thyrotoxic neuropathy (basedow's paraplegia)intrinsic hand muscles, the musculature of the rest of...

Joiurnal of Neutrology, Neuirosuirgery, and Psychiatry, 1976, 39, 491-497

Thyrotoxic neuropathy (Basedow's paraplegia)J. H. FEIBEL' AND J. F. CAMPA

From the Department of Neurology, University of Virginia School of Medicine,Charlottesville, Va., USA

SYNOPSIS Polyneuropathy is a rare but possible manifestation of severe hyperthyroidism. Thepatient reported here developed a polyneuropathy affecting mostly leg muscles (Basedow's paraplegia)during the course of severe thyrotoxicosis. The polyneuropathy was confirmed with sequentialelectrophysiological studies of nerves and muscles and by muscle biopsy. The involvement of theproximal leg muscles is also interpreted as a neuropathic or nerve-mediated process rather than aconcomitant thyrotoxic myopathy.

Several muscle diseases have been associated withhyperthyroidism. They include acute and chronicthyrotoxic myopathies, exophthalmic ophthal-moplegia, periodic paralysis, and myastheniagravis (Ramsey, 1968, 1974). In contrast tomuscle, peripheral nerve involvement in hyper-thyroidism has received little attention. We haverecently studied a severely thyrotoxic patient andhave demonstrated the presence of a peripheralneuropathy virtually restricted to the lowerextremities. A number of similar cases of flaccidleg weakness associated with thyrotoxicosis weredescribed in the European literature of the latenineteenth century, as reviewed by Sattler in1908 (Sattler, 1952). The clinical condition wascalled 'Basedow's paraplegia' (Charcot, 1889;Joffroy, 1894).

CASE REPORT

The patient, an 18 year old black male withfamilial hyperthyroidism, was admitted to theUniversity of Virginia Hospital with a four weekhistory of severe leg weakness and dysaesthesias.He had suffered from a toxic goitre for threemonths. On examination, he had pronouncedexophthalmos with lid lag, a warm grossly en-larged thyroid gland, dysphonia, and marked signsof adrenergic overstimulation including tachy-cardia, diaphoresis, agitation, and a rapid tremorof the outstretched fingers.1 Present address: Department of Neurology, The University ofRochester School of Medicine and Dentistry, Rochester, New York,USA 14642.(Accepted 9 January 1976.)

The neurological dysfunction was limited to themotor and sensory systems except for weaknessof the superior rectus muscle of the left eye.Marked proximal and distal leg weakness wasassociated with moderate muscular atrophy, severehypotonia, and absent tendon reflexes in the legsonly. With the exception of slight weakness of theintrinsic hand muscles, the musculature of therest of the body was strikingly normal. Thismarked selectivity of leg weakness resembled thatof patients with flaccid paraparesis. The patientwalked with great difficulty, showing markedsteppage and waddling gait. When he rose froma sitting position, his paraplegia-like weakness be-came more apparent as shown in the movie framesof Fig. 1. All proximal and distal leg muscleswere equally affected with slightly more than anti-gravity strength in the right leg and less thanantigravity strength in the left. Partial sensoryloss, limited to the left leg, included decreasedpain and light touch perception up to the groinand impaired proprioception in the foot and toes.There was no evidence of cerebellar, corticospinaltract, or sphincter dysfunction.Laboratory data confirmed hyperthyroidism:

T4 (Murphy-Pattee) estimation was 28 units(normal=5.2-14 units), T3 resin uptake was 53units (normal=24-35 units); plasma cholesterollevel was 2.59 mmol/l. An electrocardiogramshowed sinus tachycardia. The remainder of thelaboratory tests, including serum calcium, sodium,potassium, CO. and chloride were normal exceptfor leucopenia (WBC 4000/mm3 with 34/,,polymorphonuclear cells).Two days after admission, the patient was

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J. H. Feibel and J. F. Campa

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FIG. 1. Selected frames from movie picture showing the patient rising from a sitting position.A strong arm and trunk musculature is used to lift the body above the weak legs. Notice thepassive position of the feet during this effort.

treated with propranolol (320 mg/day) andpropylthiouracil (1200 mg/day) for two weeks.This treatment did not control the thyrotoxicosisand was discontinued because of marked leuco-penia and high fever. Repeated blood cultureswere consistently negative. Iodine therapy(Lugol's solution) promptly reversed his deteri-orating clinical condition and was followed by asubtotal thyroidectomy. The day after surgery, thepatient again developed high fever with sterileblood cultures. He was treated with Lugol'ssolution only, became afebrile in two days andwas discharged without medications in euthyroidstate. The two febrile episodes were interpretedas 'thyroid storms'.

Sequential electrophysiological testing (de-scribed below) confirmed the clinical impressionof a severe peripheral neuropathy with pro-gressive slowing of motor and sensory nerve con-ductions in the lower extremities and electrical

signs of denervation in distal, but not in proximal,leg muscles. Electrophysiological evidence ofmyasthenia gravis or other disorder involving theneuromuscular junction was not found. A biopsyspecimen from the quadriceps muscle done at thetime of the thyroidectomy showed severe musclefibre atrophy indistinguishable from that ofdenervation.One month after thyroidectomy (6 May 1974),

the patient showed significant recovery of strengthin proximal leg muscles without improvement indistal muscles. Walking was performed with lessdifficulty but hip waddling and steppage were stillpresent. Ten weeks after surgery (17 June 1974),the extraocular muscles were found to be com-pletely normal and the muscle strength in the legscontinued to improve; the patient now could bendwithout falling. Fasciculations were seen in thequadriceps and the deep tendon reflexes werenow obtainable at the knee and even at the ankle

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Thyrotoxic neuropathy (Basedow's paraplegia)

using reinforcement. Sensory deficit also im-proved, vibratory sensation became normal, andthe hypaesthesia changed to a stocking type ofminimal degree. Five months after surgery (20September 1974), the sensory deficit had disap-peared. The patient's strength continued to im-prove, more in the proximal than in the distalmuscles. The hip waddling and steppage were lesspronounced. At seven months (30 November1974), the patient could walk without much diffi-culty, although he still had bilateral foot-dropand could barely stand on his toes. Recovery wasstill incomplete one year after the onset of legweakness.

