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Juvenile Onset Diabetes Mellitus, Central Diabetes Insipidus and Optic Atrophy (Wolfram Syndrome) - Neurological Findings and Prognostic Implications By H. B. Grosse Aldenhöve[l,
u. Gallenkamp2 and c. A. Sulemana3
für Neurologie und Neurohabilitation, Neuropädiatrisch-heilpädagogische Abteilung für Kinder und Jugendliche, Bethesda, CH-3233 Tschugg, 2Abteilung für Neurologie, KdMK-Adademisches Lehrkrankenhaus der Universität Bonn, D-5880 Lüdenscheid, und 3Abteilung für Neurologie, KdMK-Akademisches Lehrkrankenhaus der Universität Bonn, D-5880 Lüdenscheid
Abstract The authors report on one case of Wolfram syndrome, a rare condition, which is characterized by juvenile onset diabetes mellitus, diabetes insipidus, optic atrophy and sensorineural deafness. The findings of this 13-year follow-up show that this patient developed typical neurological complications of long-standing diabetes mellitus as in the common type 1 variant. Moreover, some peculiar signs occurred such as anosmia, ophthalmoplegia interna, and central nystagmus. Since Wolfram syndrome is probably part of a more generalized neurodegenerative disorder, long-term prognosis will depend both upon the severity of chronic diabetic complications and upon the rapidity, by which degeneration of cerebellar, pontine and brain stern structures appear. Prognosis of the cardinal clinical signs is such that optic atrophy, though usually quite rapid in the beginning, generally does not lead to complete blindness. Sensorineural hearing loss progresses very slowly so that deafness might be expected exceptionally only. The hearing deficit in classical diabetics, however, is of retrocochlear origin. Therefore, in Wolj= ram syndrome, a combined inner-ear and retrocochlear hearing loss may occur.
Keywords Wolfram syndrome - Neurological complications - Neurodegenerative process - Long-term prognosis
from which optic atrophy and diabetes mellitus are the minimal diagnostic criteria. Associated with this syndrome some authors have reported on many abnormalities in small numbers of cases (5, 20). One sign, however, is quite common in patients with Wolfram syndrome, namely ectasy of the efferent urinary tract which was found to be present in nearly half ofthem (6). By reason of that frequency several authors recommend to designate this syndrome by enumerating ectasy of the lower urinary tract as the fifth cardinal feature (2, 4, 6). Though the etiology of Wolfram syndrome is still unknown, recent investigations on HLA-typing provide evidence that the genetic control is more complex than the presumed recessive mode of inheritance, and that diabetes mellitus in this condition is distinct from the classical type 1 variant (11, 16). Since there have only been some few references to neurological features in Wolfram syndrome and virtually no reports on signs that are characteristic of long-standing diabetes mellitus, it is unclear whether this merely reflects the rather short duration of diabetes mellitus at the time of examination when most patients are still adolescents, or whether these patients are protected from chronic diabetic complications as might be supposed in view of the findings on HLA-typing (7). Unfortunately, the few long-term observations and reevaluations did not consider this question nor aspects of long-term prognosis (21, 22, 31). We are therefore reporting on a case we were able to examine regularly over a.period of 13 years, and describe the course of the disease with particular reference to neurological issues and prognostic implications.
Case report Introduction Wolfram syndrome, first described in 1938, is characterized by central diabetes insipidus, juvenile onset diabetes mellitus, bilateral primary optic atrophy and sensorineural hearing loss (32). Up to now, about 150 cases have been reported (5, 6). Only in a third of these all components were present,
Received March 19, 1990; accepted May 14, 1990 Neuropediatrics 22 (1991) 103-106 © Hippokrates Verlag Stuttgart
The Libyan-born male patient was the product of an uncomplicated pregnancy and delivery. There was no family history of diabetes mellitus or other diseases. After birth in 1962, he progressed weIl up to early childhood. At the age of 6 years, he was noticed to have polyuria and polydipsia with fluid intakes of up to 30 litres daily, which led to the diagnosis of diabetes· insipidus some years later. When the boy was 12 years of age, he began to complain of progressive failure in his visual acuity such that only two years later, visual acuity was 3/36 on both sides. He was referred for a general medical evaluation. Bilateral optic atrophy and diabetes insipidus were confirmed. Moreover, diabetes mellitus was discovered, and he was given insulin, which he has taken ever since. In addition to insu-
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1Abteilung
Neuropediatrics 22 (1991)
lin treatment, he has been receiving DDAVP intranasally since that time. The boy was aged 15 years when he was admitted to our hospital. The results of our first clinical examination were unremarkable. His visual acuity was 1/20 bilaterally without impairments of colour vision or visual fields. He had normal audiometry, electrocardiogram, radiography of the skull and ehest, axial CCT, intravenous pyelogram, and an EEG that was unrevealing. Routine blood analysis, including ESR, white blood cell count and differential, erythrocytes, haemoglobin, haematocrit, platelets, electrolytes, urea nitrogen, creatinine, total proteins and protein electrophoresis, lipid profile, uric acid, total bilirubin, aspartate and alanine aminotransferases, cholinesterase, creatinine kinase, and luetic serology were within normal limits. Urine analysis disclosed no abnormalities. Fasting blood sugar on insulin treatment was 205 mg/100 ml and varied between 81 and 208 mg/100 ml postprandially. Serum osmolality was 282 mosmoVl, and urine osmolality ranged about 1020 mosmoVI on DDAVP therapy. Over the following years, the patient underwent several audiometrical, internal, ophthalmological and neurological checks without demonstrating new abnormalities or impairments. He went to a special school for diabetics in WestGermany where no mental deterioration became apparent. Also his somatic and pubertal development was normal. Except for a moderate increase of insulin dosage that became necessary in 1981, the boy was in a static state of health until 1985, when a generalized tonic-clonic grand mal necessitated a short-term inpatient treatment. Semi-quantitative analysis