Hereditary neuralgic amyotrophy

JourmH ol lhu Neurological Sciences, 1983, 62 : 261 279

261

Elsevier

HEREDITARY NEURALGIC AMYOTROPHY Clinical, Genetic, Electrophysiological and Histopathological Studies

W . F . M . ARTS I. H . F . M . BUSCH j, H.J. VAN DEN BRAND-', F . G . I . J E N N E K E N S ~, R.R. FRANTS 4 and S. Z. STEFANKO 5

Deparlntolt~s q/Nuuro/o~,y, I University Ho.~pital "'Di/kz~k,t", Rotterdam," ed'h~ra Hospila], Rotterdam," 'Univursitv Hospital, Utrecht; 4Department of Human Genetics, Free University, Amsterdam." and "Department o['Patholo~v. University Hospital "D(jkz~,t", Rotterdam (The Netherlands') (Received 25 May, It783) (Revised, received 28 July, 1983) (Accepted 2 August, 1983)

SUMMARY

Clinical, genetic, electrophysiological and histopathological studies in a fourgeneration family with hereditary neuralgic amyotrophy (HNA) are described. Clinically two kinds of attack could be distinguished: (1) the classical type with pain and weakness lasting for weeks to months, leaving atrophy and sometimes residual weakness ; 2) attacks consisting of recurrent pain and weakness lasting for a few days and occurring about once a week for several months, also resulting in persisting atrophy and weakness. Genetically a strong association was found between HNA and hypotelorism, probably due to pleiotropism of one single gene. Close linkage with any of 29 genetic markers was not present. The electrophysiological findings indicated that a local process in the brachial plexus, possibly demyelination or a conduction block, was the primary pathophysiological mechanism Nevertheless, the sural nerve of the index case, biopsied 5 months after the onset of an attack, showed a decreased number of myelinated nerve fibres per cross-sectional area. Apparently, other parts of the peripheral nervous system may be affected subclinically in an attack of brachial plexopathy. The central and peripheral nervous system of his mother, 30 years alter her last attack of HNA, showed only nonspecific changes. Tomacula were not seen in either case. HNA and hereditary liability to pressure palsies (HLPP) are distinctly different disorders.

Financial support for the genetic investigations was obtained Dom the Foundation for Medical Research FUNGO, and the Praeventiefonds, and for the histopathological investigations from the Prinses Beatrixfonds. Address for reprints: Dr. W. F. M. Arts, Department of Neurology, University Hospital "Dijkzigt", Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. 0022-510X/83/$03.00 ~, 1983 Elsevier Science Publishers B.V.

262 Key words" Clinical symptoms Electrophysiology Genetws amyotrophy Histopatholog), Itypotelorism mechanism

Hereditart neuralgi~ Pathophysiological

1N T R O D U CTION

Hereditary neuralgic amyotrophy (HNA. hereditary brachial plexus neuropathy) was first described by Dreschfetd (18861, later by Ungley (19331 and in more recent times by Taylor (1960). Since then. at least 28 families have been described (Jacob et at. 1%1: Roger et al. 1%5: Gardner and Maloney 1968: Poffenbarger 1968; Smith et al 1971: Guillozet and Mercer 1973: Warot et al. 1973: Erikson 1974: Geiger et al. 1974: Wiederholt 1974: Bradley et al. 1975: Dunn et al. 1978: Van Wensen 1980: Windebank et at. 19821. but the pathogenesis of the disease remains obscure. The recurrent course is very uncommon for a genetic disease [except for porphyria, which was excluded by Ungtey (19331, Taylor (19601, Jacob et at. (1961), Guillozet and Mercer (19731, Warot et al. (19731. Erikson (1974J and Geiger et al. (1974)]. Furthermore. the apparently arbitrary occurrence in various parts of the peripheral nervous system has not been explained. Only infrequent and conflicting reports of electrophysiological and nerve biopsy findings have been published. The possibility of genetic linkage has not yet been extensively studied. tn the family examined by us. some hitherto unreported clinical characteristics were present. Genetic studies, including search for linkage, were performed. Extensive electrophysiological investigations were carried out. including measurements of proximal conduction velocities in the acute stage of several attacks, and during the follow-up period, In two patients, histological examinations were carried out. A sural nerve biopsy of the index patient was investigated. The post-mortem investigauon of his mother is the first autopsy of a patient with HNA reported so far. MATERIAL A N D M E T H O D S

Clinical studies The pedigree is shown in Fig. 1. Clinical studies including measurements of the inner canthal distance were carried out on all living relatives of the index patient IlI-7, except IV-3 and V-2. Anamnestic data were obtained on l-1.1-3 and 1-4. II-3 and her children. II-5. I1-6 and II-8, IV-3. IV-13 and V-2. Genetic studies A linkage study was performed on II-7 and her descendants and their partners, excluding III-6, III-12. IV-3, 1V-4 and V-2. The following genetic marker systems were analyzed: HLA (A, B. C and D/DR), ABO, Rhesus (RH), MNS, P. Kel] (K), Lutheran (LU), Duffy (FY), Kidd (JK), acid phosphatase-I ~ACP1), adenylate kinase-1 ~AK1L diaphorase B (DIA2), esterase D (ESD), glyoxalase i (GLO1),

263

m O •

' ° .r ' - i

V

Io[~

,,.o ,,

,

AFFECTED REPORTEDLY AFFECTED PERSONALLYINVESTIGATED

,.

