Spinal cord, peripheral nerves & neuromuscular junction

201

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Clinical and Biochemical Observations in a Case of a Congenital Defect of Folate Absorption Masahiko Tsuda, MD, Hiroki Nakabayashi, MD, Yasuyuki Noguchi, MD, Hisashi Shimizu , MD, Takeshi Sakiyama, MD, Misao Owada, MD and Teruo Kitagawa,MD Department of Pediatrics, Nihon University School of Medicine, Tokyo

Treatment of the Guillain-Barre Syndrome by Plasmapheresis Mieko Yoshioka, MD, Shigekazu Kuroki, MD and Hideshige Mizue, MD Department of Pediatrics, Kobe General Hospital, Kobe

A congenital defect of folate absorption is a rare disorder which is characterized by megaloblastic anemia, mental retardation, convulsions and calcification of basal ganglia, and only three patients have been reported in J apan_ Although the primary defect is still unknown, a congenital defect of the specific carrier protein, both in the small intenstine and at the bloodbrain barrier, has been suggested. The clinical features and response to folic acid are significantly different in each patient. In order to investigate the relationship between clinical features and biochemical abnormalities of this disorder, studies were carried out on a patient with a congenital defect of folate absorption.

Case Report A 3-yr-old girl, the third child born to first-cousin parents, developed megaloblastic anemia at the age of 3 mos. After oral administration of folic acid, the hematological abnormality became normalized whereas neurological signs, such as seizures, hypotonia and calcification of basal ganglia, developed. Methods 1) Folate and its derivatives in blood and spinal fluid were determined. 2) Oral folate absorption studies, with 5 mg to 500 mg doses of synthetic folate, were performed. Results and Discussion Oral folic acid, 10 mg/day, administration produced a hematologic response and maintained a normal plasma folate level, but folate could not be detected in spinal fluid . Since there was a marked rise of folate in the spinal fluid when 250 mg of folate was given orally, the child was treated with the same dose. Intensive therapy, such as daily intramuscular injection of folic acid, is recommended for maintaining the folate level in spinal fluid. However, high dose oral folate administration is also effective to maintain the folate level in spinal fluid, and so we recommend oral folate administration for the treatment of this disorder. Key words: Congenital defect of folate absorption, high dose oral folate administration, folate level in cerebrospinal fluid, mental retardation.

The Guillain-Barre syndrome (GBS) usually has a good prognosis. However, in about 20% of the patients there is a persistent, residual disability, and 5% of cases die. So far no specific therapy for GBS exists. The increasing recognition over the past several years of the potential importance of humoral immune factors in the pathogenesis of GBS suggested that plasmapheresis might modify its clinical course. We presented here data of uncontrolled studies on acute GBS.

Patients and Methods Treatment by plasmapheresis was considered in patients who attended the Department of Pediatrics, Kobe General Hospital, Kobe, Japan, from January, 1984 to June, 1984, and who fulfilled the diagnostic criteria for GBS. Three patients had such pronounced symptoms as dyspnea and/or dysphagia. Plasmapheresis was performed with the use of an intermittent flow system (Haemonetics PEX) or by double filtration plasmapheresis (Kuraray). The duration of the disease before plasmapheresis varied between 9 and 11 days. At each session, about 500-1,500 gm of plasma was removed and replaced with Plasmanate. In the 3 treated patients, a total of 2,888 gm to 8,500 gm of plasma was removed at 4 to 6 sessions in 8 to 11 days. Cerebrospinal fluid was analyzed for blood cells, total protein, IgG, A and M content, and polyacrylamide gel electrophoresis was performed. Results All 3 patients showed marked improvement in muscle strength, and in 2 of them deep tendon reflexes reappeared soon. Before plasmapheresis, all cases had been treated with relatively high doses of steroids for 2 to 7 days, but without beneficial effects. Nerve conduction velocities were markedly decreased in Case 1, but no reduction was found in Cases 2 and 3 during the course of the disease_ Oligo clonal bands were found in all cases in CSF but the amount of myelin basic protein in CSF was elevated in none of them. Conclusion A rapid increase in muscle strength was found in 3 cases with GBS during plasmapheresis. Controlled trials should be undertaken to clarify further the role of this treatment in GBS. Key words: Guillain-Bam? syndrome, plasmapheresis, humoral immune factors, oligoclonal bands, myelin basic protein.