of his blood sugar performed within the first minutes after admission showed a level of about 140 mg/100 ml. EEG monitoring over 24 hours yielded no paroxysmal activity. In addition to optic atrophy, neurological examination disclosed large pupils that did not react to light, but the convergence response was normal. The Achilles tendon reflexes were hardly elicitable. Doppler evaluation of urine after voiding yielded volumes of up to 190 ml. Urine concentration and blood sugar profile were satisfactory. Between 1985 and 1988, the patient had to be treated for severe insulin reactions several times. He hirnself did not notice any early signs of an imminent hypoglycemia. In 1988, another generalized seizure, which caused a nasal bone fracture, required a long-term inpatient treatment. The blood sugar level measured semi-quantitatively just after admission ranged about 180 mg/100 ml. The blood pressure was 120/70 mmHg, but since the patient often complained of faintness associated with postural change, a test was carried out by measuring the pulse rate and blood pressure to postural maneuvers in recumbant and standing positions. This procedure showed a decrease of the systolic blood pressure of up to 30 mm Hg, while the pulse rate remained constant with beats between 92 and 96/min. He hirnself complained of weakness and dizziness when the erect position was assumed. Also vascular responses to the Valsalva maneuver were decreased. The ratio of the longest interval between heart beats after blowing release to the shortest interval during the test was 0.9. Neurological examination revealed anosmia and hypogeusia. The pupils were isocor, extremely mydriatic, fixed to light, and did not constrict on convergence. He had vertical nystagmus in the primary position of the eyes and on up-gaze as weIl as horizontal nystagmus to both sides. Deep tendon reflexes were 1 to 2+ bilaterally except for the Achilles tendon reflexes, which were unelicitable. Perception of light touch pain, temperature, position and vibration
H. B. Grosse Aldenhövel et al
were normal as were coordination and tandem gait. Chest and skull radiographs, CT imaging of the sella and head as weIl as cranial MR imaging were within normal limits. Motor nerve (tibial and peroneal) and sensory nerve (sural) conduction velocities were between 44 and 51 mls. Brain stern auditory and somatosensory evoked potentials from tibial nerve stimulation were also normal. Examination of his CSF was unremarkable. Excretion urography disclosed a moderate bladder dilatation, and evaluations of residual urine showed volumes of up to 340 ml. EEG was abnormal with a slow alpha-activity of 8 cps., but without clues for increased cerebral excitability. Visual acuity continued to be 1/20 on both sides. There was no retinal pigmentary degeneration and colour vision was not impaired, while perimetry demonstrated a slightly diffuse limitation of the peripheral visual fields. Fasting blood sugar was 194 mg/1 00 ml, varying between 103 and 226 mg/100 ml postprandially. HblAc was 8.4 %. Serum osmolality was 302 mosmoVI, and ADH was below the detectable limit. Therapy still included intranasal application of DDAVP and insulin combined with a dietetic treatment. Moreover, we started an anticonvulsive treatment with phenytoine for grands maux, and he was given carbachol for increased residual urine volumes. Our last examination of the patient took place in January 1990, when he was aged 27 years. His clinical state remained essentially unchanged compared to the results of the inpatient treatment in 1988.
Discussion
Most of the signs that became manifest in this case are known neurological complications of diabetes mellitus. Thus, cardiovascular reflex disturbances such as decreased vascular responses to the Valsalvar maneuver or postural hypotension are common signs of diabetic autonomie neuropathy caused by partial denervation of the vagal nerve and loss of sympathetic tone to peripheral arterioles, respectively (23, 30). Another sign of dysfunction of the autonomie nervous system is hypoglycemia unawareness, as in the case presented. Due to a decreased excretion of adrenalin, the patients are unable to perceive early signs oi hypoglycemia such as sweating, motor restlessness, vomiting, or heart palpitation, which vary in duration from 10 to 30 minutes (8). Simultaneously, the counterregulative, vagus-controlled increase of glucagon is reduced (30). Moreover, bladder dilatation is regarded as a very characteristic sign of diabetic autonomie neuropathy (23). In classical juvenile diabetics bladder dilatation was found in up to 80 % of the patients (9). In a review of 98 cases, Dreyer and co-workers reported this disorder to be present in 46 % of the patients with Wolfram syndrome (6). We also could ascertain bladder dilatation with increased residual urine volumes in our patient. Originally, in Wolfram syndrome, ectasy of the lower urinary tract has been attributed to urinary obstruction or the high urinary output of diabetes insipidus (3, 21, 24, 26), though it occurred in the absence of diabetes insipidus (22, 25,28). Bladder dilatation is caused by degeneration of the parasympathetic efferences of the pelvic nerve as weIl as by degeneration of the hypogastric plexus including sensory fibres of the bladder wall (30). As cere· bral feed back of the intramural stretch receptors is missing, the patients often failed to perceive increasing bladder capacity,
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104
Juvenile Onset Diabetes Mellitus, Central Diabetes Insipidus and Optic Atrophy (Wolfram Syndrome)
The development of generalized seizures in the case presented, are difficult to explain. Actual blood sugar levels were adequate each time so that hypoglycemia could be excluded as the proximate cause of the seizures. One possible explanation would be a diffuse lack of regular cerebral blood supply following diabetical microangiopathy or arteriosclerosis. Arteriosclerosis was originally feIt to be a complication of diabetes only in older patients, but it is now apparent that it may occur in any patient, regardless of age. Seizures and EEG abnormalities, however, have quite often been described in Wolfram syndrome (10,20, 21, 25, 28). On the other hand, it is unknown whether the incidence of idiopathic seizures is higher in diabetics compared to the general population. Finally, the loss of the Achilles tendon reflexes may indicate an early stage of peripheral neuropathy, at which nerve conduction velocities and other signs such as vibration sense are still normal.
