impossible
2.	Rigidity
	0	= none		7.	Facial expression
	1	= mild			0	= normal
	2	= moderate			1	= mild hypomimia
	3	=	severe, present despite medication		2	=	marked hypomimia, lips open, marked drooling
					3	=	masklike facies, mouth open, marked drooling
3.	Posture
	0	= normal		8.	Seborrhea
	1	=	mildly stooped		0	=	none
	2	=	arm flexion		1	=	increased sweating
	3	=	severely stooped; arm, hand, and knee flexion		2	=	oily skin
					3	=	marked deposition on face
4. Arm swing
	0	=	good bilaterally	9.	Speech
	1	=	unilaterally impaired		0	=	normal
	2	=	unilaterally absent		1	=	reduced modulation, good volume
	3	=	bilaterally absent		2	=	monotonous, not modulated, incipient dysarthria, diffi-
							culty being understood
5.	Gait				3 =		marked difficulty being understood
	0	=	normal, turns without difficulty
	1	=	short steps, slow turn	10.	Independence
	2	=	markedly shortened steps, both heels slap on floor		0	=	not impaired
	3	=	shuffling steps, occasional freezing, very slow turn		1	=	mildly impaired (dressing)
					2	=	needs help in critical situations, all activities markedly
							slowed
					3 =		cannot dress himor 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:

the akinetic-rigid subtype (without tremor),

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

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 fol- low-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

blubber blubber

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

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme All rights reserved. Usage subject to terms and conditions of license.

6

Diseases of the Brain and Meninges

130 6 Diseases of the Brain and Meninges

	is converted to dopamine in the central nervous system.	Table 6.25 The differential diagnosis of idiopathic Parkinson
	It is always given in combination with a decarboxylase	disease
	inhibitor to prevent its premature degradation in the	Arteriosclerotic parkinsonism
	periphery. A COMT inhibitor, such as tolcapone or enta-
		(e. g., in subcortical arteriosclerotic encephalopathy)
	capone, can further increase dopamine bioavailability.	Medication-induced parkinsonism
	Tolcapone, however, is occasionally hepatotoxic and is
			neuroleptic agents (most common cause)
	therefore reserved for otherwise intractable cases.		reserpine
	Neurosurgical treatment consists of the stereotactic		flunarizine
	implantation of stimulating electrodes into the	Parkinsonism of infectious origin
	thalamus, globus pallidus, or subthalamic nucleus for		postencephalitic parkinsonism (after encephalitis lethargica)
	deep brain stimulation. This method has now largely re-		cerebrospinal syphilis
	placed earlier methods involving the creation of per-		AIDS encephalopathy
		Normal pressure hydrocephalus
	manent lesions.
	In addition to medications and surgery, physical ther-	Wilson disease
	apy and speech therapy play important roles in patient	Repeated blunt trauma to the head (so-called boxer’s en-
	care, as does adequate psychological support for	cephalopathy)
	patients and their families. Self-help groups can be very	Toxic parkinsonism
	valuable in this regard.		carbon monoxide poisoning (most common cause)
			manganese poisoning
	Medication side effects and complications. Prolonged		MPTP
		Parkinsonism in the setting of other neurodegenerative diseases
	L-DOPA treatment can cause a number of problems:
		Other causes: brain tumor, subdural hematoma, polycythemia
	Fluctuations in drug effect (“on−off” phases, end-of-
	dose akinesia) can often be improved by the use of	vera
	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 ago-
	nists or COMT inhibitors.	Symptomatic Parkinsonism
	Drug-induced dyskinesias, e. g., peak-dose dyskinesia	There are a number of clinical conditions resembling id-
	or hyperkinesia (often manifest as choreiform invol-
		iopathic Parkinson disease that have another underlying
	untary movements), are seen in 40 % of patients after
		cause or pathophysiological mechanism. The clue to
	six months of L-DOPA treatment, in 60 % after two
		such a condition may be a history of a precipitating
	years, and in 100 % after six years. They are usually
		event (e. g., intoxication, medication use, trauma, or in-
	more disturbing to patients’ families than to the
		fection) or a structural abnormality of the basal ganglia
	patients themselves.
		or	other	brain areas (e. g., multiple	arteriosclerotic
	Painful foot dystonia can be managed with the use of
		changes,		hydrocephalus) revealed by	CT or MRI. A
	sustained-release preparations in the evening and
		further characteristic of symptomatic parkinsonism is
	perhaps by the subcutaneous injection of 2−5 mg of
		its relative resistance to treatment with L-DOPA, in con-
	apomorphine, as needed.
		trast to idiopathic Parkinson disease, which usually re-
	“Freezing,” i. e., sudden arrest of movement, is not
		sponds very well to L-DOPA, at least at first. Moreover,
	directly related to the serum concentration of L-
		some forms of symptomatic parkinsonism present sym-
	DOPA. Various mental techniques can help (carrying
		metrically, while idiopathic Parkinson			disease often
	a briefcase, etc.).
		presents asymmetrically. The most important differen-
	Psychosis may respond to a reduction of the dose or
		tial diagnoses of idiopathic Parkinson disease are listed
	to the addition of an atypical neuroleptic drug
		in Table 6.25.
	(clozapine, risperidone).
	Akinetic crisis is a prolonged phase of extreme rigid-
	ity causing complete immobility and accompanied	Degenerative Systemic Diseases Causing
	by hyperthermia, hyperhidrosis, other autonomic
		Hypertonia and Hypokinesia
	disturbances, and dysphagia. It is treated with water-
	soluble L-DOPA and intravenous amantadine.
	Malignant L-DOPA withdrawal syndrome, consisting	The diseases discussed in this section are other, rarer
	of rigidity, hyperthermia, autonomic disregulation,	causes of the parkinsonian syndrome.
	impairment of consciousness, and elevation of the
	serum CK, is treated with dopamine agonists and	Progressive Supranuclear Palsy
	dantrolene.
		This disease is also known as Steele−Richardson−
	Prognosis. The tremor-dominant type has a relatively
		Olszewski syndrome.
	favorable prognosis. L-DOPA treatment can shift the
	symptomatic progression curve to the right by six to	The underlying neuropathological lesion consists of
	seven years. It is hard to predict which patients will	cellular degeneration in the substantia nigra, globus
	eventually become dependent on nursing care. This	pallidus, subthalamic nucleus, periaqueductal area of
	tends to occur after about 20 years of illness.	the midbrain, and other brain nuclei.

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme

All rights reserved. Usage subject to terms and conditions of license.