Table 8.5 (Cont.) Hereditary neuropathy with predisposition to pressure palsy HNPP AD 17p11.2/PMP22 Mildly to moderately slowed Pressure palsy after minimal trauma Hereditary neuralgic amyotrophy HNA AD 17q24-q25 Normal Recurrent brachial plexus palsies, hy- potelorism Hereditary motorneuropathy HMN type II AD 12q24 Normal or mildly slowed No sensory deficit, mainly affects lower limbs HMN type V AD 7p Begins in intrinsic hand muscles, mainly abductor pollicis brevis and 1st dorsal interosseous m.; no sensory deficit, occasional pyramidal tract signs Hereditary sensory n europathy HSN type I AD 9q22 Normal or mildly slowed Dissociated sensory deficit, tendency toward plan tar ulcersandamputation, lancinating pain AD Autosomal dominant AR Autosomal recessive CMT Charcot-Marie-Tooth disease Cx32 Connexin 32 EGR2 Early growthresponse gene 2 MPZ Myelin protein 0 MTMR2 Myotubularin-related protein 2 NDRG1 N-myo downstream regulated gene 1 NF-L Neurofilament light gene PMP22 Peripheral myelin protein 22 XD X-linked dominant Polyneuropathy 591 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Table 8.6 Dyck’s classification of the hereditary motor and sensory neuropathies (HMSN) Type I (Charcot-Marie-Tooth disease) Autosomal dominant inheritance Onset in 2nd–4th decade Distal atrophy, beginning in the feet; pedal deformities Mild, mainly acral sensory deficits Marked slowing of nerve conduction velocity Peripheral nerves thickened and tough Sural nerve biopsy: axonal degeneration, de- and remyelination, onion-skin struc- tures Type II (neuronal type of peroneal muscle atrophy) Autosomal dominant inheritance Onset in 2nd–4th decade Distal atrophy in the feet and calves, hands less severely involved, pes cavus Mild, mainly acral sensory deficits Normal or mildly slowed nerve conduction velocity Peripheral nerves not thickened and of normal consistency Sural nerve biopsy: axonal degeneration, mild (secondary) segmental demyelin- ation, no onion-skin structures Type III (Dejerine-Sottas hypertrophic neuropathy) Autosomal recessive inheritance Onset in 1st decade Motor developmental delay, rapid progression, marked weakness in hands as well Marked, mainly distal sensory deficits Severely slowed nerve conduction velocity (slower than in type I) Peripheral nerves thickened, often also soft Sural nerve biopsy: hypomyelination, de- and remyelination, onion-skin structures, only thin myelinated fibers (no more than 4 mindiameter),marked widening of endoneural interstitium Ceramide monohexoside sulfate accumulation in hepatic tissue (has been demon- strated in a few cases) Type IV (hypertrophic neuropathy in Refsum’s disease) Autosomal recessive inheritance Onset in 1st–3rd decade Retinitis pigmentosa, sensorimotor neuropathy, hearing loss, cardiac and cutaneous manifestations, skeletal deformities Markedly slowed nerve conduction velocity Sural nerve biopsy: axonal degeneration, segmental de- and reinnervation, onion- skin structures, lysosomal storage in Schwann cells Phytanic acid accumulation in various tissues, and in blood plasma (Cont.) 592 8Polyradiculitis and Polyneuropathy Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Fig. 8.1a–c Typical ap- pearance of HMSN types I and II. a HMSN type I. Pes ca- vus in the varus posi- tion. The clawed ap- pearance of the toes is produced by the greater strength of the deep flexors of the toes compared to the abnormally weak dorsiflexors. Table 8.6 (Cont.) Type V (with spastic paraparesis) Autosomal dominant inheritance Onset in 2nd decade or later Slow progression with spastic paraparesis b ut nearly normal life expectancy No sensory deficit, either subjectively or on clinical testing Normal or mildly slowed nerve conduction velocity Sural n. biopsy: marked diminution of myelinated fibers in a small number of patients Type VI (with optic atrophy) Autosomal dominant or recessive inheritance Highly variable age of onset Progressive blindness, distal muscle atrophy Neurophysiologic findings unknown In rare cases, hyp ertrophic nerve changes Type VII (with retinitis pigmentosa) Probably autosomal recessive inheritance Variable age of onset Distal muscle atrophy a nd weakness Mild distal sensory deficits Slowed nerve conduction velocity Biopsy findings not specified in available reports don is lostatanearlystageofthedis- ease, and other deep tendon reflexes later follow. The atrophy and weak- ness of the calf muscles may progress over time, but the thigh muscles are hardly ever involved, so that the pow- erful thigh muscles contrast mark- edly with the wasted calf muscles (“stork legs,” “inverted champagne- bottle sign”) (Fig. 8.1b). The distal muscles of the up per extremities, particularly the intrinsic muscles of Polyneuropathy 593 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Abb. 8.1 