234 Brain & Development, Vol 7, No 2,1985

203

204

The Effect of Methylprednisolone Pulse Therapy on Polyneuritis in Childhood Masashi Shiomi, MD, Yongshun Ko , MD, Morio Yabiku, MD, Hiroko Uchida, MD, Tatsuyuki Hara, MD, Hidenori Imaishi MD, Hidekazu Okuni, MD and Takahiro Sugita, MD Department of Pediatrics, Infectious Disease Center, Osaka

Morphological Development of Sciatic Nerves in Neonatal Hypothyroidism Yoko Sugie, MD, Hideo Sugie, MD and Yoshio Igarashi, MD Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka

Serial morphometric analysis of sciatic nerves of neonatal hypothyroid rats was performed, and the The effect of steroid treatment in Guillain-Barre effect of the hypothyroid state on peripheral nerve syndrome (GBS) is controversial while that in chronic development was studied. Neonatal hypothyroidism relapsing polyneuropathy (CRP) is mostly accepted. was produced according to Verity's method using Dowling et al reported the possible beneficial effect 6 PTU . At the ages of 7, 14, 21 and 28 days, the left of high dose intravenous methylprednisolone (MPL) sciatic nerves of hypothyroid and control rats were therapy in GBS. We have also treated one patient removed after decapitation. Each age group consisted with CRP and 5 of 10 patients with GBS by MPL of 3 animals. Specimens were fixed with glutaralpulse therapy (MPL 30 mgjkgjday for 3 consecutive dehyde and 1 %osmium, and then embedded in Epon days, repeated at intervals of 2 to 4 wks.) 812. One micron thick sections were cut and stained with toluidine blue. The following quantitative Patients and Results CRP case: A 15-yr-old girl noticed the gradual onset analyses including total fascicular area, total numbers of muscle weakness with no antecedent illness and of myelinated fibers, myelinated fiber density and was admitted to a local hospital 1 mo later. Her myelinated fiber diameters were performed using muscle power improved after 1 mo treatment with unselected photomicrographs of one micron sections ACTH. However, a relapse of the weakness occurred of sciatic nerves. The body weight of hypothyroid after 3 mos, at which time she was transferred to rats was significantly lower than that of controls our hospital with paralysis of the arms and legs. after 14 days of life. The total fascicular area inPrednisolone was given daily for 2 mos and every creased with age in both groups, however, after other day thereafter. She became able to walk after 8 21 days it became significantly smaller in hypothymos and her grasping power increased from 0 kg to roid compared to control rats. The total number 17 kg. However, she again experienced weakness after of myelinated fibers of hypothyroid rats increased discontinuance of low dose prednisolone. We treated at almost the same rate as in controls. In paticular, her with MPL pulse therapy (PT) followed by low a marked increase in the total numbers of myelinated dose prednisolone on alternate days. Her grasping fibers was noticed between the ages of 7 and 14 power had increased on the second day of PT but had days. The myelinated fiber density decreased with decreased to 0 kg several weeks after a course of PT. age with a slower decrement ratio in hypothyroid Although the same response was observed repeatedly rats. Therefore, the myelinated fiber density after after each course of PT, stable improvement was seen 21 days was significantly large in hypothyroid rats. after 4 courses of PT. The 29% reduction of serum The mean diameter of myelinated fibers of controls IgG was considered to be related to the stable im- increased linearly with age. On the other hand, no provement. Prednisolone was then discontinued re- increase in myelinated fiber diameter was noticed sulting in the same clinical relapse and the same between the ages of 7 and 14 days in hypothyroid rats. However, after 14 days, the increment rate response to PT. GBS cases: We treated 5 of 10 patients with PT. of myelinated fiber diameter seemed to be the same One patient had tachycardia after intravenous MPL as in controls, suggesting retardation of myelinated and was given no steroid thereafter. The remaining 4 fiber growth. Detailed analysis with histograms of patients were not given a steroid. Two patients re- myelinated fiber diameter in hypothyroid and control quired a ventilator. No unequivocal effect of PT was rats showed almost identical patterns. There was no significant change in histograms of myelinated found . fiber diameter between the ages of 7 and 14 days in Key words: Polyneuritis, chronic relapsing polyneu- hypothyroid rats. Then, hypothyroid histograms ropathy, Guillain-Bam! syndrome, methylprednisolone showed the development of a one week shift behind controls after 21 days. By 14 days, 18% of the total pulse therapy. myelinated fibers had reached diameters of over 4 micrometers in controls, but only 3.2% in hypothyroid rats. By 28 days, 52.8% of the total myelinated fibers had reached diameters of over 4 micrometers in controls, and 31.7% in hypothyroids. These findings suggest that hypothyroidism retards the increase of the myelinated fiber diameter of neonatal rats between the ages of 7 and 14 days. However, no influence on the total number of myelinated fibers nor the basic growth pattern of myelinated fibers was demonstrated.

