Letters to the Editor

to islands of neurotoxicity.4 A contributionfrom the otherwise insignificant basal gan-glia calcification to the extrapyramidal fea-tures in our patient is doubtful.The highest concentrations of lithium in

the CNS are found in the white matter ofthe pons.4 At one stage, our patient wastotally immobile except for eyeblinks andeye movements, with which she could com-municate. A normal MRI ruled out centralpontine myelinolysis. Could this state, there-fore, be attributed to the high concentrationof lithium in the pons?

In conclusion, lithium neurotoxicity usu-ally develops after chronic treatment.Permanent sequelae are rare but the occa-sional occurrence of acute and persistentneurological symptoms warrants a note ofcaution, especially when lithium is used incombination with antipsychotic drugs.5Lithium, preferably intracellular (red bloodcells) should be carefully monitored to avoidneurotoxicity. Rarely, neurological sequelaemay develop even at therapeutic serum con-centrations. Therefore, the need for keenclinical observation, in addition to routinedrug monitoring, especially during combina-tion treatment with antipsychotics, cannotbe overemphasised.

J MANIS V TANDEL

P U SHAHDepartment ofNeurology

D R KARNADDepartment ofMedicine,

KEM Hospital, Bombay, India

1 Sansone MEG, Ziegler DK. Lithium toxicity areview of neurological complication. ClinicalNeuropharmacology 1985;8:242-8.

2 Cohen WJ, Cohen NH. Lithium carbonate,haloperidol and irreversible brain damage.JAMA 1974;230: 1283-7.

3 Donaldson M, Cunningham J. Persisting neu-rologic sequelae of lithium carbonate ther-apy. Arch Neurol 1983;40:747-51.

4 Kemperman CJF, Gerdes JH, De Rood JAM,et al. Reversible lithium neurotoxicity at nor-mal serum levels may refer to intracranialpathology. J Neurol Neurosurg Psychiatry1989;52:679-80.

5 Baastrup PC, Hollnagel P, Sorenson R, SchouM. Adverse reactions in the treatment withlithium carbonate and haloperidol. 3tAMA1976;236:2645-6.

Pure autonomic failure with motor neu-ron disease: report of a clinical studyand postmortem examination of apatient

From clinical and pathological viewpoints,primary chronic autonomic failure is dividedinto three types: pure autonomic failurewithout other neurological conditions, auto-nomic failure with multiple system atrophy,and autonomic failure with Parkinson's dis-ease.' In pure autonomic failure, the mainpathological findings were neuronal loss inthe intermediolateral columns of the spinalcord and the occurrence of eosinophilic bod-ies in the sympathetic ganglia. Furthermore,Lewy bodies in the substantia nigra or locuscoeruleus were also described.23 Because thenecropsied cases of pure autonomic failurealways showed Lewy bodies in the brain-stem, it has been considered as an extremevariant of autonomic failure with Parkin-son's disease.' Our patient was a man withpure autonomic failure whose prominentsymptom was orthostatic hypotension, andwho showed the neuropathological changesreported in pure autonomic failure as well asthose in a familial form of motor neuron dis-ease.A 78 year old man had claimed dizziness

.. 120.).,

on standing for the past five years. At theage of 76, he had noted frank syncope whichgradually increased in frequency. No othersymptoms had been experienced until thelast year, when he was admitted to our hos-pital. He had had chronic bronchitis for thepast 10 years. There was no family historysuggesting neuromuscular diseases. Onadmission, physical examination disclosedsevere orthostatic hypotension and diffusemild weakness of the limb muscles. Muscletone and deep tendon reflexes were normal.Pathological reflexes, muscle atrophy, fascic-ulation, cerebellar ataxia, and sensory dis-turbance were not seen.