paraventricular nuclei, which, as might be expected, are consistent with optic atrophy and central diabetes insipidus. There was also demyelination ofthe pons and cerebellum as weIl as atrophy of the superior olivar nuclei, which has been regarded as typical of the changes seen in olivopontocerebellar atrophy of Menzel's type with the suggestion that the ataxia which characterizes clinical onset of that condition (mean age about 40 years) might have become manifest had the patients survived (3, 17). This individual follow-up examination is feIt to be paradigmatic of the development of typical complications of diabetes mellitus as in the classical type 1 variant, though the mode of inheritance is probably different. The nature of these complications (e. g. peripheral and/or autonomie neuropathies, vascular changes), their degree of severity, and the latency of appearence will differ from case to case and may predominantly vary with the duration and control of diabetes mellitus. Thus, long-term prognosis in Wolfram syndrome as weIl as in the common type 1 variant may at least partly depend upon such sequelae, in particular upon severe autonomie neuropathies, which constitute life-limiting conditions because of potentially fatal complications including hypoglycemia unawareness, syncopes, and recurrent ascending urinary tract infections due to bladder atony (8). Therefore, in the management of these patients a careful monitoring for such signs is indispensable for alleviating prognosis and mortality.
The predominant interest of this case, however, lies in the occurrence of some peculiar features, namely anosmia, ophthalmoplegia interna and central nystagmus. Impairment of smell, occasionally being so severe as to reach the stage of anosmia, seems to be quite frequent in patients with diabetes mellitus and was found in two thirds of them (14). Despite that frequency in classical diabetics, in Wolfram syndrome, this disorder might be caused by alesion of the olfactory neuroepithelium due to intranasal application of DDAVP for years, as in the case presented and similar other cases. Adegenerative process of the first nerve and its connections has to be taken into consideration as weIl.
Naturally, prognosis of the different components of Wolfram syndrome will differ interindividually. However, the progression of optic atrophy generally is quite rapid in the beginning, but stops at a certain level of visual impairment, and if not, further progression is very slow so that complete blindness has been noted in some few cases only (25, 26). So far, diabetical retinopathies have seldom been reported (12, 21, 22). However, 3 out of 7 patients observed over aperiod of up to 17 years had developed retinopathic lesions (22), so that this disorder seems to be only a question of time in many patients with Wolfram syndrome. As could be shown in arecent epidemiological study, the risk of background retinopathy increases There have also been references to ophthal- rapidly with the duration of diabetes; after 14 years, almost all moplegia interna in Wolfram syndrome, though quite seldom so patients with type 1 diabetes mellitus had retinopathic lesions (10). Prior to convergence paresis, this lesion usually begins (19). Impairment of hearing is not obligatory in Wolfram synwith sluggish or absent reactions of the pupils to light. Transi- drome. If present, it may be detected as a slowly progressive ently it can be mistaken for an Argyll Robertson phenomenon, high frequency sensorineural hearing loss (7). Consequently, which has been noted to occur in some cases of Wolfram syn- complete deafness might be expected exceptionally only. drome (20). Differential diagnosis includes a tonic pupil as weIl. Sensorineural hearing loss in Wolfram syndrome has been reTwo of the patients, as described by Lessell and Rosman, had ferred to as probably caused by degeneration of the stria pupils resembling those in Holmes-Adie's syndrome (20). In vascularis with sparing of the retrocochlear portion of the audiboth, there was evidence of parasympathetic denervation super- tory system (22). Contrary to this, the hearing deficit that may sensitivity when tested pharmacologically. This seems to be a occur in classical diabetics is of retrocochlear origin, which has common feature of diabetic autonomie neuropathy (29). In been explained by the effect of hyperglycorrachia at Obersteinerthose patients, not only the size of the pupils, but also the degree Redlich's zone where the axons of the eighth nerve loose their of the pupillary response to light and convergence is reduced myelin sheaths and come into immediate contact with the CSF (13). These changes are not attributed to poor sensitivity to (1, 15). Therefore, it has to be taken into account that patients light in the presence of diabetic retinopathy or to increased ri- with Wolfram syndrome may develop both a cochlear and retrocochlear hearing loss. gidity of the iris (29). Ophthalmoplegia interna which refers to a rostral mid-brain lesion, and central nystagmus are signs, which possibly can be explained on the basis of the few existing neuropathological findings in Wolfram syndrome. The post-mortems not only showed axonal destruction and demyelination of the entire optic system and degeneration of the supraoptic and
105
It is yet unknown if Wolfram syndrome is a distinct nosological entity, or occurs as part of a more generalized degenerative process such as olivopontocerebellar atrophy as mentioned above. Provided this syndrome is part of such a neurodegenerative condition, then, apart from diabetical and urological sequelae, prognosis will also depend upon the rapidi-
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which subsequently leads to dilatation of the bladder tissue, and vesicoureteral reflux threatens to occur. Thus, this degenerative process causes weakness or paralysis of the detrusor respectively reduced tone of the vesical trigone and the sphincter internus. As could be shown immunohistologically in one patient with Wolfram syndrome suffering from severe urinary tract ectasy, there was a marked diminution of sensory nerve fibres of the bladder wall (4).