b HMSN type I. Typical“storklegs.” The marked atrophy of the calf muscles contrasts with the normal bulk of the relatively preserved quadriceps femoris muscle. c HMSN type II.Atrophy of the distal forearm muscles and of the intrinsic muscles of the hand (from C. Me- ier, W. Tackmann, Fort schr Neurol Ps ychi- atr 1982; 50: 349–65). the hands, may eventually be in- volved (Fi g. 8.1c). Only about one-quarter to half of all patients develop a distal sensory defi- cit to vibration and light touch, usu- ally only later in the course of the dis- ease. The examiner may be able to palpate thickened nerve trunks in the subcutaneous tissue, particularly in the neck. Rarely, there are other, ac- companying neurologic abnormali- ties such as proximal muscle atrophy, nystagmus, posterior column signs, optic atrophy, pupillary anomalies, or essential tremor. Cases with pyrami- dal tract signsaresepara tely desig- nated as HMSN type V. 594 8Polyradiculitis and Polyneuropathy Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Diagnostic Evaluation Electroneurography is of basic impor- tance. The nerve conduction velocity is markedly diminished in all cases, sometimes even before the appear- ance of symptoms in persons with a positive family history. Nerve biopsy reveals wid ening of the endoneural interstitium, signs of chronic segmental denervation and regeneration, onion-skin-like Schwann cells, and axonal de- gene ration. Muscle biopsy reveal s signs of neuro- genic atrophy and , frequently, an ac- companying myopathy. Course This disorder generally progresses very slowly. Th e pa tients are often re- markably free of impairment and can work even into old age. HMSN Type IB This autosomal dominant disorder is due to a mutation of the PO-MPZ gene on chromosome 1q22-23. It is more severe than type IA. Proximal muscle atrophy and pes planus are often present. The sensory deficit is also more pronounced than in type IA. The illness often appears before age 10; it is occasionally accompa- nied by other neurologic abnormali- ties such as hearing loss, pupillary anomalies, pain, etc. Electrophysio- logic studies may reveal no more than amodestslowingof nerve conduc- tion velocity. HMSN Type II This neuronal type of peroneal mus- cle atrophy is a disorder of autosomal dominant inheritance whose clinical features closely resemble those of neural hypertrophic neuropathy (see below), though its onset i s some what later and the hands are less severely involved. The peripheral nerve trunks are not palpably thickened, and the nerve conduction velocity is only mildly slowed. Electromyographic study reveals evidence of involve- ment of the anterior horn ganglion cells. Nerve biopsy reveals similar, though less extensive, changes to those seen inTypeI. Acomparisonoftheelectrophysio- logic and histologic findings in HMSN types I and II suggests that these are two independent diseases that are separately inherited. Autosom al re- cessive forms that begin in early childhood and progress rapidlythere- after have also been described. HMSN Type III Genetics This disorder, also called Dejerine- Sottas hypertrophic neuropathy, is of autosomal recessive inheritance. Clinical Features The clinical m anifestations resemble those of HMSN typeIbutgenerally appear earlier, impairing the child’s motor development. The motor defi- cit is more severe and more rapidly progressive,inproximalaswellas distal muscles. The reflexes are ab- sent, the peripheral nerves (including major trunks) are markedly thick- ened, and the spinal nerve roots may be so thickened astocause spinal cord compression. Diagnostic Evaluation The CSF protein concentration is often elevated. The motor conduction veloc- ity is more severely slo wed than in HMSN type I, and nerve biopsy revea ls alargenumberofonion-skin struc- tures (abnormal Schwann cells). Sural Polyneuropathy 595 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. nerve biopsy and liver biopsy reveal abnormal quantities of cerebrosides and sulfatides in the tissue. The disor- der is probably caused byaninborn error in the metabolism of ceramine hexoside and ceramide hex oside sul- fate. Hereditary Motor Neuropathy, Hereditary Sensory Neuropathy, Hereditary Neuralgic Amyotrophy See Table 8.5. Hereditary Neuropathy with Predisposition to Pressure Palsies (HNP P,Tomaculous Neuropathy) Genetics This autosomal dominant disorder is due to a mutation in chromosome 17p11 (611, 740b). Clinical Features Affected individuals develop recur- rent pressure palsies of individual pe- ripheral nerves or of the brachial plexus. These may arise after even light pressure and can regress fully afterward. Writer’s cramp and hand dystonia have been reported in some cases of this disorder (913a), pares- thesiae, myoclonus, and fascicula- tions in others (28b). Diagnostic Evaluation Electrophysiologic study reveals the characteristic marked slowing of con- duction velocity in peripheral nerves, even in those that are clinically unin- volved. His tologic examin ation shows asausage-like(“tomaculous”) inter- nodal swelling of myelin sheaths, combined with segmental demye lin- ation. Polyneuropathy in acute hepatic porphyria Genetics Porphyria is a genetic disorder of au- tosomal domina ntinheritance. Pathophysiology The underlying genetic defect of pyr- role metab olism, a partial deficiency of uroporphyrinogen synthetase, leads to accumulation of -amino- levulinic acid, porphobilinogen, and uro- and coproporphyrins, which are excreted in the urine. A change in the color of the urine after exposure to light, due to the light-induced trans- formation of the colorless leuko-form to the r eddish- bro wn uro- and copro- porphyrins, may suggest the diagno- sis. Alternatively, urinary porphobili- nogen can be demonstrated with Ehr- lich’s urobilinogen reagent. Pathologic Anatomy Sporadic myelin loss in peripheral nerves with axonal preservation is occasionally accompanied by second- ary (retrograde) gan glion cel l loss in the central nervous system, as well as foci of vascular change. Clinical Features (123) The disorder classically manifests it- self in intermittent acute abdominal attacks (colic, constipa tion, vomit- ing), accompanied by high blood pressure, which may be induced by the administration of barbiturates. The major neurologic manifestations, which appear more orlesssimulta- neously with the abdominal attacks, include signs of CNS involvement such as delirium, psychosis, seizures, impairment of consciousness, central blindness, and other focal ischemic phenomena. 596 8Polyradiculitis and Polyneuropathy Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Within a few days of the onset of the disease, polyneuropathy b ecomes clinically evident, either in the form of mononeuritis multiplex (p. 607) or as a severe, mainly motor polyneu- ropathy or polyradiculopathy causing arapidlyprogressive, ascending, flac- cid quadriplegia. A sensory deficit is hardly ever pr esent, though pain and paresthesiae may be felt in the para- lyzed limb s. The spatial distribution of the motor neuropathy is often unusual, particu- larly at its onset. Thus, it may begin in the upper limbs and affect mainly the proximal muscle groups. Cranial nerve palsies, transient blindness due to vasosp asm of the retina l art eries , and fluctuating central nervous man- ifestations are also occasionally seen. The autonomic nervous manifesta- tions of porphyria include tachycar- dia, arterial hypertension, constipa- tion, and sometimes bladder dysfunc- tion. Agitation, hallucinations, im- pairment of consciousness, bizarre, hyst eriform mental changes, and epi- leptic seizures can also occur. Diagnostic Evaluation The CSF is usually normal. Albumino- cytologic dissociation is seen in rare cases. Prognosis The prognosis is poor. As many as one-third of patients eventually die during an acute attack of porphyria, genera lly be cause of brainstem in- volvem ent leading to respiratory pa- ralysi s. Treatment Adeno sine-5-monophosphate (AMP) and hematin have been found to be of therapeutic value. Patients should meticulously avoid taking barbiturates, which can induce at- tacks of porphyria. Polyneuropathy in Primary Amyloidosis Genetics Primary amyloidosis is an uncommon disorder. Most cases are familial, of autosomal dominant inheritance; the remainder are sporadic. Clinical Features Some 15% of patients have neurologic manifestations, of which chronic poly- neuropathy is the most p rominent. It becomes evident at some time be- tween the ages of 10 and 60, most of- ten between 20 and 30, more com- monly in men than in women. Distal paresthesiae and a sensory d eficit in the calves (often dissociated) are the initial symptoms, followed by pro- gressive, mainly distal weakness and muscle atrophy, which may be asym- metrical at first. There are often signs of autonomic dysfunction as well, in- cluding autonomic hypotension, ab- normalities of sweating, impotence, and trophic ulcers. Gastrointestinal manifestations such as diarrhea or constipation are pre- sent in nearly every case, and hoarse- ness, cardiac and renal manifesta- tions, and opacification of the vitre- ous body are common. The disease continues to progress for many years. Diagnostic Evaluation The diagnosis is established by biopsy of the gingiva, rectalmucosa,muscle, or peripheral nerve. Polyneuropathy 597 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. Giant Axon Polyneuropathy This autosomal recessive disorder manifests itself in childhood with a severe, slowlyprogressivepolyneu- ropathy and l ater affects thecentral nervous system as