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63666ournal ofNeurology, , and Psychiatry 1996;61:636-640 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.6.636 on 1 December 1996. Downloaded from SHORT REPORT

Massive root enlargement in chronic inflammatory demyelinating

W Schady, P J Goulding, B R F Lecky, R H M King, C M L Smith

Abstract series' and in up to a third of relapsing cases.4 Objective-To report three patients with Greatly enlarged nerve roots have been identi- chronic inflammatory demyelinating fied in a few typically affected patients at polyneuropathy (CIDP) presenting with necropsy,'6 by myelography,7 at , and symptoms suggestive of cervical (one by MRI.9 "We report three patients who pre- patient) and root disease. sented with symptoms suggestive of radicu- Methods-Nerve conduction studies, lopathy, in whom MRI or CT myelography EMG, and nerve biopsy were carried out, showed massive hypertrophy. having found the nerve roots to be very Subsequent investigation, including nerve enlarged on MRI, CT myelography, and root biopsy in one patient, showed CIDP. at surgery. Results-Clinically, peripheral nerve thickening was slight or absent. Subsequently one patient developed facial Case reports nerve hypertrophy. This was mistaken for CASE 1 an inner ear tumour and biopsied, with A man aged 58 developed severe left groin consequent facial palsy. Neuro- while walking, eased by flexing the limb, physiological tests suggested a demyeli- with associated low backache and decreased nating polyneuropathy. Sural nerve walking speed. He then noticed deadness and biopsy showed in all cases some loss of increased sensitivity of his right little finger. myelinated fibres, inflammatory cell He was thought to have a cervical spondylotic infiltration, and a few onion bulbs. radiculomyelopathy, for which a decompres- Hypertrophic changes were much more sive cervical laminectomy was performed at prominent on posterior nerve root biopsy another hospital in 1985. The clinical and in one patient: many fibres were sur- radiological findings at that time are not rounded by several layers of Schwann cell known. The operation was not helpful and his cytoplasm. There was an excellent walking continued to deteriorate. By 1993 his http://jnnp.bmj.com/ response to steroids in two patients but condition had progressively worsened result- Department of not in the third (most advanced) patient, ing in weakness of his right arm and both legs, , who has benefited only marginally from sensory disturbance in his hands and in the Manchester Royal intravenous immunoglobulin therapy. lower half of his body, and occasional urge Infirmary, His balance was poor, especially Manchester, UK Conclusions-MRI of the incontinence. W Schady may be a useful adjunct in the diagnosis of in the dark, and he was unable to stand with-

P J Goulding CIDP. out the aid of a stick. There was no family his- on October 1, 2021 by guest. Protected copyright. Walton Centre for tory of polyneuropathy. Neurology and (3 Neurol Neurosurg Psychiatry 1996;61:636-640) Examination showed restricted and Neurosurgery, Rice Lane, Liverpool low back movements. There was profound L9 1AE, UK wasting of the forearms and small hand mus- B R F Lecky Keywords: root hypertrophy; chronic idiopathic cles, worse on the right. His upper limbs were Royal Free Hospital, demyelinating polyneuropathy very weak, more so distally, with moderate Pond Street, London predominantly proximal asymmetric weakness NW3 2QG, UK R H M King Chronic inflammatory demyelinating poly- of the lower limbs. All tendon reflexes were Royal Hallamshire neuropathy (CIDP) is a relapsing or chroni- absent but the plantar responses were exten- Hospital, Glossop cally progressive disorder most commonly sor. The peripheral felt slightly thick- Road, Sheffield presenting with limb weakness, distal sensory ened. There was hypersensitivity of the skin in S10 2JF, UK 2 forearms and C M L Smith disturbance, and hyporeflexia.' The CSF both little fingers and medial Nerve con- loss from the umbilicus downwards in Correspondence to: protein is almost always raised.3 sensory Dr W Schady, Department duction studies show slowing of motor con- a patchy distribution. Joint position sense was of Neurology, Manchester in the feet and vibration could Royal Infirmary, Manchester duction and sural nerve biopsy discloses impaired only M13 9WL, UK. segmental demyelination and remyelina- be detected above the shoulders. He was Received 25 August 1995 tion.'I CIDP is one of the causes of "hyper- unable to stand without support but he could and in final revised form take a few with the aid of a stick. 7 August 1996 trophic neuropathy". Thickened peripheral steps Accepted 20 August 1996 nerves were detected in 11% of one large Romberg's test was strongly positive. Massive nerve root enlargement in chronic inflammatory demyelinating polyneuropathy 637 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.6.636 on 1 December 1996. Downloaded from