,,;

,6

Fig. I. Pedigree of family "'M".

phosphoghlcomutase-1 (PGM1), phosphoglycolate phosphatase (PGP), allotypes of the immunoglobulin chains (A2M, GM and KM), :g-antitrypsin (PI), groupspecific component (GC), haptoglobin (HP), transcobalamin 2 (TC2), transferrin (TF), salivary amylase (AMY1) and urinary pepsinogen (PG1) (for technical details see Breuning et al. 1977). Estimation of linkage between: (1) the gene for HNA and each one of the genetic markers, and (2) the gene for HNA and a hypothetical gene for hypotelorism, was performed according to standard statistical methods (Smith 1969).

Eh,ctrophysiologica/ studies Electrophysiological investigations were performed in 111-1, II1-13, 111-15 and IV-15 some weeks after the onset of weakness, and in lII-1 and III-7 in a latent stage of the disease. They consisted of conventional E M G recordings, determination of motor and sensory nerve conduction velocities and of motor latencies, combined with compound muscle action potentials in a number of cases, and of F-wave latency of the ulnar nerve in one case.

Histopathological studies The index patient (Ill-7) underwent a sural nerve biopsy at the ankle at the age of 44, five months after the onset of a severe attack of pain and weakness in the left shoulder and arm. At the time the biopsy was performed, the ['unction of the left arm had already improved, and there were no signs of motor or sensory involvement of the legs. The autopsy of patient I1-7, who died at the age of 72, was performed 4 hours after death. The last attack of HNA had occurred about 30 years previously, but she had retained weakness and atrophy of the musculature of the arms and shoulder girdle and generalized areflexia.

264 As a control, the spinal cord and spinal nerve roots of a 70-year-old man. previously healthy and dying from an acute myocardial infarct, were investigated. One part of the sural nerve biopsy was divided into small pieces, l?ozen in isopentane cooled in liquid nitrogen and stored at - 8 5 ° C until used. The second part of the sural nerve biopsy as well as small samples of the spinal cord. spinal nerve roots and cervical and lumbosacral plexuses of the autopsied patient with HNA and of the control patient were fixed in a 2",~ glutaraldehyde solution buffered with 0.1 M Na-phosphate at pH 7.2. These samples were postfixed for 2 h in 1~o OsO4, dehydrated and embedded in epon. except for one sample of the sural nerve from which teased fibres were prepared. The remaining material of the central and peripheral nervous system of both autopsies was fixed in a formaldehyde solution, and selected parts were embedded in cetloidin o r paraffin~ Cryostat sections of the sural nerve biopsy were stained with hematoxylin and eosin. Glees-Marsland's method, sudan-black. PAS and acid phosphatase. One-micron sections of the epon-embedded material were stained with totuidineblue and paraphenylene-diamine (PFD). Transverse l-/~m sections of the sural nerve, stained with PFD. were used for quantitation of the diameters o f one thousand myelinated nerve fibres and of the density of myelinated nerve fibres. using a Zeiss TGZ3 particle size analyzer. Thin sections of the epon-embedded material were stained with uranyl acetate and lead citrate, and examined under Phifips 200 and 301 electron microscopes. Sections of the tbrmalin- and celloidin-embedded autopsy material were stained with hematoxylin and eosin, PAS. sudan-black. Alcian blue. and the methods of Holzer. KliJver-Barrera and Bodian.

CLINICAl_ D E T A I L S Ill- 7 the index patient, was first seen at the age of 44. For 3 months, he had been expertencmg bouts of pain in the right shoulder, the elbows and the wrists. The pain was associated with redness o f the h a n d s and forearms a n d was followed, hours to days later, by weakness in the involved extremity. These bouts lasted for only a few days. hut recurred about once a week. At the age of 14. a "cervical rib" had been removed because o f pain and weakness of the left arm. Thereafter. the weakness had persisted for some years. At the age of 41. he had had a similar episode, consisting of periods of pain and weakness lasting about 3 days and occurring about once a month. Examination 3 m o n t h s after the onset of the attack revealed close-set eyes (see Table 1). and syndactyly of the ,second and third toes of b o t h feet. He had weakness of the left supraspinatus muscle (grade 4. M e d i a l Research Council 1943), a slight hyporeflexia in the left arm. and analgesia in the cutaneous area of the left radial nerve and in a zone on the lateral side of the left thigh. An E M G was performed at that time ~see results). One m o n t h later, he returned with complaints o f pain in the left shoulder and at the base o f the left hypothenar, which appeared red and swollen, followed a few days later by weakness of the left hand. On examination, the ulnar nerve was extremely sensitive to pressure, but not palpably thickened. There was a paresis of the left deltoid (grade 1), supraspinatus (grade 3) and biceps, brachioradialis and triceps (grade 4) muscles: squeezing, extension and abduction of the fingers and thumb, extensmn of the wrist, and pro- and supination were virtually impossible. Fascieulations were not apparent: slight atrophy of the left first interosseous muscle was noted. X-ray revealed elevatiofi of the left hemidiaphragm. There were no rheumatic abnormalities of the hands and wrists, nor spondylotic or spondylarthrotic changes of the cervical spine. Haematological and blood chemical analysis gave normal results, including a normal ereatine kinase (CK). Five m o n t h s later a lump i n the right biceps~-which