Key words: Neonatal hypothyroism, peripheral nerve, development. Brain & Development, Vol 7, No 2, 1985 235

205

A Case of Nonprogressive Hereditary Motor and Sensory Neuropathy with Early Infantile Onset and Unique Histopathologic Findings of Sural Nerve Kenji Sugai, MD, Norio Sakuragawa, MD and Ikuya Nonaka,MD Divisions of Child Neurology (KS, NS) and Ultrastructural Research (IN), National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo A case of nonprogressive hereditary motor and sensory neuropathy (HMSN) with early infantile onset was investigated for its pathogenesis and efficacy of high dose ATP and nicotinic acid therapy_

Case Report The patient, ll-yr-old girl, had been suffered from gait disturbance and poor coordination since early infancy _ She started to walk with aid at 3 yrs of age and without aid at 5 yrs. Her gait was ataxic and unsteady, but had been improving with age went on without any treatment. Neurological examination revealed the following; normal mentality, no palpable hypertrophic nerve, awkward walking with broad-based stance and stamping, markedly impaired vibration and. mild~y ~pa?,ed tactile sensation (glove and stockmg dlstnbutlOn) with normal position sense, positive Romberg's sign, absent deep tendon reflexes, slightly poor coord~na­ tion dysdiadochokinesis without other cerebellar sign, abse~t gag reflex, and normal muscle strength and tone. MCV and SCV of all nerves, SEP and blink reflex could not be evoked except for MCV of ulnar nerve, 2 m/sec_ ABR showed normal wave pattern but all the latency of wave II to VI prolonged by 0.5 msec. CSF contained 58 mg/dl of protein without pleocytosis. CT scan, EEG, VEP, SVR, EMG and other laboratory examination were all within normal limits. The mother had mildly impaired tactile sensation and her MCV and SCV were just below normal. The father was neurologically normal, but his MCV and SCV were subnormal. The brother and sister showed no abnormality in these study. Sural nerve biopsy was performed. Myelinated fibers were extremely decreased in number and large ked axon " myelinated fiber was absent, and m~ny "na. were observed in return, but unmyelmated fibers were normal in number and size distribution. Myelinated fibers and naked axon were surrounded concentrically by double layered basement membrane devoid of cytoplasm. Many onion bulbs were found and ~hey consisted of the basement membrane descnbed above and Schwann cells, but Schwann cell processes with cytoplasm were rarely found in the onion b~lb. Thinly myelinated fibers with incomplete compaction of myelin layers were also found. Intravenous administration of high dose ATP and nicotinic acid was effective to improve sensory disturbance but ineffective to improve MCV, SCV and deep tendon reflexes. Discussion The present case is a kind of HMSN, and several cases have been reported as congenital hypomyelin~­ tion neuropathy. The most specific features of thiS 236 Brain & Development, Vol 7, No 2, 1985

disorder are an early infantile onset with nonprogressive course and concentric lamellar structure of basement membrane devoid of cytoplasm which surrounded myelinated fibers and naked axon. The possibility of remyelination was suggested and the nature of this disorder is considered to be not hypomyelination but dysmyelination with. remyel~nating process. The essential defect of thiS disorder ~s concluded as dysfunction of Schwann cell. This case showed an autosomal recessive inheritance. High dose ATP and nicotinic acid therapy was effective to sensory disturbance_