Neuropediatrics 22 (1991)
H. B. Grosse Aldenhävel et al
Neuropediatrics 22 (1991)
ty, by which degeneration of brain stern, mid-brain, pontine and cerebellar structures appear. In addition to the post-mortems cited, there is an increasing number of reports on patients with Wolfram syndrome, who were found to have mental deterioration, cerebellar ataxia, central nystagmus, pontine and cerebellar atrophy, and pupillary disorders, all of which are common signs that include degeneration of the pons and cerebellum (10, 18, 20, 22, 26, 27, 28). Thus, there is some reason to suggest that Wolfram syndrome is not an entity per se, but part of, or associated with a widespread generalized neurodegenerative disorder.
Referenees 1 2
Axelsson, A., S. E. Fagerberg: Auditory function in diabetes. Acta 010laryngol. 66 (1968) 49-64 Boltshauser, E., U. Zellweger, M. Zachmann: Diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deafness - An autosomal recessive syndrome (DIDMOAD syndrome). Monatsschr. Kinderheilkd. 126 (1978) 205-208
Carson, G. W., U. T. Slager, R. M. Steinberg: Simultaneous occurrence of diabetes mellitus, diabetes insipidus and optic atrophy in a brother and sister. Am. J. Dis. Child. 131 (1977) 1382-1385 4 Chu, P., W. G. Staff, J. ·A. Morris, J. M. Polak: DIDMOAD syndrome with megacystis and megaureter. Postgrad. Med. J. 62 (1986) 859-863 5 Cremers, C. W. R.J., P. G. A. B. Wi}devald, A.J. L. G. Pickers: Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder and other abnormalities (Wolfram syndrome). Acta Paediatr. Scand. 264 (supp!.) (1977) 1-16 6 Dreyer, M., H. W. Rüdiger, K. Bujara, C. Herberhold, J. Kühnau, P. Maack, H. Bartelheimer: The syndrome of diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and other abnormalities (DIDMOAD syndrome). KIin. Wochenschr. 60 (1982) 471-475 7 Editorial: DIDMOAD (Wolfram) syndrome. Lancet 1(1986) 1075-1076 8 Ewing, D.J., 1. W. Campbell, B. F. Clarke: The natural history of diabetic autonomic neuropathy. Quart. J. Med. 49 (1980) 95-108 9 Faerman, 1., M. Maler, M.Jadzinski: Asymptomaticneurogenicbladder in juvenile diabetics. Diabetologia 7 (1971) 168-1 72 10 Foerster, K., J. Spranger, J. Beyer, F. Regli: The occurrence of diabetes mellitus, optic atrophy and neurogenic deafness in one patient. J. Neurol. 210(1975)71-76 11 van Haeften, T. W., P. P. Razenberg: DIDMOAD syndrome and HLA-DR haplotypes. Horm. Metab. Res. 21 (1989) 214-215 12 Halmos, T.,1. Suba, L. Barta: Optic nerve atrophy and diabetes mellitus. Wien. klin. Wschr. 92 (1980) 279-282 13 Hreidarsson, A. B.: Pupil motility in long-term diabetes. Diabetologica 17(1979) 145-150 14 Jorgensen, M. B., N. H. Buch: Studies on the sense of smell and taste in diabetics. Acta Otolaryngol. 53 (1961) 539-545 15 Jorgensen, M. B., N. H. Buch: Studies on inner-ear function and cranial nerves in diabetics. Acta Otolaryngol. 53 (1961) 350-364 3
16
17
Karasik, A., C. O'Hara, S. Snkanta, W. Swift,J. S. Soeldner, C. R .. Kahn: Genetically programmed selective islet beta-cellioss in diabetic subjects with Wolfram's syndrome. Diabetes Care 12 (1989) 135-138 Karp, M., Z. Laron, U. Sandbank: Wolfram syndrome. Am. J. Dis. Child. 132(1978)818-819
Kehl, 0., U. Keller: DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) with cerebello-pontine atrophy. Schweiz. med. W schr. 112 (1982) 348-352 19 Krolewski, A. S.,J. H. Wa"am, L. 1. Rand, C. R. Kahn: Epidemiologie approach to the etiology of type 1 diabetes mellitus and its complications. N. Engl. J. Med. 317 (1987) 1390-1398 20 Lessell, S., N. P. Rosman: Juvenile diabetes mellitus and optic atrophy. Arch. Neurol. 34 (1977) 759-765 21 Marquardt, J. L., D. L. Lonaux: Diabetes mellitus and optic atrophy with associated findings of diabetes insipidus and sensory hearing loss in two siblings. Arch. Int. Med. 134 (1974) 32-37 22 Najjar, S. S., M. G. Saikaly, G. M. Zaytoun, A. Abdelnoor: Association of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. The Wolfram or DIDMOAD syndrome. Arch. Dis. Child. 