265 proved to be a desmoid tumour~ was removed, and a biopsy of this muscle was taken at the same time. There were no histological or histochemical abnormalities. A biopsy of the left sural nerve was also performed at that time (see Results). A few weeks later, severe pain and slight weakness of the right shoulder and arm supervened. The weakness was most pronounced in the extensors of the right hand and fingers. Hypalgesia was present on the lateral side of the entire right arm, including the thumb and index finger. The weakness of the left arm had not yet improved. He was treated with 45 mg prednisone daily, reduced aller 2 weeks to 15 mg daily, and stopped after 3 months because of lack of effect, During the following months, the strength in both arms gradually returned, but leaving residual weakness in both deltoids and the left lower arm and intrinsic hand muscles. Bouts of pain of varying intensity and weakness in one or both arms persisted tk)r the next few years. /-3, the grandmother of the index patient, was reported to have had a number of attacks of pain and subsequent weakness of either the left or right shoulder and arm, starting at the age of 20. Her family remembers that she was not able to lift her arms nor to carry heavy objects with either arm. She died at the age of 72 of unknown cause. Two of her children (11-3 and 11-6) were reported to have had no complaints suggestive of HNA.

1/-7, the mother of the index patient, had had 5 attacks of severe pain and weakness, either on the right or on the left side, but never on both sides at the same time. These attacks always started 2 3 weeks alter a delivery, and occurred after the second, fourth, seventh, eighth and ninth pregnancies (all boys, all affected themselves). Her first attack occurred at the age of 21, She never recovered her strength completely. She was first seen in our department at the age of 69 and later at the age of 71 : the findings on both occasions were essentially the same. The interpupillary distance was 55 mm (normal for women 61 mm or more (Geiger et al. 1974). There was global atrophy of the musculature of both shouldcrs and upper arms, less so in the lower arms and hands. There was a moderate weakness of both deltoids and of the right biceps, extensors and flexors of the wrist and flexors of the fingers. There was a generalized areflexia. On the ulnar and volar sides of the right lower arm and hand there was a hypalgesic/hypaesthetic area. The strength in her legs was normal. In October 1979, she underwent surgery for a pancreatic carcinoma. She died in November 1980, at the age of 72, because of widespread metastases, ileus and liver failure.

II/- 1, the eldest brother of the index case, had his first attack at the age of 13, with pain and weakness in the left arm. At that time, a scalenotomy was performed. Thereafter, he had 4 attacks of pain and weakness: 3 m the right and 1 in the left arm. There was always a period of 7 10 years between thc attacks, the last occurred at the age of 52. Although their strcngth returned to normal, the muscles of the affected limb remained thinner than bet\~re. He experienced 3 further episodes, possibly related to his illness: on one occasion he had vocal chord paralysis of one year's duration, and twice a severe pain in the area of the right femoral nerve. Examination at the age of 52, three weeks after the onset of his last attack on the left side. revealed a healthy man of average height, but with rather close-set eyes (Table 1) and a slight syndactyly of the 2nd and 3rd toes of both l~ect. He had a stooped right shoulder and a winged scapula on the right side, with weakness (grade 4) of the deltoid, biceps, triceps, and lower arm and hand muscles. The right lower arm was thinner than the left. On the left side, the strength of the already severely atrophic deltoid was grade 1, of the intYaspinatus grade 2, the other muscles had normal strength The right thigh was 2 cm thinner than the left (the patient was right-legged), but its strength was normal. The deep tendon reflexes were all absent. There were no sensory signs. X-Ray showed an elevation of the left hemidiaphragm. Two years later, atrophy could still be shown, but some of the strength of the deltoid muscle had returned. An EMG was carried out I month after the beginning of his last attack, and at the age of 55 (see Results).

I11-3, tile second brother of the index patient, had his first attack at the age of 42, with severe pain in the right shoulder and neck, radiating into the arm, followed by weakness of the entire right arm.