Key words: Nonprogressive HMSN, congenital hypomyelination, dysfunction of Schwan~ c~ll,. aut~­ somal recessive inheritance, ATP and mcotzmc aCid therapy.

206

Pathophysiology and Treatment of Spinal Dysraphism-Clinical and Neuroradiological Evaluation of Our 33 Cases of Spinal Lipoma Takayuki Shirakuni, MD, Norihiko Tamaki, MD and Satoshi Matsumoto, MD Department of Neurosurgery, Kobe University School of Medicine, Kobe, Hyogo There has been much controversy as to the timing and indications for surgery for spinal lipoma. We classified spinal lipoma into three types and five subtypes on the basis of the location and extent of the tumor. The pathophysiology of the mechanism of neurological signs was reviewed in relation to the indications. We studied 33 patients with spinal lipomas, 16 males and 17 females (aged from 3 days to 20 yrs; average 5.5 yrs). They were classified into three types, type A: intraspinal-intradural (Is-Id) lipoma (11 extended subtypes and 7 localized subtypes), type B: intraspinal-extradural (Is-Ed) lipoma (3 subtypes without meningocele and 11 subtypes with meningocele) and type C: one extraspinal (Es) lipoma. In 30 cases, abnormalities of the back were seen, i.e., 25 lumbosacral masses, 12 dimples, and 7 hemangiomatous nevi. Twenty-five patients presented with neurological signs: rectourinary disturbance in 19, motor disturbance in 19, and sensory disturbance in 19. In the 19 patients with sensory disturbance, 8 aged more than 6 complained of back or leg pain on exercise. The course of disorder was progressive in types A and B, and there was a time gap between the two types in the onset of neurological signs. We speculated that the mechanism of the neurological signs might be from spinal dysplasia and/or tethering of the cord in type A, and the complication of tight filum term in ale and/or adhesion of the filum terminale and cauda equina to the fibrous wall of meningocele or dura in type B. It is desirable to devise a therapeutic plan for spinal lipoma on the basis of the neurological signs, clinical course and neuroradiological findings.

Key words: Spinal lipoma, pathophysiology, tethering, adhesion, operative treatment.

207

Long-Term Prognosis of Childhood Myasthenia Gravis (MG)-Patients with More Than 10 Years Follow-Up Yoshiko Nomura, MD, Seiichi Saito, MD, Yuko Okamura, MD, Susumu Hakamada, MD and Masaya Segawa,MD Segawa Neurological Ginic for Children, Tokyo The age at onset of MG in Japan is characterized by the highest peak in the first 5 yrs, followed by another in the 20's and a heterogeneous pathogenesis of childhood MG has been suggested. The purpose of this paper is to discuss the long-tenn prognosis of childhood MG and its relation to adult MG.