60 (1985) 823-828 23 Neundör[er, B.: Diabetische Polyneuropathie. In: Polyneuritiden und Polyneuropathien. Neundörfer, B. (Ed.) Weinheim, Edition Medizin VCH, (1987) 352-362 24 Page, M. M., A. C. Asmal, C. R. W. Edwards: Recessive inheritance of diabetes: The syndrome of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Quart. J. Med. 45 (1976) 505-520 25 Peden, N. R., J. D. L. Gay, R. T. Jung, K. Kuwayti: Wolfram (DIDMOAD) syndrome: A complex long-term problem in management. Quart. J. Med. 58 (1986) 167-180 26 Rose, F. C., G. R. Fraser, A. 1. Fnedman, E. M. Kohner: The association of juvenile diabetes mellitus and optic atrophy: Clinical and genetical aspects. Quart. J. Med. 35 (1966) 385-405 27 Sanarelli, L., M. Boatta, F. Paun, C. Blasi, P. A. Rizzo: Rilievi elektrofisiologici in alcuni casi di sindrome di Wolfram. Riv. Neurol. 56 (1986) 18
48-54 28
29 30
Sauer, H., H. Chüden, H. Gottesbören, P. Schmitz-Valckenber, D. Seitz: Familial syndrome of diabetes mellitus, primary optic nerve atrophy and inner-eardeafness. Dtsch. Med. Wochenschr. 98 (1973) 243-255 Smith, S. E., S. A. Smith, P. M. Brown: Pupillary signs in diabetic autonomic neuropathy. Br. J. Med.. 2 (1978) 924-927 Tackmann, W.: Diabetische Neuropathien. In: Polyneuropathien. Ludin, H.-P., W. Tackmann (Eds.) Stuttgart, New York, Thieme, (1984) 233244
Turnbridge, R. E., R. G. Paley: Primary optic atrophy in diabetes mellitus. Diabetes 5 (1956) 295-296 32 Wolfram, D. J.: Diabetes mellitus and simple optic atrophy among siblings: Report of four cases. Proc. Mayo. Clin. 13 (1938) 715-718
31
Dr. med. Dipl.-Psych. Heinz B. GrosseAldenhövel Chefarzt a.i. und Ärztlicher Leiter der Abteilungen für Neurologie und Neurorehabilitation und der neuropädiatrisch-heilpädagogischen Abteilung für Kinder und Jugendliche Bethesda CH -3233 Tschugg
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106
Juvenile Onset Diabetes Mellitus, Central Diabetes Insipidus and Optic Atrophy (Wolfram Syndrome) - Neurological Findings and Prognostic Implications By H. B. Grosse Aldenhöve[l,
u. Gallenkamp2 and c. A. Sulemana3
für Neurologie und Neurohabilitation, Neuropädiatrisch-heilpädagogische Abteilung für Kinder und Jugendliche, Bethesda, CH-3233 Tschugg, 2Abteilung für Neurologie, KdMK-Adademisches Lehrkrankenhaus der Universität Bonn, D-5880 Lüdenscheid, und 3Abteilung für Neurologie, KdMK-Akademisches Lehrkrankenhaus der Universität Bonn, D-5880 Lüdenscheid
Abstract The authors report on one case of Wolfram syndrome, a rare condition, which is characterized by juvenile onset diabetes mellitus, diabetes insipidus, optic atrophy and sensorineural deafness. The findings of this 13-year follow-up show that this patient developed typical neurological complications of long-standing diabetes mellitus as in the common type 1 variant. Moreover, some peculiar signs occurred such as anosmia, ophthalmoplegia interna, and central nystagmus. Since Wolfram syndrome is probably part of a more generalized neurodegenerative disorder, long-term prognosis will depend both upon the severity of chronic diabetic complications and upon the rapidity, by which degeneration of cerebellar, pontine and brain stern structures appear. Prognosis of the cardinal clinical signs is such that optic atrophy, though usually quite rapid in the beginning, generally does not lead to complete blindness. Sensorineural hearing loss progresses very slowly so that deafness might be expected exceptionally only. The hearing deficit in classical diabetics, however, is of retrocochlear origin. Therefore, in Wolj= ram syndrome, a combined inner-ear and retrocochlear hearing loss may occur.