Figure 1 (a) MRI axial Tl weighted gradient echo image, patient 1; (b) myelogram, patient 2; (c) CT myelogram, patient 3. There is pronounced enlargement of the lumbosacral nerve roots, which in patient 1 (a) are seen to expand in a dumbbell shape outside the exit foramen (arrow).

and slowing of nerve conduction and motor conduction block, in keeping with a demyeli- nating polyneuropathy. A lumbar laminectomy was undertaken to decompress the cauda equina. On opening the A blood count, erythrocyte sedimentation dura several thickened, white, and matted rate, liver and renal function tests, blood glu- nerve roots were seen (fig 2). No CSF was cose, immunoglobulins, and plasma protein obtained. A fascicular biopsy of a posterior and urine electrophoresis were all normal. A nerve root showed loss of myelinated axons full antibody screen (including MAG antibod- and a few endoneurial inflammatory cells. ies) was negative. Molecular genetic studies Many large fibres had thin myelin sheaths and http://jnnp.bmj.com/ disclosed no duplication at 17pl 1 2. No acid were surrounded by several layers of Schwann fast bacilli were seen on skin scrapings. cell cytoplasm ("onion bulbs"). A sural nerve Magnetic resonance imaging showed biopsy disclosed similar but less advanced of the cervical cord. There was striking bilat- changes. Unmyelinated axons were normal. eral enlargement of all cervical nerve roots The neurophysiological and pathological with widening of the exit foraminae, especially findings supported a diagnosis of CIDP. at C6-7 and C7-T1. The thoracic spine, cord, Treatment with prednisolone and azathio-

and nerve roots appeared normal. There was prine resulted in initial worsening of hand on October 1, 2021 by guest. Protected copyright. homogeneously increased signal from the strength, bladder control, and mobility, such cauda equina, with multiple areas of nodular that he became unable to stand unassisted. enhancement and no visualisation of CSF. Pooled intravenous immunoglobulin therapy The lumbar nerve roots were grossly enlarged, (Sandoglobulin (04 g/kg/day) for five days filling and expanding the exit foramina (fig followed by monthly infusions of 22-24 g for la). Nerve conduction studies (table) showed 10 months) led to mild improvement in hand reduced sensory and motor action potentials function (less than 1 MRC grade) but had no

Nerve conduction data Motor Sensory Amplitude (mVI) % Conduction block Distal latency (ms) Conzduction velocity (mls) Amlplitude (p V) Patient 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 Median 1.9 11-3 9-2 58 15 28 6-0 - 8 1 25 47 37 5 - 1 Ulnar 2 4 9-3 3-9 8 44 13 5-6 2 9 5 1 34 43 41 0 12 0 Peroneal 0 3 3-2 0 4 78 12 0 14-0 9 0 14 0 23 31 38 0* 1* 2* *Lower limb sensory action potentials are for the sural nerve. Compound muscle action potential amplitudes correspond to those obtained on distal nerve stimula- tion. Sensory action potentials were recorded orthodromically in the upper limbs and antidromically in the lower limbs. % Conduction block refers to the drop in motor potential amplitude between distal and proximal stimulation sites. 638 Schady, Goulding, Lecky, King, Smith 4: J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.6.636 on 1 December 1996. Downloaded from

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Figure 2 Operativefindings in patient 1. The lumbar nerve roots are grossly thickened and matted together.

sustained effect on lower limb strength. He has remained confined to a wheelchair.

