176 10 Polyradiculopathy and Polyneuropathy

Polyneuropathy

Fundamentals

Polyneuropathy is a condition affecting multiple peripheral nerves, usually simultaneously, though possibly in more or less rapid sequence. The clinical manifestations are usually symmetrically distributed and slowly progressive. The first signs of polyneuropathy are practically always in the lower limbs. Its causes are many.

Etiology. The common causes of polyneuropathy are listed in Table 10.1.

Pathogenesis. A variety of harmful influences affect peripheral nerves in different ways and produce correspondingly different histopathological lesions. Initial

Table 10.1 Causes of the more common types of polyneuropathy

Hereditary polyneuropathy			porphyria
	hereditary motor and sensory
	neuropathies			primary amyloidosis
	neuropathy with tendency
	to pressure palsy
Polyneuropathy due to a metabolic disorder
	diabetic neuropathy:			uremia
		symmetric, mainly distal		cirrhosis
		type		gout
		asymmetric, mainly		hypothyroidism

proximal type

“mononeuropathy”

amyotrophy or myelopathy

Polyneuropathy due to improper or inadequate nutrition

Polyneuropathy due to vitamin B12 malabsorption

Polyneuropathy due to dysproteinemia or paraproteinemia

Polyneuropathy due to infectious disease
	leprosy		spotted fever
	mumps		HIV infection
	mononucleosis		diphtheria
	typhoid and paratyphoid		botulism
	fever		tickborne diseases
	typhus		(borreliosis)

Polyneuropathy due to arterial disease

polyarteritis nodosa atherosclerosisother collagenoses

Polyneuropathy due to sprue and other malabsorptive disorders

Polyneuropathy due to exogenous toxic substances
	ethanol		solvents (e. g., carbon
	lead		disulfide)
	arsenic		drug toxicity (isoniazid,
	thallium		thalidomide, nitrofurantoin)
	triaryl phosphate
Polyneuropathy of other causes		sarcoidosis
	serogenic
	malignant neoplasia

damage of the neuronal nuclei, as in diabetes mellitus, leads to secondary, distal, retrograde axonal degeneration. On the other hand, primary damage to axons leads to Wallerian degeneration of the distal axon segments, as seen in many toxic polyneuropathies. The Schwann cells are another possible “target” of pathogenic influences, e. g., dysproteinemia. Loss of Schwann cells leads to demyelination.

General clinical manifestations. Polyneuropathy is usually characterized by:

first signs usually appearing distally in the lower limbs,

paresthesiae in the toes or soles of the feet, mainly at night,

tingling,

muffled sensation on the soles, “as if I had socks on,”

loss of the Achilles’ reflexes,

diminution or loss of vibration sense, beginning distally.

as the condition progresses, there is paresis of the short toe extensors on the dorsum of the foot, as well as of the interossei (the patient can no longer spread his or her toes),

later, paresis of the long toe extensors and foot extensors,

producing bilateral foot drop,

finally, sensory disturbances and weakness spread to the upper limbs as well.

Diagnostic evaluation. When the typical clinical findings reveal the presence of polyneuropathy, a series of laboratory tests is performed to determine its etiology (particularly a complete blood count, electrolytes, glucose, CRP, electrophoresis, daily blood sugar profile, glucose tolerance test, HbA1c, renal and hepatic function tests, serum vitamin B12 and folic acid levels, vasculitis parameters, TSH, and perhaps further endocrine tests and tumor markers). Electroneurography reveals a variable degree of impairment of impulse conduction, depending on etiology. If the underlying lesion is primarily axonal, EMG reveals evidence of denervation or neurogenically altered potentials. The CSF protein concentration is elevated in many types of polyneuropathy (e. g., diabetic polyneuropathy); in rare cases, CSF examination may yield evidence of an infectious process. Sural nerve biopsy is an additional means of distinguishing axonal from demyelinating forms of polyneuropathy, if the findings of ENG and EMG are inconclusive; it may also provide direct evidence of certain etiologies (e. g., vasculitis).

Particular Etiologic Types

of Polyneuropathy

The types of polyneuropathy that are clinically most important, either because they are common or for other reasons, are described in the following sections.