Keywords Wolfram syndrome - Neurological complications - Neurodegenerative process - Long-term prognosis
from which optic atrophy and diabetes mellitus are the minimal diagnostic criteria. Associated with this syndrome some authors have reported on many abnormalities in small numbers of cases (5, 20). One sign, however, is quite common in patients with Wolfram syndrome, namely ectasy of the efferent urinary tract which was found to be present in nearly half ofthem (6). By reason of that frequency several authors recommend to designate this syndrome by enumerating ectasy of the lower urinary tract as the fifth cardinal feature (2, 4, 6). Though the etiology of Wolfram syndrome is still unknown, recent investigations on HLA-typing provide evidence that the genetic control is more complex than the presumed recessive mode of inheritance, and that diabetes mellitus in this condition is distinct from the classical type 1 variant (11, 16). Since there have only been some few references to neurological features in Wolfram syndrome and virtually no reports on signs that are characteristic of long-standing diabetes mellitus, it is unclear whether this merely reflects the rather short duration of diabetes mellitus at the time of examination when most patients are still adolescents, or whether these patients are protected from chronic diabetic complications as might be supposed in view of the findings on HLA-typing (7). Unfortunately, the few long-term observations and reevaluations did not consider this question nor aspects of long-term prognosis (21, 22, 31). We are therefore reporting on a case we were able to examine regularly over a.period of 13 years, and describe the course of the disease with particular reference to neurological issues and prognostic implications.
Case report Introduction Wolfram syndrome, first described in 1938, is characterized by central diabetes insipidus, juvenile onset diabetes mellitus, bilateral primary optic atrophy and sensorineural hearing loss (32). Up to now, about 150 cases have been reported (5, 6). Only in a third of these all components were present,
Received March 19, 1990; accepted May 14, 1990 Neuropediatrics 22 (1991) 103-106 © Hippokrates Verlag Stuttgart
The Libyan-born male patient was the product of an uncomplicated pregnancy and delivery. There was no family history of diabetes mellitus or other diseases. After birth in 1962, he progressed weIl up to early childhood. At the age of 6 years, he was noticed to have polyuria and polydipsia with fluid intakes of up to 30 litres daily, which led to the diagnosis of diabetes· insipidus some years later. When the boy was 12 years of age, he began to complain of progressive failure in his visual acuity such that only two years later, visual acuity was 3/36 on both sides. He was referred for a general medical evaluation. Bilateral optic atrophy and diabetes insipidus were confirmed. Moreover, diabetes mellitus was discovered, and he was given insulin, which he has taken ever since. In addition to insu-
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1Abteilung
Neuropediatrics 22 (1991)
lin treatment, he has been receiving DDAVP intranasally since that time. The boy was aged 15 years when he was admitted to our hospital. The results of our first clinical examination were unremarkable. His visual acuity was 1/20 bilaterally without impairments of colour vision or visual fields. He had normal audiometry, electrocardiogram, radiography of the skull and ehest, axial CCT, intravenous pyelogram, and an EEG that was unrevealing. Routine blood analysis, including ESR, white blood cell count and differential, erythrocytes, haemoglobin, haematocrit, platelets, electrolytes, urea nitrogen, creatinine, total proteins and protein electrophoresis, lipid profile, uric acid, total bilirubin, aspartate and alanine aminotransferases, cholinesterase, creatinine kinase, and luetic serology were within normal limits. Urine analysis disclosed no abnormalities. Fasting blood sugar on insulin treatment was 205 mg/100 ml and varied between 81 and 208 mg/100 ml postprandially. Serum osmolality was 282 mosmoVl, and urine osmolality ranged about 1020 mosmoVI on DDAVP therapy. Over the following years, the patient underwent several audiometrical, internal, ophthalmological and neurological checks without demonstrating new abnormalities or impairments. He went to a special school for diabetics in WestGermany where no mental deterioration became apparent. Also his somatic and pubertal development was normal. Except for a moderate increase of insulin dosage that became necessary in 1981, the boy was in a static state of health until 1985, when a generalized tonic-clonic grand mal necessitated a short-term inpatient treatment. Semi-quantitative analysis of his blood sugar performed within the first minutes after admission showed a level of about 140 mg/100 ml. EEG monitoring over 24 hours yielded no paroxysmal activity. In addition to optic atrophy, neurological examination disclosed large pupils that did not react to light, but the convergence response was normal. The Achilles tendon reflexes were hardly elicitable. Doppler evaluation of urine after voiding yielded volumes of up to 190 ml. Urine concentration and blood sugar profile were satisfactory. Between 1985 and 1988, the patient had to be treated for severe insulin reactions several times. He hirnself did not notice any early signs of an imminent hypoglycemia. In 1988, another generalized seizure, which caused a nasal bone fracture, required a long-term inpatient treatment. The blood sugar level measured semi-quantitatively just after admission ranged about 180 mg/100 ml. The blood pressure was 120/70 mmHg, but since the patient often complained of faintness associated with postural change, a test was carried out by measuring the pulse rate and blood pressure to postural maneuvers in recumbant and standing positions. This procedure showed a decrease of the systolic blood pressure of up to 30 mm Hg, while the pulse rate remained constant with beats between 92 and 96/min. He hirnself complained of weakness and dizziness when the erect position was assumed. Also vascular responses to the Valsalva maneuver were decreased. The ratio of the longest interval between heart beats after blowing release to the shortest interval during the test was 0.9. Neurological examination revealed anosmia and hypogeusia. The pupils were isocor, extremely mydriatic, fixed to light, and did not constrict on convergence. He had vertical nystagmus in the primary position of the eyes and on up-gaze as weIl as horizontal nystagmus to both sides. Deep tendon reflexes were 1 to 2+ bilaterally except for the Achilles tendon reflexes, which were unelicitable. Perception of light touch pain, temperature, position and vibration
H. B. Grosse Aldenhövel et al
were normal as were coordination and tandem gait. Chest and skull radiographs, CT imaging of the sella and head as weIl as cranial MR imaging were within normal limits. Motor nerve (tibial and peroneal) and sensory nerve (sural) conduction velocities were between 44 and 51 mls. Brain stern auditory and somatosensory evoked potentials from tibial nerve stimulation were also normal. Examination of his CSF was unremarkable. Excretion urography disclosed a moderate bladder dilatation, and evaluations of residual urine showed volumes of up to 340 ml. EEG was abnormal with a slow alpha-activity of 8 cps., but without clues for increased cerebral excitability. Visual acuity continued to be 1/20 on both sides. There was no retinal pigmentary degeneration and colour vision was not impaired, while perimetry demonstrated a slightly diffuse limitation of the peripheral visual fields. Fasting blood sugar was 194 mg/1 00 ml, varying between 103 and 226 mg/100 ml postprandially. HblAc was 8.4 %. Serum osmolality was 302 mosmoVI, and ADH was below the detectable limit. Therapy still included intranasal application of DDAVP and insulin combined with a dietetic treatment. Moreover, we started an anticonvulsive treatment with phenytoine for grands maux, and he was given carbachol for increased residual urine volumes. Our last examination of the patient took place in January 1990, when he was aged 27 years. His clinical state remained essentially unchanged compared to the results of the inpatient treatment in 1988.