266 Both pain and weakness resolved after a few momhs. Blockade of the stellate ganglion did little to diminish the pain. Since then. he has had increase in pain and weakness of the tight arm 2 3 times a year. and lasting for a few months, with more or less weekly exacerbations and remissions On exammauon at the age of 52. we saw a normally built man with a normal inner canthal distance (Table 11. The trophic state and strength of the muscles of the left arm were normal He had a slightly stooped right shoulder with some atrophy of the shoulder girdle muscles. The right shoulder girdle and upper arm muscles were grade 3. the lower arm and instrinsic hand muscles grade 4. The deep tendon reflexes were normal. There was an area of hypatgesia and hypaesthesia corresponding to the dermatomes C4 and C5 on the right side. 111-5 the eldest sister of the index patient, had never had any attacks of pare or weaktlcss of the shoulders or arms. However. at the age of 47. she had had an acute left peripheral facial paralysis, preceded by pain behind the left ear, with almost complete recovery. II1-9 and I 1. younger sisters of the index patient, aged 45 and 43 at the time of examination, had never had an y complaints of pain or weakness, and were entirely normal on examination. III- 13, had his first attack at the age of 14. in the right shoulder: the pain lasted for b weeks, and the ensuing weakness never disappeared completely. At the age of 27. he had an attack o f pain in the left shoulder, but without weakness. At the age of 41 an attack of severe pain in the left shoulder and elbow radiating to the hand occurred. This attack may have been related to physical exertion. Two weeks after the onset of the pain. weakness of the entire left arm supervened, combined with a numb feeling and paraesthesias in the thumb, index and third fingers. Slight relief of the pare could be achieved by heat. On examination 2 weeks later, we saw a hypoteloric but otherwise normally built man. On the right he had severe atrophy of the shoulder girdle muscles and a winged scapula: the strength in the muscles of the right shoulder, arm and hand was almost normal. On the left. severe atrophy of the shoulder and upper arm muscles was already evident, and the muscles were extremely hypotonic. The triceps, extensors of the wrist and f'mgers and abductor of the little finger were grade (~ 1. the deltoid, latissimus dorst, supraspinatus, deep flexors of the fingers were grade 2, the biceps was grade 3. All deep tendon reflexes of the left arm were absent. In the dermatome C6. a hypalgesia and hypaesthesm were present. During the following months, a gradual improvement occurred despite a progressing atrophy. An EMG was made four weeks after the onset of weakness (see Results). 111-15 had two attacks of pain and weakness m the right shoulder and arm. at 33 and 35 years of age, leaving atrophy of the right deltoid, and grade-4 weakness of the deltoid, opponens and abductor pollicis and intrinsic hand muscles, An E M G was carried out 7 and 11 weeks after the onset of the last attack tsee Results). 111-16. the youngest brother of the index patient, had also had one severe left-sided attack, at the age of 28. Since the age of 6. however, he had had bouts of pain. sometimes associated with weakness. especially in the right shoulder, also in the legs, occurring about 3--4 times a year. He had experienced three periods of hoarseness and dysphonia. He suffers from a congenital let~-sided perception deafness. On examination at the age of 29. both deltoids were severely atrophic, both upper arms and the fight pectoralis major were moderately atrophic. The left deltoid (grade 3). serratus anterior, supra- and infraspinatus (grade 4) were paretic, but e ne year later their strength had almost returned |o normal. In the next generation. 11/-1, IV-5, 1I/-7. IV-9, IV-IO. I V - t l . IV-12 and IV-14 were examined and found to have no neurological abnormalities. However. since they were all examined between 5 and 26 years of age. some of them may have been too young to have had an attack of HNA F-I

was a 6-year-old child without neurological abnormalities. At the age of 5, however, he had had a left-sided facial palsy spontaneous recovery after about 6 weeks.

267 /1'-3. 1"-2 arid IV-13 ,acre reported to bc normal; IV-13 had died at thc age of 16 from a traffic accident. /I-/5 had had an attack of severe pain in the right shoulder and arm at the age of 14, with severe paresis of the deltoid, Iriceps and rotator muscles. Two weeks after the onset an EMG was curried out Isce Results). Hc was treated with 40 mg prednisone per day, tapering the dose after 4 weeks. without apparent result. The pain subsided afler 6 weeks, but the weakness persisted much longer. On examination 6 months later, he showed severe atrophy of the right shoulder and entire arm. with a global paresis (grade 2 3), arellexia, and hypalgesia in the dermatome ('6. A! that timc the EMG was repeated. His f'a/hcr reported that he had recovered to an acceptable l'unctional level.

II -/6 was examined at 4~ years of age. He was reported to have had two attacks of pain lasting I'or several weeks in the right shoulder and arm, and during this period he could not elewtte the arm, and generally did not rise it. On examination, he had a slighl to moderate proximal weakness and no dislal weakness. The deep tendon reflexcs were normal. RESULTS

Gellelic Slzldies

There was a strong association between H N A and hypotelorism {Table 1). All patients but two (III-3 and 1V-15) had an inner canthal distance equal to or less than 2 SD below the mean value for their age. Assuming two different loci for HNA and hypotelorism, linkage between these traits was calculated. The lod score was 1.65 at a recombination percentage of 12.5. The linkage calculations with the genetic markers were negative. Of the investigated genetic markers K, LU, A2M, TC2, ACPI, AKI, D1A2, ESD, GLOI. PGP, and AMY1 were non-informative. The linkage calculations with the other genetic markers were based on the assumption that all patients in generations 11I 1ABI, F. I INNER C A N T H A L DISTANCES (1CD)

Patients

ICD (ram) ~'

Normal relatives

ICD (mm)

II1-1 111-3 111-7 111-13 111-15 111-16 IV-15 1\"-16

27 32 23 27 25 22 33 21 h

111-5 11I-9 111-11 IV-1 1V-5 IV-7 IV-9 IV-10 IV-II IV-12 IV-14

33 33 35 33 31 31 29 35

~* M e a n + 2 SD t' Mean + 2 SD

3 2 k 5 mm (Laestadiuset al. 1969). for his age 27_+5 mm.

-8 31 34

268

and IV are now known. No significant linkage was found between H N A and an'.' o f the genetic markers. Nor could linkage between a hypothetical gene for hypotelorism and one of the genetic markers be demonstrated. Linkage of HNA with the geneuc markers was also calculated with III-5 and V-1 (the subjects with Bell's palsy) and consequently IV-I (V-l's mother) as patients. This did not alter the results.

TABLE 2 ELECTROMYOGRAPHIC FINDINGS

Patient

Age (yr)

Time after onset of lasl attack (side)

Muscle

111-1

52

I month (LI

55

3 years (L)

[. deltoid l_ biceps L deltoid

MP IP MP

IlI-7

44

3 months (R)

R abd. poll. br. L supraspin.

IP IP

III-13

41

4 weeks {L)

L L t. L L l_ L L L R

deltoid supraspin. teres major serr. ant. biceps triceps ext. dig. comm abd. poll br. abd. dig. V ext. dig. comm.

absent IP SP MP MP absent SP IP IP IP

R R R R R R

deltoid biceps abd. poll. br. deltoid infraspin. abd. dig. V

lP IP IP IP. polyphasia lP IP. t~lypha sia

R R R R R R R R R R

deltoid biceps triceps infraspm. supras pro. ext. dig. conma. deltoid biceps triceps ext. dig. comm.

il [3 St.' 111

111-15

35

" weeks fRl

11 weeks (R)

IV-15

14

2 weeks (R)

4{ months (R)

Fibrillations pos. denerv, pot.