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Polyneuropathy 177

Table 10.2 Hereditary motor and sensory neuropathies (after Dyck)

Type of HMSN	Inheritance	Age at onset	Muscle	Sensory	Nerve	Other remarks
	pattern		weakness and	deficit	conduction
			atrophy		velocity
Type I	autosomal	2nd to 4th	mainly distal, be-	none or mild,	markedly	peripheral nerves thickened;
Charcot−Marie−	dominant	decade	ginning in the	mainly acral	slowed	sural n. biopsy reveals axonal
Tooth disease			feet and calves,			degeneration, deand re-
			later in the			myelination, onion-skin
			hands and fore-			structures
			arms; pes cavus
Type II	autosomal	2nd to 4th	distal atrophy,	mild,	mildly slowed	peripheral nerves not thick-
neuronal type of	dominant	decade	mainly in the	mainly acral		ened; sural n. biopsy reveals
peroneal muscle			feet and calves;			axonal degeneration, no
atrophy			pes cavus			onion-skin structures
Type III	autosomal	1st decade	rapidly progres-	marked,	severely slowed	peripheral nerves thickened;
Dejerine−Sottas	dominant		sive weakness in	mainly acral		sural n. biopsy reveals hypo-,
hypertrophic			legs and hands			de-, and remyelination,
neuropathy						onion-skin structures, only
						thin myelinated fibers
Type IV	autosomal	1st−3rd	mainly distal	marked,	markedly	sensorineural hearing loss;
hypertrophic	recessive	decade		mainly distal	slowed	occasional retinitis pigmen-
neuropathy in						tosa; thickened peripheral
Refsum disease						nerves; sural n. biopsy reve-
						als axonal degeneration, de-
						and remyelination, onion-
						skin structures; phytanic acid
						accumulation in various tis-
						sues
Type V	autosomal	2nd decade	mainly distal	none or mild	normal or	sural n. biopsy may reveal
HMSN with spas-	dominant	or later	muscle atrophy		mildly slowed	reduced number of myelina-
tic paraparesis			and spastic para-			ted fibers
			paresis
Type VI	autosomal	highly variable	mainly distal	none or mild	normal or	visual loss, progressive blind-
HMSN with optic	dominant or				mildly slowed	ness; thickened nerves in
atrophy	recessive					rare cases
Type VII	autosomal	variable	mainly distal	mild	slowed	retinitis pigmentosa
HMSN with reti-	recessive
nitis pigmentosa

Hereditary Motor and Sensory Neuropathies (HMSN)

The current classification of hereditary polyneuropathies is given in Table 10.2.

HMSN Type I (Charcot−Marie−Tooth disease) is the most common hereditary polyneuropathy, with a prevalence of two per 100 000 persons. It is genetically subdivided into Type Ia, caused by duplication on chromosome 17p11, and Type Ib, caused by a point mutation on chromosome 1q22−23. Clinically, its earliest manifestation is pes cavus (Fig. 10.2a), later followed by atrophy of the calf muscles, while the thigh muscles retain their normal bulk (“stork legs,” “inverted champagne-bottle sign,” Fig. 10.2). As the disease progresses, predominantly distal muscle atrophy is seen in the upper limbs as well (Fig. 10.2c). Distal sensory impairment may not arise until much later and even then is usually only mild. Electromyography reveals marked slowing of nerve conduction; histopathological examination of a sural nerve specimen reveals axonal degeneration, myelin changes, and onion-skinlike Schwann cells. HMSN Type I pro-

gresses very slowly. Patients can often keep working until the normal retirement age or beyond.

Hereditary neuropathy with predisposition to pressure palsies (HNPP) is an autosomal dominant disorder due to a point mutation in chromosome 17p11.2−12. Clinically, patients develop recurrent pressure palsies of individual peripheral nerves, even after very light pressure. The histopathological substrate of the disorder is an abnormality of the myelin sheaths of peripheral nerves. Microscopy reveals sausagelike, segmental swelling of the sheaths (“tomaculous neuropathy”).

Diabetic Polyneuropathy

Epidemiology. Diabetic polyneuropathy is the second most common type of polyneuropathy (only the alco- hol-induced type is more common). It typically afflicts persons aged 60 to 70 who have suffered from diabetes for five to 10 years or more and 20 to 40 % of diabetics have it to some degree. In 10 % of patients with diabetic neuropathy, it is only the diagnostic evaluation of neuropathy that brings the underlying diabetes to light.

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178 10 Polyradiculopathy and Polyneuropathy

a

c

Pathogenesis. Polyneuropathy is caused both by diabetic angiopathy and by the direct effect of elevated blood sugar. Axonal degeneration is usually the most prominent histological finding, though segmental demyelination sometimes predominates.

Clinical manifestations. Irritative sensory symptoms are most prominent at first, including paresthesia and, often, burning dysesthesia of the feet. Typically, Achilles reflexes are absent and there is a mainly distal impairment of touch and position sense. It is only later that about half of the affected patients develop motor deficits. The condition may present with an asymmetrical neurological deficit, or with isolated disease of an individual nerve, such as cranial nerves I−II, IV, and VI or the femoral n. Disturbances of autonomic innervation are also typical: dry, often reddened skin, bladder dysfunction, orthostatic hypotension, tachycardia, diarrhea, and impotence in young male diabetics. The effects of diabetes on the nervous system are listed in Table 10.3.