Discussion
Most of the signs that became manifest in this case are known neurological complications of diabetes mellitus. Thus, cardiovascular reflex disturbances such as decreased vascular responses to the Valsalvar maneuver or postural hypotension are common signs of diabetic autonomie neuropathy caused by partial denervation of the vagal nerve and loss of sympathetic tone to peripheral arterioles, respectively (23, 30). Another sign of dysfunction of the autonomie nervous system is hypoglycemia unawareness, as in the case presented. Due to a decreased excretion of adrenalin, the patients are unable to perceive early signs oi hypoglycemia such as sweating, motor restlessness, vomiting, or heart palpitation, which vary in duration from 10 to 30 minutes (8). Simultaneously, the counterregulative, vagus-controlled increase of glucagon is reduced (30). Moreover, bladder dilatation is regarded as a very characteristic sign of diabetic autonomie neuropathy (23). In classical juvenile diabetics bladder dilatation was found in up to 80 % of the patients (9). In a review of 98 cases, Dreyer and co-workers reported this disorder to be present in 46 % of the patients with Wolfram syndrome (6). We also could ascertain bladder dilatation with increased residual urine volumes in our patient. Originally, in Wolfram syndrome, ectasy of the lower urinary tract has been attributed to urinary obstruction or the high urinary output of diabetes insipidus (3, 21, 24, 26), though it occurred in the absence of diabetes insipidus (22, 25,28). Bladder dilatation is caused by degeneration of the parasympathetic efferences of the pelvic nerve as weIl as by degeneration of the hypogastric plexus including sensory fibres of the bladder wall (30). As cere· bral feed back of the intramural stretch receptors is missing, the patients often failed to perceive increasing bladder capacity,
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Juvenile Onset Diabetes Mellitus, Central Diabetes Insipidus and Optic Atrophy (Wolfram Syndrome)
The development of generalized seizures in the case presented, are difficult to explain. Actual blood sugar levels were adequate each time so that hypoglycemia could be excluded as the proximate cause of the seizures. One possible explanation would be a diffuse lack of regular cerebral blood supply following diabetical microangiopathy or arteriosclerosis. Arteriosclerosis was originally feIt to be a complication of diabetes only in older patients, but it is now apparent that it may occur in any patient, regardless of age. Seizures and EEG abnormalities, however, have quite often been described in Wolfram syndrome (10,20, 21, 25, 28). On the other hand, it is unknown whether the incidence of idiopathic seizures is higher in diabetics compared to the general population. Finally, the loss of the Achilles tendon reflexes may indicate an early stage of peripheral neuropathy, at which nerve conduction velocities and other signs such as vibration sense are still normal.
paraventricular nuclei, which, as might be expected, are consistent with optic atrophy and central diabetes insipidus. There was also demyelination ofthe pons and cerebellum as weIl as atrophy of the superior olivar nuclei, which has been regarded as typical of the changes seen in olivopontocerebellar atrophy of Menzel's type with the suggestion that the ataxia which characterizes clinical onset of that condition (mean age about 40 years) might have become manifest had the patients survived (3, 17). This individual follow-up examination is feIt to be paradigmatic of the development of typical complications of diabetes mellitus as in the classical type 1 variant, though the mode of inheritance is probably different. The nature of these complications (e. g. peripheral and/or autonomie neuropathies, vascular changes), their degree of severity, and the latency of appearence will differ from case to case and may predominantly vary with the duration and control of diabetes mellitus. Thus, long-term prognosis in Wolfram syndrome as weIl as in the common type 1 variant may at least partly depend upon such sequelae, in particular upon severe autonomie neuropathies, which constitute life-limiting conditions because of potentially fatal complications including hypoglycemia unawareness, syncopes, and recurrent ascending urinary tract infections due to bladder atony (8). Therefore, in the management of these patients a careful monitoring for such signs is indispensable for alleviating prognosis and mortality.