--

Voluntary motor umt potentials

lP ~.tlJs~ll I

-

IP = interference pattern: MP = mixed pattern: SP = single pattern.

MP MP MP MP. polyphasla MP. polyphasia absm~,t SP. polyphasia

269

Electrophysiological studies A s u m m a r y is presented in Tables 2 ( E M G ) and 3 ( m o t o r latencies); normal values are given in Table 4. Eight investigations were performed on 5 patients. Six investigations were carried out during attacks. Signs o f denervation at rest were lound in 2 patients (III-13, IV-15). In IV-15, these abnormalities increased at follow-up investigation 4 m o n t h s later. Loss o f m o t o r units became apparent in severely paretic muscles, and this process o f denervation apparently continued for some m o n t h s alter the onset o f an attack, while at the same time signs o f reinnervation appeared (see Table 2, patient IV-15 and also 111-15). The m o t o r and sensory nerve conduction studies in the main nerves o f the upper and lower arms and hands were normal. Definite abnormalites were found in the acute stage o f an attack, when terminal latencies and evoked potentials were measured alter stimulation o f the brachial plexus at Erb's point. Completely paralyzed muscles o f the shoulder girdle could not be stimulated indirectly (patient 111-13 and 1V-15). The terminal latency to paretic muscles was increased and sometimes associated with a decrease in the evoked muscle potential. In one case (IV-15), the terminal latency to the biceps muscle was normal initially, but with a distinctly decreased amplitude o f the evoked potential. At a later stage, it was TABLE 3 MOTOR LATENCIES Patient

Latency from brachial plexus

Motor latency ( m s )

tO

R

Comments

L

111-1 (1)~

deltoid biceps

8.2 8.2

III-1 (2)

deltoid

5.3

111-13

deltoid triceps ext. dig. comm.

6.4

no resp. no resp. 8,5

I11-15 (1)

deltoid biceps

9.6 4.5

111-15 (2)

deltoid

3.8

IV-15 (1)

deltoid biceps triceps

no resp. 5.5 i)o resp.

ampl. evoked pot. decreased

biceps

28 no resp.

amp1. evoked poi. 1o~, and polyphasic

IV-15 (2)

triceps

Underlined values: abnormal result. a See Table 2.

ampl. evoked pot. decreased ampl. evoked pot. normal

270 TABL.E 4 NORMAL VALUES OF MOTOR LATENCIES IN THE ARMS. WHEN STIMULATING I'HI~ BRACHIAL PLEXUS AT ERB'S POINT Distal latency tms) t+2 SD) Erb-Erb ErbErb -

:> deltoid > biceps ~ n'iceps ) ext dig. comm,

4.4 4.7 4.9 7.6

~0.6)" +1.2/~' (0.8)u I0.6)n

a Gassel 1964. b Mean of 18 adult controls.

severely prolonged. In IIl-15. the terminal latency to the deltoid was increased initially, but had returned to normal a few weeks later. In one case (1II-15), the sensory conduction velocity was measured over the thoracic outlet a n d )bund to be normal, as was the F-wave latency o f the ulnar nerve.

Histopathological studies The biopsy o f the left sural nerve o f II1-7 contained 12 fascicles. Their diameter varied from 180 to 500 ,am (mean diameter o f the smallest a n d the largest fascicle in 10 control biopsies 170 and 600 #, respectively). The n u m b e r o f myelinated nerve fibres was c o u n t e d in an intrafascicular area o f 0.2 m m 2. There were 5860 myelinated fibres/ram 2 (cf, normal >~7000/mm:; D y c k et al. I971~. Histoeoaphic analysis o f the distribution o f sizes of myelinated nerve fibres revealed a normal bimodal pattern. The epi- and permeurium a n d subperineural spaces were n o r m a l (Fig. 2). In longitudinal sections, some myelinated fibres showed an a b n o r m a l variation o f myelin thickness. Neither onion-bulb structures nor clusters o f fibres were seen (Fig. 2), T w e n t y - f o u r teased-nerve fibres were analyzed: 18 werc normal. 5 showed signs o f remyelination, and 1 fibre showed myelin change as Ls seen with axonal degeneration. N o sausage-like myelin swellings were seen, M a c r o ~ o p i c a l l y . the spinal cord o f II-7 appeared flattened and the roots were thin. At the light-microscopic level, some loss o f anterior horn cells in the cervical and thoracic parts, and degenerative changes in m a n y o f the remaining anterior horn cells at all levels were apparent. A x o n a l swellings were seen at the junction of the spinal grey and white matter. The posterior c o l u m n s showed a slight demyelination and gliosis: m a n y c o r p o r a amylacea were present. The findings in the spinal cord o f the control patient were essentially similar. N o obious decrease o f myelinated nerve fibres was f o u n d in the cervical and l u m b a r spinal nerve roots. Focal degeneration o f myelin was noted. At the lightmicroscopic level, some nerve fibres were enlarged. This swelling seemed to be due to the accumulation o f a weakly PAS-positive material inside the myelin sheath. At the ultrastructural level, a b n o r m a l material was f o u n d in the Schwann-cell

271

Fig. 2. transverse section of a fascicle of the sural nerve of the mdcx patienl. Sec the lexl ['or lurther details. Epon-embedded l-~m section, stained with paraphcnylcne dmmine, x 320.