Laboratory studies of blood, urine, andCSF were within normal limits. A chestradiograph showed mild reticular changes inthe lower fields of the lungs. Cranial CT,MRI, and ECG showed no abnormal find-ings. Needle EMG and nerve conductionstudies were not performed. A blood pres-sure of 106/30 mm Hg in the supine posi-tion decreased to 50/30 mm Hg on headup tilt, with no change in the heart rate(58 bpm). There was no postural changein serum noradrenaline concentration(0 03 ng/ml (controls: 0 05-0 40 ng/ml)),although plasma renin activity and serumarginine vasopressin were appropriatelyincreased. The cold pressor test caused adecrease in blood pressure, from 104/54 to90/50 mm Hg. An exaggerated increase inblood pressure (from 100/40 to 186/100 mmHg) was obtained after treatment with intra-venous noradrenaline. The coefficient ofvariation of the mean R-R interval of theECG was reduced to 0-39% (controls> 1-14%). Intravenous infusion of atropineinduced no change in heart rate. The phaseIV overshoot of blood pressure after aValsalva manoeuvre was absent. The pupil-lary responses to the instillations of both 5%tyramine and 1-25% noradrenaline werenormal. The Schirmer test showeddecreased lacrimation. Volume of residualurine was 10 ml and cystometry was normal.The patient died of subacute interstitialpneumonia eight months after admission.

His brain weighed 1020 g. Macroscopicfindings were not remarkable. Paraffin sec-tions were stained with haematoxylin-eosin,cresyl violet/Luxol fast blue, and silverimpregnation (Bodian stain, Gallyas stain).Immunohistochemical staining with the

avidin-biotin peroxidase procedure for iden-tification of ubiquitin and phosphorylatedhigh molecular weight neurofilaments wascarried out. Multiple sections from variouscortical areas including the precentral gyruswere unremarkable. No neuronal inclusionscould be identified. Neuritic plaques wereabsent. Neurofibrillary tangles were notedonly in the hippocampus. The striatum,globus pallidus, thalamus, subthalamicnucleus, and hypothalamic nucleus appearednormal. The cerebral white matter was unre-markable. No glial cytoplasmic inclusionswere noticed. The substantia nigra and locuscoeruleus were examined at two and four dif-ferent levels, respectively. Several sectionsfrom each level were stained with haema-toxylin-eosin and immunohistologically withantibodies against ubiquitin and neither neu-ronal loss nor Lewy bodies were detected.The oculomotor and Edinger-Westphalnuclei showed normal appearances. Mildneuronal loss and gliosis had occurred in thefacial and hypoglossal nuclei. In both nuclei,chromatolytic neurons and intracytoplasmicLewy body-like hyaline inclusions were occa-sionally noted. Almost total neuronal losswas found in the dorsal motor nuclei of thevagal nerve (fig 1). The accessory cuneatenuclei showed mild neuronal loss. The retic-ular formation in the medulla exhibited mildastrogliosis as well as a few hyaline inclu-sions. The red nuclei, raphe nuclei, pontinenuclei, inferior olivary nuclei, and pyramidswere not affected. In the cerebellum,Purkinje cells were slightly decreased innumber, and the dentate nucleus showed amild degree of grumose degeneration. Therewas no noticeable myelin pallor of the cere-bellar white matter. In the spinal cord, therewas severe loss of sympathetic neurons of theintermediolateral columns. This was accom-panied by moderate loss of anterior hornmotor neurons throughout the thoracic andlumbar cord. Clarke's columns also showedneuronal loss (fig 2A). In the anterior horns,chromatolytic neurons, spheroids, intraneu-ronal conglomerates, and hyaline inclusionswere occasionally encountered. Swollencord-like axons were seen in theintramedullary portion of the spinal anteriorroot. Astrogliosis and a few hyaline inclu-sions were also noted in the intermediatezone of the spinal cord. No pathologicalfindings were recognised in Onuf's nucleus.