CASE 2 N. This 25 year old woman presented in 1989. AV. For several years she had noted minor non- .:, 's 1...... 1 specific leg weakness which she had attributed to being "unfit". In the previous year she had Figure 3 Sural nerve from patient 2 showing an onion developed progressive difficulty with climbing bulb consisting of a small, normally myelinatedfibre (A) stairs and had become unable to run or rise surrounded by two layers of circumferentially oriented from a squatting position. She had backache Schwann cells. The thinly myelinatedfibre (B) is surrounded by a less well defined layer ofsmall Schwann but no pain or sensory complaints. The upper cell profiles. Bar = 5 limbs were asymptomatic except for occa- gm. sional cramping of the hands. There was no family history of neuromuscular disease. Examination showed mild wasting and as well as small but definite deposits of both weakness of the small hand muscles. There CD4+ and CD8+ cells. was moderately severe symmetric wasting and The initial clinical impression was of a lum- weakness of the quadriceps and mild weakness bar polyradiculopathy, possibly in relation to of hip flexion, hip extension, and ankle dorsi- her spina bifida occulta. However, the results flexion. The upper limb reflexes were pre- of investigations pointed to CIDP and she was http://jnnp.bmj.com/ served but the knee jerks were sluggish and the therefore treated with 60 mg prednisolone and ankle jerks were absent. Plantar responses 150 mg azathioprine daily. Improvement were flexor. There was no sensory deficit began within a few weeks and after eight except for loss of vibration sense at the toes. months she was almost asymptomatic. Standard haematological and biochemical Prednisolone was gradually withdrawn over a tests were normal. Serum creatine kinase con- year and azathioprine was stopped after three

centration was mildly raised at 335-462 U/I years. Her strength has remained normal. on October 1, 2021 by guest. Protected copyright. (upper limit of normal 175 U/1). There was no abnormal paraprotein. The CSF protein was CASE 3 1 06 g/l. Anti-MAG antibodies were not A 49 year old man was referred in 1989 detected and there were no genetic markers for because of foot drop. He reported several HMSN1. Spina bifida occulta was seen on episodes over the previous 20 years of severe radiography of the lumbar spine. A lumbar low radiating to the anterior thighs, myelogram showed pronounced hypertrophy resolving with conservative treatment. In 1981 of all lumbosacral nerve roots (fig lb). Motor he developed pain in his left foot, which was conduction was slowed in the upper and lower helped by a metatarsal support. Five years limbs (table). On EMG there was evidence of later his wife noticed that his left foot slapped chronic partial denervation in vasti and active down when he walked. The foot drop gradu- denervation in tibialis anterior, with fascicula- ally worsened and in 1988 he became aware of tion. A biopsy of the quadriceps showed mild difficulty rising from a squat, and twitching of neurogenic atrophy. A sural nerve biopsy dis- the thigh muscles. His medical history closed some loss of myelinated axons and included surgery to correct a squint in 1948 occasional axonal sprouts. A few thinly myeli- and 1983. In 1987 he developed a postural nated fibres were surrounded by whorls of tremor which responded to treatment with Schwann cell cytoplasm (fig 3). Slight propranolol. His mother had a similar tremor. perineurial macrophage infiltration was seen There was no family history of a polyneuropa- Massive nerve root enlargement in chronic inflammatory demyelinating polyneuropathy 639