272

Fig. 3. Thin section o1' a dorsal spinal nerve root of the ~utopsied patient with lqNA~hows mostly granular material in the Schwann-cell cytoplasm between the myelin sheath and the a×on ('A) Bar ] pl~.

273

Fig. 4. -rrzlnsvcrsc sccfi~m of ~l t'~lsciclc of the hrachial plexus of lhe autopsicd patient with HNA. shows the same granukir m~ltcrial as demonstrated in Fig. 2 (arrow.he,iris) ~md signs of myelin hrc~lkd o ~ n (ilrrow'). Epon-cmhedded l-ltm section, stained wifll Iohndin,:-bluc. x 500.

274 cytoplasm, either between the axon and the myelin sheath, or between layers of the myelin sheath. This material was mostly granular, but myeloid figures, small vacuoles and mitochondria were also seen (Fig. 3). It compressed and/or displaced the axons, but both the axon and the myelin sheath of these nerve fibres seemed to be otherwise intact. This material was also looked for in the control spinal nerve roots, and indeed found to be present. In the brachial and in the lumbosacral plexus, the same material was tound (Fig. 4k but here only a few fibres were affected. Apart from this. the parts of the plexuses that were investigated showed only minor abnormalities a slight increase in endoneural connective tissue, a slight and focal decrease in the myelinated nerve fibres (estimated, not counted because o f lack of control values), and myelin degeneration in a few fibres (Fig. 4). DISCUSSION

In this family 10 out of 27 relatives in 4 generations suffered from H N A There was a striking preponderance o f affected males. In contrast to the sporadic type of neuralgic amyotrophy (NA), this is an unusual finding in HNA, as males and females are usually affected to an equal extent (Geiger et al. t974), Since male-to-male transmission occurs, this pedigree is in accordance with autosomal dominant inheritance. The age of onset of the disease varied in our family from 4 to 42 years, which is in agreement with the literature data. Of the 18 Welbdocumented serious attacks. 12 were on the right and 6 o n the left side. This predominance of the right side was only observed in males; in the female patients, both sides were equally affected, a phenomenon also observed by Taylor (1960). This finding is not easy to explain. Attempts to relate the attacks to physical exertion have been unsuccessful. In our family, most affected males were used to doing strenuous work using both arms. and heavy exertion could not be held responsible for the occurrence of the attacks. Nor was there any relationship with infections or vaccinations, but in the female patient (II-7), a relationship with the puerperium was evident. Striking but unexplained is the finding that this woman only had attacks when she had given birth to a boy who proved to have the disease himself (with one exception: the birth of Iti-1 had not ted to an attack of HNA). Some other aspects of the clinical picture m our patients merit attentiom Two kinds of attack occurred, only one of which has so far been described m the literature. This "classical" attack starts with severe pain and is followed days to weeks later by weakness of several months' duration, with complete or partial recovery of strength, but persisting muscular atrophy. However. some of our patients, notably III-7. the index case. 1II-3 and Iti-16, also had periods of pain and weakness lasting for several months, during which they experienced more or less weekly exacerbations of pain. sometimes but not always followed within hours by weakness. and remitting after a few days Usually, after a few months, such a series of recurrent attacks subsided, leaving serious muscular atrophy in the affected area. but little or no residual weakness.

275 Affections of parts of the body other than the upper extremities have already been reported (Taylor 1960: Jacob et al. 1961; Poffenbarger 1968; Geiger et al. 1974). In our family, dysphonia (III-1, 111-16) and affection of the lumbosacral plexus (II-7, III-1, III-7) were noted. Recurrent Bell's palsy has also been observed as part of the syndrome of HNA (Wiederholt 1974). Two of the titmily members, 1II-5 and V-I, had had one attack of Bell's palsy. However, they did not have any other attacks of pain and/or weakness, there was no hypotelorism, and V-l's mother did not have clinical signs of HNA nor hypotelorism either. Therefore, it was decided not to include 11I-5 and V-1 in the patient group. However, it was also decided to calculate linkage in two ways: with 1II-5, V-l, and consequently IV-1 as normal subjects, and then as diseased subjects (see below). Therapeutic results have so titr been meagre, both with regard to the pain and the weakness. Conventional analgesics seem to confer little relief. We prescribed prednisone on two occasions, but without apparent improvement, The literature data concerning the use of prednisone in HNA have been conflicting: some authors reported improvement (Poffenbarger 1968 : Warm et al. 1973), other authors only saw initial improvement but no lasting effect (Taylor 1960: Geiger el al. 1974), while still others did not observe any effect at all (Roger et al. 1965: Smith et al. 1971 : Guillozet and Mercer 1973). One of the most striking features of HNA is its frequent association with dysmorphic features. Hypotelorism is mentioned most frequently, but small stature, cleft palate etc. have also been encountered. Most authors who report on the canthal distance state either that all their patients have close-set eyes (Jacob et al. 1961, "G"-family: Gardner and Maloney 1968: Smith et al. 1971; Guillozet and Mercer 1973; Erikson 1974: Geiger et al. 1974, '~S" and "~H"-families: Dunn et al. 1978), or that none of their parents have close-set eyes (Warot et al. 1973: Wiederholt 1974). Exceptions are the "S"-family described by Jacob et al. (1961), in which an affected mother of 2 affected children with hypotelorism herself had a normal interocular distance, and the "C"-family described by Geiger et at. (1974) in which the index case but not his equally affected lather had a normal interpupillary distance. In our family, two affected relatives had a normal inner canthal distance (III-3 and 1V-15): the other patients all had close-set eyes and the healthy relatives had normal inner canthal distances (see Table 1). Two explanations seem possible: either there is one single gene for HNA and hypotelorism, and the occurrence of close-set eyes depends on pleiotropism with variable gene expressivity, or there are two distinct genes showing close linkage. The latter explanation would allow for recombination. However, only a moderately close linkage between the two postulated genes is present (lod score 1.65, at a recombination percentage of 12.5). Furthermore, the frequent association between two rare traits like HNA and hypotelorism argues more for pleiotropism. It is not known, whether the normal people with an inner canthal distance below the 3rd percentile have a separate gene for hypotelorism. Other genetic and environmental Factors might also determine this phenotypic appearance. The existence of