well. Nerve biopsy reveals segmental axonal swelling due to an accumulation of neurofila- ments. Affected children have kinky hair. Polyneuropathy Due to Metabolic Disorders Diabetic Polyneuropathies (422b, 602, 791) Frequency The frequency of neurological com- plications in diabetes mellitus has been variably estimated in published reports; themorecarefullythepa- tients are examined, the more deficits are found. If reflex abnormalities and minor sensory disturbances are counted, 20–40 % of diabetics in an otherw iseunselected patient group will be found to have a neurologic deficit. Diabetic neuropathy most commonly arises between the ages of 60 and 70, when thepatienthas had overt diabetes for 5–10 years. In about 10 % of cases, however, it is the diagnostic work-up for peripheral neuropathy that leads to the discov- ery of diabetes. Men and women are equally affected. Pathogenesis and Clinical Features The disturbance of glucose metabo- lism affects the peripheral nerves both indirectly, through pathologic changes in the blood vessels supply- ing them, and directly. Neurologic deficits of sudden onset are best ex- plained as being due to suddenly im- paired perfusion through the vasa nervorum. In patients with diabetic neuropathy, the walls of the vasa ner- vorum are hyalini zed and contain de- posits of abnormal material; these changes are significantly less com- mon i n diabetics without neuropathy, and in nondiabetics (343). They can be seen even before the onset of neuropathy, and their extent is corre- lated with the severity of the neurop- athy. The fact that the sensory nerve fibers are often affected early in the course of diabetic neuropathy, with resulting paresthesiae, pain, and areflexia, speaks for a direct effect of altered glucose metabolism rather than an is- chemic effect, because these thin, poorly myelinated fibers are rela- tively resistant to ischemia. Simi larly, the many reversi ble manifestations of diabetic neuropathy (e.g., pareses of the extraocular muscles) are likely to be of metabolic rather than ischemic origin. Nonetheless, there is no clear correlation between the severity of the metabolic disturbance and that of the neurologic manifestations, which may a ppear even incasesofmild or well- treated diabetes. It is important to realize that neuro- pathy can develop even inlatentpre- clinical diabetes, which can be diag- nosed only by an abnormal glucose tolerance test. Nonetheless, measure- ment of the motor conduction veloc- ity in the peripheral nerves of dia- betic patientshasrevealed a correla- tion between the degree of slowing and the elevation of the blood glucose concentration. Neuropathy also tends to im prove, or at least stop progress- ing, once the patient’s blood glucose is under optimal therapeutic control. Parenthetically, we note here that not only hyperglycemia, but also recur- 598 8Polyradiculitis and Polyneuropathy Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. 89% 72% 76% 62% 47% 32% 24% Sensory phenomena Su b jective Subjective weakness Reflexes Objective Sensation Weakness A utonomic nervous system Cranial nerves Fig. 8.2 Neurologic def- icits in 200 diabetic pa- tients (from A. Bischoff, Die diabetische Neuropa- thie, Stuttgart: Thieme, 1963). rent hypogl ycemia due to insulinoma can cause a motor polyneuropathy (or perhaps chronic injury to the anterior horn ganglion cells). The frequency of theindividual signs and symptoms of diabetic neuropa- thy in a group of 2 00 patients is shown graphically in Fig. 8.2.Distal paresthesiae and sensory de ficits are the most common clinical findings. Contrary to the prevailing belief among many clinicians, the pain of diabetic neuropathy is frequently proximal (near the trunk), and more commonly uni- than bilateral. The ex- tent to whichthevarioussignsand symptoms are expressed in the indi- vidual patient is highly variable, but one can nonetheless group certain patterns of clinical presentation into characteristic syndromes, whose fea- tures are summarized in Table 8.7. Diagnostic Evaluation Electroneurography reveals sl owed conduction in motor nerve fibers, even in cases where the abnormality is still too mild to cause clinically evi- dent weakness. The CSF,too,isoftenabnormal.The CSF protein concentration may be el- evated in diabetic patients even in the absence of clinically evident pe- ripheral neuropathy. Some two-thirds of diabetics have an abnormally high total protei n conc entration, wi th val- ues ranging as high as 400mg/dL. The cell count is always normal; thus, there is an albuminocytologic dissoci- ation in such cases. As expected, the CSF glucose concentration is high in 75% of cases. Sensorimotor Diabetic Polyneuropathy Symmetric, predominantly distal dia- betic polyneuropathy is the most common neurologic complication of diabetes. Mild form. The milderclinicalformis usually seen inpatientswith type II diabetes, who complain of symmetri- cal paresthesiae and burning sensa- tions in the lower limbs, and rarely in the upper limbs as well. The Achilles reflexes are practically always absent, and sometimes other deep tendon re- flexes as well. Vibration sense is usu- ally impaired distally, while position sense is lessfrequentlyimpaired.Mo- tor deficits, whe n present, are gener- ally mild. Polyneuropathy 599 Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. [...]