Material Among 125 patients with childhood-onset MG who visited this clinic, 23 (7 males, 16 females) who had been followed for more than 10 yrs were subjected to this study. The subtypes of MG were classified into pure ocular (~C), latent generalized (LG) and generalized (G) according to clinical symptoms and evoked EMG. The effects of treatment were classified into a) complete remission, b) left with non-fluctuating strabismus and c) fluctuating ocular symptoms. Results Ages at onset ranged between 11 mos and 15 yrs (mean 3.57 yrs). The present ages of the patients are 11 yrs 10 mos to 27 yrs 2 mos (mean 18.07 yrs) and the duration of illness was 10 yrs 4 mos to 22 yrs 9 mos (mean 14.5 yrs). There were 6 ~C, 9 LG and 8 G types at onset. Treatments consisted of (I) antiChE 9, (II) antiChE + Endoxan 1, (III) antiChE + steroid 9, (IV) antiChE + steroid + Endoxan 2, (V) antiChE + steroid + thymectomy 1; the effects of treatments were (I): 1 complete remission, 4 left with nonfluctuating strabismus, 4 fluctuating ocular symptoms; (II): 1 complete remission; (III): 4 complete remission, 2 left with non-fluctuating strabismus, 3 fluctuating ocular symptoms; (IV): 1 complete remission, 1 left with nonfluctuating strabismus and (V): 1 left with nonfluctuating strabismus. There was one spontaneous remission. The present status was compared to the MG types at onset and showed - complete remission: 8 (DC 1, LG 5, G 2); left with nonfluctuating strabismus: 8 (DC 3, LG 2, G 3) and fluctuating ocular symptoms: 7 (DC 2, LG 2, G 3). Duration from onset to stable condition was 8 yrs 8 mos with DC and LG, and 13 yrs 4 mos with G type. Relapses occurred in one within 5 yrs, in 6 within 5 to 10 yrs and in 3 at more than 10 yrs (maximum 15 yrs in one antiChE-treated case). Five suffered from other autoimmune diseases; 4 of them had been treated with antiChE only. Two patients (20 and 23 yrs old) treated with antiChE showed enlarged thymuses.

miSSion, 35% left with strabismus and 30% with fluctuating ocular symptoms. Patients who went into remission only with antiChE tended to relapse and develop other autoimmune diseases. These features suggest that an autoimmune pathophysiology similar to adult MG underlies some childhood MG, and careful choice of treatment is necessary.

Key words: Childhood MG, long-term prognosis of childhood MG, antiChE, relapse of MG. 208

Prognosis of Ocular Myasthenia Gravis in Childhood-A Comparison of Steroid Therapy with Anticholinesterase Therapy Akihisa Mitsudome, MD, Hiroko Ogata, MD, Masaharu Ohjit, MD, Katsuichi Irie, MD, Hidetoshi Hirano, MD and Toru Kurokawa, MD Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka (AM, HO, MO, KI, HH); Department of Pediatrics, School of Medicine, Kyushu University, Fukuoka (TK) We studied the prognosis of ocular myasthenia gravis in childhood and compared the effects of steroid therapy with those of anticholinesterase therapy.

Materials and Methods Twenty-three cases were treated with anticholinesterase alone and the effects of the treatment were clinically assessed 3-13 yrs after the initial administration. Thirteen cases were treated with steroid hormone and assessed 1 yr 6 mos-9 yrs after the initial administration. The cases that became generalized later were excluded. Results 1. Comparison of the effects of steroid therapy with those of anticholinesterase therapy. Therapy

Steroid

Complete remission Improvement Mild improvement Unchanged

7 4 2 0

5 5 6 7

13

23

Total (case)

Anticholinesterase

2. Nine of the 23 cases with anticholinesterase administration became generalized later, on the other hand, only one of the 13 cases with steroid administration became generalized later. The mean time to generalization was less than 1 yr. 3. Our data demonstrate that steroid therapy is more effective than anticholinesterase therapy and may prevent generalization.

Key words: Myasthenia gravis, ocular type, steroid therapy.

Conclusion The overall prognosis of childhood MG is fair compared to adult MG. However, long-tenn (more than 10 yrs) follow-up revealed 35% into complete re-