thy and nerve conduction studies in both his neurophysiological, and pathological criteria J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.6.636 on 1 December 1996. Downloaded from children were normal. for CIDP.'2 There was no family history of Examination of the legs disclosed some neuropathy or foot deformity and genetic wasting of the quadriceps, hamstrings, and markers for HMSN 1 a were absent. Nerve extensor digitorum brevis muscles. There was conduction studies in the children of patient 3 mild weakness of the iliopsoas and hamstrings were normal. Further support for the diagno- and severe weakness of the tibialis anterior and sis of CIDP comes from the remarkable peronei, more so on the left. The ankle jerks response to steroids in patients 2 and 3. In were just present with reinforcement. The patient 1 the disease was so advanced that other tendon reflexes were normal and plantar response to treatment has been only modest. responses were flexor. There was a full range The first patient presented with a left L1-2 of low back movements and straight leg raising and back pain followed by fea- was not restricted. Sensation was normal save tures of a right C8 root lesion, for which a for a small area of decreased sensitivity on the decompressive laminectomy was carried out. left big toe. He walked with a left foot drop. Patient 2 had proximal lower limb weakness, Blood count, erythrocyte sedimentation initially thought to be due to lumbar root dis- rate, biochemical profile, glucose, thyroid ease. The third patient had several episodes of function tests, immunoglobulins, protein elec- back pain and symptoms suggesting bilateral trophoresis, and phytanic acid were all nor- L2-3 root irritation before the development of mal. There was a weakly positive antinuclear a left foot drop. factor with a homogeneous pattern but there Radiculopathy is an unusual presentation of were no anti-MAG antibodies. DNA studies CIDP. Symptoms of root disease were not showed no duplication at 17pl 1 2. A lumbar recorded in three large series totalling 205 CT myelogram (fig lc) showed thickening of affected patients.'"3 It has, however, been all the nerve roots of the cauda equina, espe- stressed that a pattern of weakness which cially at the SI level, where the exit foraminae includes proximal as well as distal muscles is a were enlarged. No bony or disc lesions were distinctive feature of CIDP.3 This probably seen except for L4-5 disc space narrowing. indicates painless root involvement and it is The CSF protein content was very high at thus correct to use the term polyradiculoneu- 2-2 g/l. Nerve conduction studies (table) indi- ropathy when referring to CIDP, as is now cated a mixed polyneuropathy. EMG of distal commonly done. It also explains the apprecia- lower limb muscles showed large motor unit ble increase of the CSF protein seen in our potentials with a decreased interference pat- and other patients. tern, in keeping with chronic partial denerva- Nerve root enlargement in our patients was tion and reinnervation. A left sural nerve striking. It was radiologically evident in the biopsy showed reduced numbers of myeli- lumbar region in all three and was most nated fibres, some clusters of small regenerating advanced in patient 1. This patient also had fibres, thinly myelinated fibres, and a few massive cervical root hypertrophy, whereas the onion bulbs. thoracic region was seemingly unaffected. He was treated with 80 mg prednisolone Why the dorsal nerve roots should be spared is daily. An increase in strength was demonstra- unclear, but it raises the possibility that nerve ble by three months and nerve conduction root thickening is in some way dependent on studies showed improvement in most nerves influences which arise in the limbs but not the by six months. A year after starting treatment trunk. At surgery the lumbosacral nerve roots http://jnnp.bmj.com/ he could play 18 holes of golf. Examination were matted together so thickly that they filled after a further year was normal apart from the spinal canal and no CSF could be mild weakness of ankle dorsiflexion, more so obtained. on the left. His steroid dose was slowly By contrast, peripheral nerve thickening was reduced to 5 mg on alternate days. Despite his not a feature in our patients except in patient clinical improvement MRI of the lumbar 1, in whom it was mild. This discrepancy region performed 30 months after starting between nerve root and peripheral nerve on October 1, 2021 by guest. Protected copyright. steroids showed almost identical findings to involvement was also found pathologically, the initial CT myelogram. although it was the reverse pattern from that In July 1992 he noticed left sided deafness. reported by Matsuda et al.6 Sural nerve biopsy auditory evoked responses showed showed some cellular infiltration and a mixed a delayed wave I and MRI disclosed a tumour picture of axonal loss and regeneration on the in the inner ear. The lesion was biopsied and one hand and demyelination on the other. was found to be an enlarged facial nerve. Whorls of Schwann cell cytoplasm were Postoperatively he had a complete left facial scanty. By comparison, such onion bulbs were palsy. A facial nerve anastomosis was per- plentiful in the biopsy of a posterior nerve root formed using a greater auricular nerve graft, in patient 1. It could thus be that nerve biopsy which has resulted in substantial recovery of in CIDP might be unrewarding or even mis- mobility, particularly in the lower half of the leading. Dyck and colleagues' have already face. pointed out that sural nerve biopsy in these circumstances is often not as helpful as might have been expected. More recent authors have Discussion underlined the fact that the nerve pathology in We have reported three patients who had CIDP is relatively non-specific and that clini- symptoms suggestive of lumbar root disease, cal and electrodiagnostic assessment usually in whom subsequent findings fulfilled clinical, suffices to make the diagnosis." 640 Schady, Goulding, Lecky, King, Smith