Treatment. Optimal glycemic control is of paramount importance. The pain of diabetic neuropathy, which is often severe, can be treated with carbamazepine, gabapentin, thioctic acid, clomipramine, or local capsaicin ointment. These drugs can also be combined with neuroleptic agents.

b

Fig. 10.2 Hereditary motor and sensory neuropathy (HMSN), type I (a and b) and type II (c). a Pes cavus. b Severe calf atrophy with normal muscle bulk in the thighs (“stork legs”). c Atrophy of the distal forearm muscles and of the intrinsic muscles of the hand. (From: Meier, C., Tackmann, W.: Die hereditären motorisch-sensi- blen Neuropathien. Fortschr Neurol Psychiat 50:1982.)

Toxic Polyneuropathies

The numerous substances that can cause a toxic polyneuropathy will not all be listed here. We will merely illustrate the breadth of the clinical spectrum of toxic polyneuropathy by describing two very different, highly characteristic syndromes.

Though alcoholic polyneuropathy is very common, its pathogenesis is not fully understood. In addition to the direct effects of ethanol and acetaldehyde, alcoholics often suffer from nutritional deficiencies. Further contributing factors include possible defects of the enzymes alcohol dehydrogenase and acetaldehyde dehydrogenase. Clinically, intense pain in the lower limbs is often the most prominent symptom. Many patients also suffer from muscle cramps. The intrinsic muscle reflexes are diminished; Achilles reflexes are usually absent. Proprioception is impaired and touch and vibration sense are diminished distally. The calves are often tender to deep pressure. The dorsiflexors of the feet are weak. Motor conduction in the peroneal n. is slowed. The major finding of sural nerve biopsy is axonal degeneration.

Triaryl phosphate poisoning will serve here as an example of an acute toxic neuropathy whose manifestations can persist, either fully or in part. This substance is found in certain mineral oil derivatives used in industry. Their erroneous use as cooking oil leads to a clinical syndrome manifested at first by diarrhea and one to five weeks later by fever and other constitutional symptoms.

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Polyneuropathy 179

Tabelle 10.3 Effects of diabetes mellitus on the nervous system

	Site	Manifestation	Special features
	Central nervous system	cerebrovascular accidents
		spinal cord ischemia
	Peripheral nervous system	polyneuropathy:	distal, perhaps painful, symmetric, gradually worsening
		sensorimotor	paresthesiae or burning pain in the feet, absent Achilles
			reflexes, diminished vibration sense, hypesthesia in a stock-
			ing distribution, occasional dorsiflexor weakness, occasional
		proximal asymmetric	toe ulcers and joint destruction
			mainly affects lumbar plexus or femoral nerve, unilateral,
			acute, painful, weakness of hip flexors and quadriceps m.,
			diminished knee-jerk reflexes, positive reverse Lasègue sign,
			hypesthesia in femoral n. distribution, occasional similar find-
			ings in upper limbs, spontaneous improvement possible (as
			in mononeuropathy, see below)
		mononeuropathy:
		CN III (most common)	painful, affects only extraocular muscles, regresses within a
			few months
		other peripheral nerve	e. g., thoracic nerves with abdominal muscle weakness
	Autonomic nervous system	bladder dysfunction	sphincter disturbance, atonic flaccid bladder
		impotence	in younger male patients
		diarrhea	chiefly at night
		necrobiosis lipoidica	polycyclic cutaneous atrophy in women
		osteoarthropathy	particularly in the toes
		ulcers	particularly on the soles of the feet
	Ten to 38 days after the exposure, flaccid paresis ap-		sequence. As for their pathogenesis, most cases of these
	pears in the feet and then, within a few days, in all four		two entities are due to a vasculopathy, such as diabetic
	limbs. Sensation is also impaired. In many patients, the		microangiopathy, polyarteritis nodosa, systemic lupus
	deficits resolve only in part, or not at all, and spasticity		erythematosus, Sjögren syndrome, Wegener granulo-
	of central origin frequently develops over the ensuing		matosis, or atherosclerosis. Clinically, they are charac-
	years. Histopathological examination reveals axonal le-		terized by asymmetrically distributed weakness,
	sions both in peripheral nerves and in the central		sensory deficits, or autonomic dysfunction in the dis-
	nervous system.		tribution of a single peripheral nerve, or, in later stages
			of mononeuritis multiplex, in the distribution of multi-
	Mononeuropathies and Mononeuritis Multiplex		ple peripheral nerves. Other manifestations of the un-
			derlying illness are usually present as well, e. g., consti-
	Mononeuropathy is a neuropathy affecting a single pe-
			tutional symptoms such as fever, night sweats, and
	ripheral nerve; mononeuritis multiplex is a type of pe-		weight loss, an elevated erythrocyte sedimentation rate,
	ripheral neuropathy in which single nerves are affected		and symptoms referable to the internal organs.
	one after the other, in a	highly variable temporal

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