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352 Letters to the Editor

Figure 2 (A1) Neuronal loss is apparent in the

intermediolateral column, Clarke's column, and

anterior horn of the thoracic spine (cresylvioletiLuxolfast blue x 80). (B) Myelinpallor in the pyramidal tracts of the thoracicspine is accompanied by symmetric patches ofmyelin loss in the posterior columns (cresylviolet/Luxolfast blue x 22).

There was myelin pallor of the lateral cor-ticospinal tracts and posterior columns, andthe latter assumed the symmetric butterflyshape of the middle zone (fig 2B). Spino-cerebellar tract degeneration was noted atthe level of the pyramidal decussation. Theposterior root ganglia were normal. The cer-vical sympathetic ganglia showed no appar-ent neuronal loss. Increases in satellite cellswere not noticed. A few Lewy bodies andround or elongated eosinophilic bodies wereoccasionally encountered in the interstitium.Immunohistochemically, hyaline inclusionsin a-motor neurons of the brainstem andspinal cord, and eosinophilic bodies in thecervical sympathetic ganglia were stainedpositive for ubiquitin. A few intraneuronalconglomerates appeared to stain in a granu-lar fashion. Spheroids and conglomerateswere positive for neurofilaments.

This patient had pure autonomic failurewith the features of motor neuron disease,which is not usually complicated by primaryautonomic failure. The patient clinicallyshowed autonomic failure, mainly mani-fested by orthostatic hypotension. The lowresting noradrenaline concentration andimpaired heart rate response to atropinewith low mean R-R interval of ECG sug-gested dysfunction of the postganglionicadrenergic and the cardiac parasympathetic

system respectively. Thus the whole clinicalfeature of the patient could be diagnosed as

pure autonomic failure, which chiefly con-cerned the cardiovascular system. The mainpathological changes were found in thedorsal vagal nuclei and intermediolateralcolumns, which were considered to be theneuroanatomical system with the predomi-nant involvement of the degenerativeprocess. Along with the existence ofeosinophilic bodies in the sympathetic gan-glia, these findings were similar to thosedescribed in pure autonomic failure.2' Bycontrast with the previously reported cases,this patient showed the absence of neuronalloss or Lewy bodies in the substantia nigraand locus coeruleus. This suggests that pureautonomic failure could be recognised as aclinicopathological entity separated frommultiple system atrophy or Parkinson's dis-ease.

Although motor neuron disease does notusually coexist with autonomic failure, ourpatient exhibited loss of anterior horn cellsand pyramidal tract degeneration. In addi-tion, we found symmetric patches of myelinloss in the posterior columns, degenerationin the spinocerebellar tracts, and loss of cellsfrom Clarke's columns. This type of distrib-ution is similar to that reported in cases of afamilial form of motor neuron disease.4Furthermore, Lewy body-like hyaline inclu-sions and swollen cord-like axons, whichwere both noted in our patient, have oftenbeen described in these familial cases.4Whether a familial form of motor neurondisease constitutes a distinct disease entityor not, our patient shares its characteristics.The autonomic nervous system may be

affected in motor neuron disease, with-forexample, a mild degree of neuronal loss inthe intermediolateral columns.' However,out patient showed the obvious neurodegen-erative changes reported in pure autonomicfailure as well as those described in a familialform of motor neuron disease. Thereforethis case shows an unusual constellation ofpure autonomic failure and motor neurondisease.We thank Dr M Obata and Dr S Fukuyama forhelping evaluate the autonomic nervous system.

K NODADepartment of Internal Medicine,

Fukushima Seikyo Hospital,Hiroshima, JapanS KATAYAMAC WATANABEY YAMAMURAS NAKAMURA

Third Departmenit of Internal MedicineS YONEHARA

K INAISeconid Department of Pathology,

School ofMedicine,Hiroshimia University,

Hiroshima, _apan

Correspondence to: Dr K Noda, Division ofInternal Medicine, Fukushima Seikyo Hospital,42-7, Miyakomachi, Nishiku, Hiroshima-shi, 733,Japan.