Brain & Development, Vol 7, No 2, 1985 237

209 Atypical Form of Juvenile Myasthenia Gravis: Association with Severe Emaciation, Muscle Atrophy, Ophthalmoplegia, Bulbar Signs and Joint Contracture Megumu Tojo, MD, Norio Sakuragawa, MD and Ikuya Nonaka,MD Division of Child Neurology, National Musashi Research Institute for Mental and Nervous Diseases, Kodaira, Toky o A case of an atypical form of juvenile myasthenia gravis (MG) characterized clinically by severe emaciation, muscle atrophy, ophthalmoplegia, bulbar signs and joint contracture was reported. The patient was a 13-yr-old girl who complained of marked emaciation and persistent moist coughs. The parents noticed her unclear pronunciation 3 yrs prior to admission . Moist coughs have lasted all day long for the past 10 mos. In addition, she developed occasional double vision and ptosis at the same time. On admission, she was markedly emaciated (body weight, 28 kg) with diffuse muscle atrophy including tongue muscle. Her muscle strength was almost within normal limits except for neck flexor muscles. Muscle fatigability was not induced by repetitive exercises; eye blinking and hand-grip test. Joint contracture was present in her superior spine. Her chin did not come into contact with her chest on neck flexion. Ocular movement in upper and lateral gazes was limited moderately. There was no ptosis. Facial muscle was involved, causing poor facial expression and a mask-like face. Bulbar signs such as difficulty in swallowing were present. Laboratory data were essentially normal. The Tensilon test did not give constant results on different days. The antiacetylcholine receptor (ACh-R) antibody titer was markedly increased to 2.66 pmoles/m!. A whole body CT scan did not show thymoma. Muscle biopsying demonstrated mild neurogenic findings; scattered small angulated fibers, mild variation in fiber size and an increased number of type 2C fibers. An electrophysiological study showed waning and waxing of the orbicularis oculi and thenar muscles on repetitive evoked M wave testing. Prednisolone therapy (80 mg, every other day) for 2 wks resulted in a complete recovery from the ophthalmoplegia and a rapid decrease in the anti-AChoR antibody titer to normal range.

Discussion Muscle atrophy and bulbar signs are rare manifestations in childhood MG. Joint contracture in MG has not been reported previously. Although the prognosis of our case was at first thought to be poor because of her muscle atrophy and bulbar signs, good response to prednisolone therapy was against our initial expectation. Key words: Myasthenia gravis, muscle atrophy, ophthalmoplegia, bulbar signs, joint contracture.

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A Histochemical Analysis of AMP Deaminase in 220 Biopsied Muscles from Children Takehisa Fujita, MD, Kenjiro Terasawa, MD, Ikuya Nonaka, MD, Hideo Sugita, MD and Hideo Nagao, MD National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo (TF, KT, IN, HS); Department of Pediatrics, Ehime University School of Medicine, Ehime (HN) AMP deaminase deficiency (ADD) was first described by Fishbein et al in 1978. Several cases of ADD have been reported subsequently, but the distinctive clinical and histological features of the patients have yet to be clarified. Because only a few childhood cases were described, we examined many biopsied muscles for AMP deaminase by means of histochemical stain.

Materials and Methods 220 muscle biopsies from patients with various neuromuscular disorders aged from 0 to 15 yrs, were evaluated in our institution during 1982 and 1983. The sections for AMP deaminase were stained according to the method described by Fishbein. Muscle biopsy specimens were also studied by routine histological and histochemical stains. Results AMP deaminase activity was decreased or absent in the following disorders: 2 of 12 patients with Fukuyama type congenital muscular dystrophy, 2examined cases of congenital myotonic dystrophy, 3 patients with congenital myopathy without specific features (severe form) and 10 of 12 with Werdnig-Hoffmann disease. In these patients, there were a markedly increased number of type 2C fibers and a number of fibers with structural characteristics of immaturity. Discussion Little is known about the exact role of AMP deaminase and the consequence of its deficiency in the muscle. It has been thought that complete ADD is transmitted in part through an autosomal recessive trait and causes exertional myalgia. The results of the present study, decreased enzyme activity in WerdnigHoffmann disease and congenital myopathy, suggest that the premature or regenerating fibers in the decreased status are also low in the enzyme activity. There may be a close relationship between decreased activity of this enzyme and muscle fiber maturation. Key words: AMP deaminase, Werdnig-Hoffmann disease, congenital myopathy, muscle histochemistry.