How reliable are nerve conduction studies deafness, in whom subsequent necropsy J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.6.636 on 1 December 1996. Downloaded from in these circumstances? It is accepted that showed noticeable enlargement of cranial motor conduction is slowed in CIDP, to the nerves 3-12. Cranial nerve enlargement may extent that this finding forms part of the be mistaken for other pathology and biopsy mandatory criteria for the diagnosis of this should be avoided in these patients in view of condition.'2 In our patients there seemed to be the risk of damage such as that which occurred a gradient, the most severely affected clinically in our patient. Fortunately his facial palsy has and radiologically (patient 1) having the slowest recovered after nerve grafting. conduction velocities and the most obvious We thank Professor PK Thomas for helpful advice on patient 2 motor conduction block, whereas the least and Dr J Gillespie for performing the CT and MRI. affected (patient 2) barely met the criteria laid down by Cornblath et al. 2 1 Dyck PJ, Lais AC, Ohta M, et al. Chronic inflammatory a to . Mayo Clini Proc 1975;621-37. Spine MRI is valuable addition the 2 McCombe PA, Pollard JD, McLeod JG. Chronic inflam- diagnostic armamentarium in CIDP. Enlarged matory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases. Brain 1987; spinal roots may be identified in patients being 110:1617-30. investigated for a demyelinating polyneuropa- 3 Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic as in our be discovered inflammatory demyelinating polyradiculoneuropathy. thy or, patients, may Clinical characteristics, course and recommendations for unsuspectingly when root disease is being con- diagnostic criteria. Arch Neurol 1989;46:878-84. nerve root 4 Austin JH. Recurrent and their corticos- sidered. Even in the absence of teroid treatment with five-year observations of a placebo- thickening, abnormal enhancement of the controlled case treated with corticotrophin, cortisone and prednisone. Brain 1958;81:157-94. cauda equina after intravenous gadolinium 5 Harris W, Newcomb WD. A case of relapsing interstitial -DTPA may be demonstrable in CIDP'4 as hypertrophic polyneuritis. Brain 1929;52: 108-16. as in acute 6 Matsuda M, Sakurai S, Yanagisawa N. Hypertrophic neuri- well inflammatory polyradicu- tis due to chronic inflammatory demyelinating polyradi- loneuropathy. Other conditions which need culoneuropathy (CIDP): a postmortem pathological study. Muscle Nerve 1996,19:163-9. to be considered in the differential diagnosis of 7 Symonds CP, Blackwood W. compression in nerve root hypertrophy are neurofibromatosis, hypertrophic . Brain 1958;85:251-60. and To 8 de Leon GA, Hodges FJ. Subarachnoid block and enlarge- HMSN, lymphoma, amyloidosis.'6 ment of the spinal canal in hypertrophic neuritis. _7 Neurol date few patients with CIDP have undergone Sci 1976;28:139-46. are to 9 Naganuma M, Doi S, Shima K, et al. Chronic inflamma- lumbar MRI and further studies needed tory demyelinating polyradiculoneuropathy associated determine whether a substantial proportion of with multifocal nerve hypertrophy-report of a case with nerve root or MRI study. Ri'tsho-Shinkeigaku 1991;31:1186-91. patients have spinal enlargement 10 De Silva R, Doyle D, Hadley D, et al. Nerve root hypertro- whether this is only a rare association. phy in chronic inflammatory demyelinating