1 Bannister R, Mathias CJ. Introduction andclassification of autonomic disorders. In:Bannister R, Mathias CJ, eds. Autonomic fail-ure. A textbook of clinical disorders of the auto-nomic ntervous system. 3rd ed. Oxford: OxfordUniversity Press, 1992: 1-12.

2 Johnson RH, Lee G de J, Oppenheimer DR,Spalding JMK. Autonomic failure withorthostatic hypotension due to intermedio-lateral column degeneration; a report of twocases with autopsies. Q J7 Med 1966;35:276-92.

3 Roessmann U, van den Noort S, McFarlandDE. Idiopathic orthostatic hypotension. ArchNeurol 1971;24:503-10.

4 Hirano A, Kurland LT, Sayre GP. Familialamyotrophic lateral sclerosis: a subgroupcharacterized by posterior and spinocerebel-

lar tract involvement and hyaline inclusionsin the anterior horn cells. Arch Neurol 1967;16:232-43.

5 Kennedy PGE, Duchen LW. A quantitativestudy of intermediolateral column cells inmotor neuron disease and the Shy-Dragersyndrome. J Neurol Neurosurg Psychiatry1985;48:1103-6.

Glutaric aciduria type 1 in adulthood

Glutaric aciduria type 1 (GA-1) is an auto-somal recessive disorder caused by defi-ciency of the mitochondrial enzyme glutarylCoA dehydrogenase, which oxidises andcarboxylates glutaryl CoA, an intermediatestep in the metabolism of lysine and trypto-phan.' The onset of clinical manifestations isusually within the first year of life with anacute encephalopathic illness, often trig-gered by intercurrent infection. A severe

dystonic-dyskinetic syndrome develops inmost patients, but others are less severelyaffected and asymptomatic cases have beendescribed. It is a rare condition with onlyabout 100 cases reported in the medical lit-erature since its original description in1975.2 However, it has been suggested thatGA-1 is underdiagnosed and may existundetected in populations of children andadults labelled as having cerebral palsy.2We report a patient with GA-I in whom thediagnosis was made at the age of 50 yearswhen she was referred for reassessment ofchronic neurological disability.The patient was the product of a full term

normal delivery and there were no problemsin the neonatal period. Motor developmentwas mildly delayed, and she did not start towalk until the age of 18 months when shewas noted to drag her right leg. At the age of7 years she was admitted to hospital with a

"paralytic illness". She remained in hospitalfor four months and at the time of dischargerequired callipers to walk. Her manual dex-terity was poor and her speech was slurred.These neurological disabilities subsequentlyremained stable. At the age of 12 a rightsubtalar fusion was performed, and eightyears later the left femur was shortened. Shewas able to complete her education at a nor-mal school and then worked for 10 years ina factory before getting married. She wasreferred to us at the age of 50 because ofincreasing difficulty in walking caused bypain in the right ankle. There were no newneurological symptoms and no symptoms ofautonomic dysfunction. She was beingtreated with a non-steroidal anti-inflamma-tory drug and was on hormone replacementtherapy. She had not received any neurolep-tic medication. Both her parents were cau-casian and had died in their 80s. They hadhad no neurological illnesses, and there wasno consanguinity. The patient has two sib-lings and three children of her own, all ofwhom are well with no neurological dis-order.

Examination showed a severe dysarthriawhich made her speech very difficult tocomprehend. Psychometric testing, how-ever, showed her performance to be in theaverage range, with a verbal IQ of 93. Thenon-verbal part of the WAIS-R was not per-formed because of limited manual dexterity,but good average scores were achieved onother tests of non-verbal reasoning. Therewas a left exotropia, but eye movementswere otherwise normal. There was pro-nounced lingual dystonia and orofacial dysk-inesia. Her right leg was hypoplastic and sheused callipers and two sticks to walk. There

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