The predominant interest of this case, however, lies in the occurrence of some peculiar features, namely anosmia, ophthalmoplegia interna and central nystagmus. Impairment of smell, occasionally being so severe as to reach the stage of anosmia, seems to be quite frequent in patients with diabetes mellitus and was found in two thirds of them (14). Despite that frequency in classical diabetics, in Wolfram syndrome, this disorder might be caused by alesion of the olfactory neuroepithelium due to intranasal application of DDAVP for years, as in the case presented and similar other cases. Adegenerative process of the first nerve and its connections has to be taken into consideration as weIl.
Naturally, prognosis of the different components of Wolfram syndrome will differ interindividually. However, the progression of optic atrophy generally is quite rapid in the beginning, but stops at a certain level of visual impairment, and if not, further progression is very slow so that complete blindness has been noted in some few cases only (25, 26). So far, diabetical retinopathies have seldom been reported (12, 21, 22). However, 3 out of 7 patients observed over aperiod of up to 17 years had developed retinopathic lesions (22), so that this disorder seems to be only a question of time in many patients with Wolfram syndrome. As could be shown in arecent epidemiological study, the risk of background retinopathy increases There have also been references to ophthal- rapidly with the duration of diabetes; after 14 years, almost all moplegia interna in Wolfram syndrome, though quite seldom so patients with type 1 diabetes mellitus had retinopathic lesions (10). Prior to convergence paresis, this lesion usually begins (19). Impairment of hearing is not obligatory in Wolfram synwith sluggish or absent reactions of the pupils to light. Transi- drome. If present, it may be detected as a slowly progressive ently it can be mistaken for an Argyll Robertson phenomenon, high frequency sensorineural hearing loss (7). Consequently, which has been noted to occur in some cases of Wolfram syn- complete deafness might be expected exceptionally only. drome (20). Differential diagnosis includes a tonic pupil as weIl. Sensorineural hearing loss in Wolfram syndrome has been reTwo of the patients, as described by Lessell and Rosman, had ferred to as probably caused by degeneration of the stria pupils resembling those in Holmes-Adie's syndrome (20). In vascularis with sparing of the retrocochlear portion of the audiboth, there was evidence of parasympathetic denervation super- tory system (22). Contrary to this, the hearing deficit that may sensitivity when tested pharmacologically. This seems to be a occur in classical diabetics is of retrocochlear origin, which has common feature of diabetic autonomie neuropathy (29). In been explained by the effect of hyperglycorrachia at Obersteinerthose patients, not only the size of the pupils, but also the degree Redlich's zone where the axons of the eighth nerve loose their of the pupillary response to light and convergence is reduced myelin sheaths and come into immediate contact with the CSF (13). These changes are not attributed to poor sensitivity to (1, 15). Therefore, it has to be taken into account that patients light in the presence of diabetic retinopathy or to increased ri- with Wolfram syndrome may develop both a cochlear and retrocochlear hearing loss. gidity of the iris (29). Ophthalmoplegia interna which refers to a rostral mid-brain lesion, and central nystagmus are signs, which possibly can be explained on the basis of the few existing neuropathological findings in Wolfram syndrome. The post-mortems not only showed axonal destruction and demyelination of the entire optic system and degeneration of the supraoptic and
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It is yet unknown if Wolfram syndrome is a distinct nosological entity, or occurs as part of a more generalized degenerative process such as olivopontocerebellar atrophy as mentioned above. Provided this syndrome is part of such a neurodegenerative condition, then, apart from diabetical and urological sequelae, prognosis will also depend upon the rapidi-
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which subsequently leads to dilatation of the bladder tissue, and vesicoureteral reflux threatens to occur. Thus, this degenerative process causes weakness or paralysis of the detrusor respectively reduced tone of the vesical trigone and the sphincter internus. As could be shown immunohistologically in one patient with Wolfram syndrome suffering from severe urinary tract ectasy, there was a marked diminution of sensory nerve fibres of the bladder wall (4).
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ty, by which degeneration of brain stern, mid-brain, pontine and cerebellar structures appear. In addition to the post-mortems cited, there is an increasing number of reports on patients with Wolfram syndrome, who were found to have mental deterioration, cerebellar ataxia, central nystagmus, pontine and cerebellar atrophy, and pupillary disorders, all of which are common signs that include degeneration of the pons and cerebellum (10, 18, 20, 22, 26, 27, 28). Thus, there is some reason to suggest that Wolfram syndrome is not an entity per se, but part of, or associated with a widespread generalized neurodegenerative disorder.
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Turnbridge, R. E., R. G. Paley: Primary optic atrophy in diabetes mellitus. Diabetes 5 (1956) 295-296 32 Wolfram, D. J.: Diabetes mellitus and simple optic atrophy among siblings: Report of four cases. Proc. Mayo. Clin. 13 (1938) 715-718
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Dr. med. Dipl.-Psych. Heinz B. GrosseAldenhövel Chefarzt a.i. und Ärztlicher Leiter der Abteilungen für Neurologie und Neurorehabilitation und der neuropädiatrisch-heilpädagogischen Abteilung für Kinder und Jugendliche Bethesda CH -3233 Tschugg
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