276 a separate gene tor hypotelorism ~s. to the best of our knowledge, at present only hypothetical. The exact c h r o m o s o m a l localisation of H N A is not known. Theretore. the linkage study was performed, but linkage between the loci for H N A (or hypotelorism) with one of the investigated genetic markers could not be demonstrated, Our calculations were based on the assumption that we were aware of all patients in this family. This assumption m a y prove unjustified since the age at onset of H N A in this family varied considerably and not all relatives, notably in generations IV and V. had reached middle age. Thus, some individuals in these generations may yet prove to carry the gene for H N A . despite the fact that they all had a normal inner canthal distance. The electrophysiological observations described in the literature are sparse and incomplete. Signs of denervation in affected muscles were gener~ly found (Taylor 1960: Jacob et al. 1961 Poffenlyarger 1968; Smith et al. 1971 Warot et al. 1973: Erikson 1974; Geiger et al. 1974 Wiederholt 1974: Dunn et al. 1978; Van Wensen 1980), mostly in combination with normal conduction velocities in the main nerves of the upper and lower arm (Jacob et al. 1961' Poffenbarger 1968: Smith et al. 1971 ; Erikson 1974: Geiger et al. 1974; Dunn et ak 1978: Van Wensen 1980). Signs of re-innervation appear in a later stage of the attack. Such findings could point to a distal axonal lesion or to a more proximal undefined lesion. This had led to controversy concerning the site of the lesion in H N A (Bradley et al. t975: Dunn et al. 1978). Hypotheses have varied from a mononeuritis multiplex (Dunn et al. 1978), to a lesion in the plexus (Bradley et al. 1975) or to a myeloradicuiar affection (Smith et al. 1971). However, measurement of the proximal m o t o r an d sensory conduction through the brachial plexus, which could clarify this. has only been done sporadically. Geiger et al. (1974) in 1 patient, and Windebank et al. (1982) in 4 patients found evidence suggesting a lesion of the plexus. Windebank et al. state that they found evidence of axonal destrucuon within t h e plexus. A prolonged latency and a reduced evoked muscle potential were found by Geiger et al.. when stimulating at Erb's point. However. an increased latency could also be caused by re-innervation, when found in a more chronic stage of an attack. as Dunn et al. (1978) indicated. The patient of Geiger et al. was not investigated until 4 months after the onset of an attack, and this long interval m a y m a k e their findings inconclusive. Finally, Bradley et al. (1975) investigated 3 patients: however. 1 was a non-familial case and the other 2 m a y have suffered from hereditary liability to pressure palsies (Van Wensen 1980). We measured m o t o r latencles in the brachial plexus in the acute stage of an attack in 4 patients (III-1, !11-13. III-15, tV-15) and again in a more chronic stage in 3 of them (III-1. III-15 and IV-15) (Table 3). Retardation or interruption of the conduction through the brachial plexus to the affected muscles was demonstrated, and this affection could apparently continue for some weeks or months after the onset o f an attack (IV-I 5), while in another instance improvement in the conduction rate had occurred (III-15). A temporary interruption or retardation of the conduction through the brachial

277 plexus could be due to local demyelination or to a conduction block. The finding of a diminished evoked potential amplitude together with a normal interference pattern in patient IV-15 is also in agreement with this hypothesis. However, in muscles that remain atrophic (and possibly also paretic), loss of motor units must have occurred, suggesting that subsequent axonal degeneration occurs in the more severely affected nerve fibres. The electrophysiological findings presented here, therefore, give a strong indication that in HNA the brachial plexus is the most frequently and most severely involved site. The usefulness of a sural nerve biopsy will therefore, depend on whether this nerve is subclinically affected during an attack of HNA. Nerve biopsy findings have been reported infrequently, and no biopsy has been taken in the acute stage of an attack. Furthermore, the results have been conflicting. One group of authors (Bradley et al. 1975; Madrid and Bradley 1975) reported sausage-like thickenings of the myelin sheath, as observed in hereditary liability to pressure palsies (HLPP): another group found only slight signs of de- and remyelination, or no abnormalities at all (Van Wensen 1980). A third group reported the results of the examination of fascicular biopsies of the brachial plexus, in a short communication (Windebank et al. 1982). They did not find any gross abnormalities, but here, selection and timing problems may have played a role (Dr. P.J. Dyck, personal communication 1982). The sural nerve biopsy of the index case, taken 5 months after the onset of an attack in the left arm, was slightly but definitely abnormal, indicating that subclinical lesions of peripheral nerves other than the brachial plexus could be a feature of HNA. The loss of myelinated nerve fibres suggests an axonal lesion. It may be concluded that the study of sural nerve biopsies in the acute stage of an attack would indeed be worthwhile. Examination of the spinal cord, spinal nerve roots and plexuses at autopsy revealed only nonspecific changes. These were probably comparatively recent and not the result of the HNA attacks, but of ageing and/or neoplastic disease. In our opinion, the autopsy investigation did not contribute significantly to our knowledge of the location or pathogenesis of HNA. On the contrary, the density of" myelinated nerve fibres in the plexuses was not conspicuously decreased, a surprising finding since the clinical signs (weakness and atrophy) suggested a persisting loss of motor units following the last attack of HNA. Exact identification of the granular material found in the Schwann cells in the spinal nerve roots and plexuses of the patient with HNA and of the control patient was not possible, because we could not examine frozen tissue. It is tempting to speculate that we are dealing with a polysaccharide-like material, which might be a nonspecific and age-dependent phenomenon, occurring especially in the proximal parts of the peripheral nervous system. Further research is necessary to clarify this issue. From the histopathological studies, one important conclusion may be drawn : the absence of sausage-like thickenings of the myelin sheath, both in the sural nerve biopsy and in the autopsy material, is a strong argument against the supposition