polyneuropa- thy. Muscle Nerve 1994;17:168-70. Upper motor neuron signs or features of 11 Ginsberg L, Platts AD, Thomas PK. Chronic inflammatory more widespread CNS dysfunction have been demyelinating polyneuropathy mimicking a lumbar syndrome. _7 Neurol Neurosurg Psychiatry reported in a proportion of patients with 1995;59: 189-91. CIDP."'' Long tract signs may be due to cord 12 Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diag- compression by enlarged nerve roots, as in our nosis of chronic inflammatory demyelinating polyneu- patient 1. There is a previously reported clini- ropathy (CIDP). Neurology 1991 ;41 :617-8. who after 13 Krendel DA, Parks HP, Anthony DC, et al. Sural nerve cally similar patient improved biopsy in chronic inflammatory demyelinating decompressive laminectomy.7 Alternatively, polyradiculoneuropathy. Muscle Nerve 1989; 12:257-64. with mul- 14 Crino PB, Grossman RI, Rostami A. Magnetic resonance several patients have been described imaging of the cauda equina in chronic inflammatory tiple sclerosis-like plaques in the optic nerves, demyelinating polyneuropathy. Ann Neurol 1993;33: white 311-3. cerebral matter, brainstem, cerebellum, 15 Morgan GW, Barohn RJ, Bazan III C, et al. Nerve root and spinal cord,'7 '1 but our patients had no enhancement with MRI in inflammatory demyelinating http://jnnp.bmj.com/ of of the polyradiculoneuropathy. Neurology 1993;43:618-9. features suggestive demyelination 16 Antoine JC, Baril A, Guettier C, et al. Unusual amyloid CNS. polyneuropathy with predominant lumbosacral nerve roots and plexus involvement. Neurology 1991;41: Cranial nerve involvement occurs in about 206-8. one in six patients with CIDP,'I probably 17 Schoene WC, Carpenter S, Behan, PO, Geschwind N. The most "Onion bulb" formations in the central and peripheral caused by segmental demyelination. nervous system in association with multiple sclerosis and common finding is facial weakness followed by hypertrophic polyneuropathy. Brain 1977;100:755-73. bulbar an movement and 18 Rosenberg NL, Bourdette D. Hypertrophic neuropathy palsy, eye disorder, and multiple sclerosis. Neurology 1983,33: 1361-4. on October 1, 2021 by guest. Protected copyright. papilloedema. Patients with pronounced nerve 19 Thomas PK, Walker RWH, Rudge P, et al. Chronic also have cranial nerve demyelinating associated with root enlargement may multifocal demyelination. Brain hypertrophy, as in our patient 3, who devel- 1987;110:53-76. to nerve 20 Ormerod IEC, Waddy HM, Kermode AG, et al. oped neural deafness due auditory Involvement of the central nervous system in chronic compression by an enlarged facial nerve. No inflammatory demyelinating polyneuropathy: a clinical, electrophysiological, and magnetic resonance imaging such cranial nerve thickening has been study. _7 Neurol Neurosurg Psy,chiatry 1990;53:789-93. reported on cranial MRI of patients with 21 Hawke SHB, Hallinan JM, McLeod JG. Cranial magnetic resonance imaging in chronic demyelinating polyneu- CIDP,2"2' even in those with focal cranial ropathy. _7 Neurol Neurosurg Psychiatry 1990;53:794-6. nerve involvement.22 Schoene and colleagues'I 22 Waddy HM, Misra VP, King RHM. Focal cranial involve- ment in chronic inflammatory demyelinating polyneu- described a patient whose clinical features ropthy: clinical and MRI evidence of peripheral and included bilateral facial weakness and nerve central lesions. . Neurol 1989;236:400-5.