... facial palsy (which is often bilateral) ( 377 ) Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 614 8 Polyradiculitis and Polyneuropathy The distribution of weakness is highly variable The clinical picture may be of a painful, localized neuropathy or radiculopathy, a painful polyradiculitis of Guillain-Barre type, or cranial ´ polyradiculitis... occurring especially at night Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license Polyneuropathy Sexual dysfunction One-fourth of male diabetics suffer from impotence or retrograde ejaculation Other autonomic disturbances The diabetic patient may suffer from tachycardia, orthostatic hypotension, pedal edema, and lack of sweating, particularly in areas... vasa nervorum due to macroglobulin-induced erythrocyte “sludging,” as well as a competitive Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 606 8 Polyradiculitis and Polyneuropathy effect of the neoplastic process on the nervous system with respect to the demand for cocarboxylase ascending polyradiculoneuritis (p 576 ) with elevation of the CSF... disease are fever spikes, fatigue, arthralgia, cardiac distur- Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license Polyneuropathy bances, renal failure, skin rash, anemia, and often an elevated erythrocyte sedimentation rate Neurologic manifestations are the first sign of the illness in about one-half of all cases Those affecting the CNS were already... polyneuropathy, often sensory with marked ataxia, sometimes with cranial nerve deficits Primary myopathy also occurs (see pp 3 27 and 909) Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 608 8 Polyradiculitis and Polyneuropathy | Churg-Strauss Syndrome Patients with asthma and allergic vasomotor rhinitis may develop a form of necrotizing arteritis with... mentioned above (p 77 3), an arteriovenous fistula surgically created to facilitate hemodialysis can cause carpal tunnel syndrome by producing focal ischemia of the median nerve Generalized polyneuropathy, too, can be caused by hypoxemia: distal, sensorimotor polyneuropathy was found in one-fifth of a group of patients with long-standing hypoxemia due to chronic obstructive pulmonary disease (75 9) Its severity... 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 sole of the foot Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license Polyneuropathy Severe form Severe sensorimotor diabetic polyneuropathy typically... neuropathy is also rare The manifestations are most severe distally in the lower limbs Tremor is frequent, pain not uncommon Paraprotein-associated polyneuropathy (IgM, IgG, or IgA) has essentially the same clinical picture (1038) Benign, anti-myelin-associated IgM gammopathy ( 271 a, 568a), a special type of monoclonal gammopathy, occurs mainly in elderly men and produces a mainly sensory polyneuropathy A... combination of metabolic Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 602 8 Polyradiculitis and Polyneuropathy and vascular involvement of the peripheral nerves Both types of proximal diabetic neuropathy have a favorable prognosis for spontaneous recovery Recovery is less likely, however, in cases involving chronic hypoxic-ischemic injury of... contributory factor toward neurologic dysfunction in practically all alcoholics Mumenthaler, Neurology © 2004 Thieme All rights reserved Usage subject to terms and conditions of license 610 8 Polyradiculitis and Polyneuropathy Effects of Alcohol on the Nervous System The effects of alcohol on the nervous system are summarized in Table 2 .79 We will not discuss the psychopathological phenomena any further here . colorless leuko-form to the r eddish- bro wn uro- and copro- porphyrins, may suggest the diagno- sis. Alternatively, urinary porphobili- nogen can be demonstrated with Ehr- lich’s urobilinogen reagent. Pathologic. 8Polyradiculitis and Polyneuropathy Mumenthaler, Neurology © 2004 Thieme All rights reserved. Usage subject to terms and conditions of license. 89% 72 % 76 % 62% 47% 32% 24% Sensory phenomena Su b jective Subjective. sense is usu- ally impaired distally, while position sense is lessfrequentlyimpaired.Mo- tor deficits, whe n present, are gener- ally mild. Polyneuropathy 599 Mumenthaler, Neurology © 2004 Thieme All