278

that tomaculous neuropathy (hereditary HNA are one and the same disease, as We agree with Van Wensen (1980) and H L P P are two different diseases, both point of view.

liability to pressure palsies. H LPP) and was suggested by Bradley et al. (1975). Windebank et al. (I982) that HNA and from the clinical and histopathotogical

A C K N O W LEDG E M E N T S

L. Bernini. M.D.. P. Meera Khan. M.D., L. Nijenhuis. Ph.D. andl. Schreuder. Ph.D. performed certain determinations of the genetic markers. W. Volkers, Ph.D. performed the linkage calculations. K. Mechelse, M.D. performed the EMG in patient III-13. J. Boldewey, M.D. performed the general autopsy. Expert technical assistance was given by Mrs. D. Kiers. Mrs. S. Piethaan, H. Veldman. H. Eelderink and A. De Jong. Mrs. J. Doornbosch provided secretarial assistance. REFERENCES Bradley, W . G , , R. Madrid. D. C, T h r u s h and M.J. Campbell ~1975) Recurrent bracbial plexus neuropathy, Brain. 98 : 381 -398. Breuning, M. H.. E . M . Van den Berg-Loonen. L.F. Bernini. J.B. Bijlsma. E Van Loghem. P. Meera K h a n and L. E. Nijenhuis (1977) Localization of H L A on the short arm of chromosome g, Hum, Genet.. 37: 131-139. Dreschfeld. J. (1886) On some of the rarer | b r m s of muscular atrophies. Brain, 9 : 1 7 8 195 Dunn. H . G . . J.R. D a u b e and M R G o m e z (1978) Heredofamilial brachial plexus neuropathy (hereditary neuralgic amyotrophy with brachial predilectionJ in childhood. Develop. :tied. Child Neurol. 20: 28-46. Dyck. P.J.. E . H . Lambert and P.C. Nichols (1971) Quantitative measurement of sensation related to c o m p o u n d action potential and number of sizes of myelinated and unmyelinated fibers of sural nerve in health. Friedreich's ataxia, hereditary sensory neuropathy and tabes dorsalis. In A. R6mond (Ed.k Handbook o f Electroencephalography and Clinical Neurophysiology Vo/ 9, Elsevier. Amsterdam. p p 83 .-118 Erikson. A. f19741 Hereditary syndrome consisting in recurrent attacks resembling brachial plexus neurms, special facial features and cleft palate. Aeta Paediat. Scand,, 63: 885--888. Gardner. J. H. and W. Maloney 119681 Hereditary brachial and cranial neuritis genetically linked with ocular hypotelorism and syndactyly, Neurology (Minneap.), 18:278 (A). Gassel. M . M . (1964) A test of nerve conduction to muscles of the shoulder girdle as an aid in the diagnosis of proximal neurogenic and muscular disease. J. Neurol, Neuro~urg. PsvOuat.. 27: 200-2(/5. Gelger, k . R . . E. k Mancall. A.S. Penn and S H. Tucker (1974) Familial neuralgic amyotrophy Report of three families with review of the literature. Brain, 97:87-102. Guillozet. N. and R . D . Mercer 11973) Hereditary recurrent brachial neuropathy. Amer. ,l Dis, Child., 125: 884-887. Jacob, J, C.. F. A n d e r m a n n and J.P. Robb (19613 Heredo-familial neuritis with brachial predilection. Neurology ~Minneap. J. 11 : 1025-1033, Laestadius. N . D . . J. M. Aase a n d D . W . Smith [19691 Normal inner canthal and outer orbital dimensions. J. Paediat., 74: 465M68. Madrid. R. and W . G . Bradley (t975) The pathology of neuropathies with focal thickening of the myelin sheath ( tomaculous neuropathy) Studies on the formation o f the abnormal myelin sheath, J. Neurol. Sci., 25:415~448. Medical Research Council (t943) Aids' to the Investigation 0t' Peripheral Nerve lnjurws (War Memor a n d u m . No. 7~. Her Majesty's Stationery Office. London. Poffenbarger. A. L. (1968) Heredofamitial neuritis with bracbial predilection, W. Virginia Med. J.. 64: 425-429.

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