ELECTROPHYSIOLOGICAL STUDIES The initialstudies were performed on 14 March 1974, ninedays after the onset of treatment with propranololand propylthiouracil. Needle electromyographyof the right and left quadriceps muscles revealedan interference to mixed pattern of decreasedamplitude (less than 2.0 mV) with maximumeffort. Activity at rest was not seen. The majorityof the motor unit potentials were irregular, oflow amplitude and short duration. Approximately20% of the motor unit potentials were short andpolyphasic. The left quadriceps was more severelyaffected than the right. The same findings werealso seen in the right tibialis anterior muscle, butthe clinically strong left biceps femoris was com-pletely normal. The impression was that of'electromyographic myopathy'.Evoked potential study of the left abductor

digiti minimi muscle with stimulation of the ulnarnerve revealed a normal amplitude of the evokedpotential (8 mV) and no spontaneous decrementwhen stimulated at a rate of 3/s. Minimal post-tetanic facilitation and no post-tetanic exhaustionor decrement at 3/s stimulation were observed inthe four minutes after maximal voluntary con-traction.

Motor and sensory conduction velocity studiesrevealed abnormalities in the left peroneal andleft sural nerves but not in other nerves of thelegs (Table). Motor and sensory conductionvelocities in ulnar and median nerves were withinnormal limits.The above studies were repeated on 8 April

1974, two weeks after the first 'thyroid storm'and one week after surgery. They showed im-provement of the 'myopathic' electromyogramfrom the right and left quadriceps muscles withalmost complete disappearance of the short poly-phasic and other 'myopathic' type motor unitpotentials. Denervation potentials were never seenin these proximal muscles. By contrast, theelectromyogram from both right and left tibialisanterior muscles, also of myopathic type in theinitial study, now revealed frank denervation withfibrillation and positive sharp waves in more thantwo-thirds of muscle insertion sites. This wasaccompanied by severe loss of motor units withfew remaining motor unit action potentials. Themotor conduction velocities in all distal nervesof the legs were now severely affected (Table).

Subsequent nerve conduction studies at threeand five months (6 May and 17 July 1974) afterthyroidectomy demonstrated further deteriora-tion in the motor and sensory conductionvelocities in the lower extremities and for the firsttime minimal slowing of the sensory, but not themotor, conduction velocities in the upperextremities.

MUSCLE HISTOCHEMISTRY The left quadricepsmuscle was biopsied at the time of thyroidectomy(2 April 1974) two weeks after the first and sixdays before the second electromyographic studies.The muscle specimen was frozen for histochemicalincubation and histological staining for haema-toxylin and eosin, modified Gomori's trichrome,DPNH dehydrogenase, SDH, phosphorylase,

B L E

SEQUENTIAL STUDIES OF NERVE CONDUCTION

Peroneal Tibial Sural

R L R L R L R L L L

14 March 40.6 34.7 5.6 7.6 44.7 4.5 40.6 3.78 April 30.2 25.6 6.9 8.9 36.2 31.6 8.2 6.86 May 28.6 nEP II nEP 32.6 34.1 7.1 7.5 35.0 5.117 July 25.2 nEP 8.7 nEP 31.5 nEP 6.3 nEP nEP nEP

MCV DML MCV DML SCV DSLNormal range 42-58 m/s 7.8 ms 40-52 m/s 8.5 ms 42-56 m/s 4 ms

Motor and sensory conduction velocities (MCV and SCV) in metres per second (m/s) and distal motor and sensory latencies (DML and DSL) inmilliseconds (ms). No evoked potential to maximal nerve stimulation is abbreviated as nEP.

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PAS, esterase, alkaline phosphatase, and myo-fibrillar ATPase (pH 4.4, 4.7, and 10.2).The muscle sections revealed pronounced and

extensive atrophy of muscle fibres (Fig. 2). Theatrophic angular fibres were scattered almostregularly throughout the specimen in groups ofvariable size, interspersed with normal musclefibres. The DPNH staining was abnormally in-creased in some but not all the small fibres (Fig.3). With myofibrillar ATPase, the groups ofatrophic fibres were composed of mixtures of

FIG. 2. A trophic muscle fibres are scatteredthrough the field in small and large groups.Modified Gomori's trichrome, X.120.

three histochemical fibre types (Figs 4, 5). Like-wise, the intact fibres were also a mixture of threetypes without predominance of any type. Thenon-selectivity for the atrophic, as well as forthe normal fibres was also demonstrated with themethod for DPNH dehydrogenase, phosphorylase,SDH, and esterase. Target fibres and type group-ing were not seen. There was one small bloodvessel with a perivascular cell reaction near twonecrotic muscle fibres. No other abnormalities in-cluding abnormal material were seen in vessels or

FIG. 4. The groups of atrophic fibres containtype I (light) and type II (dark) fibres. MyofibrillarATP-ase reaction at pH 10, X120.

FIG. 3. Some of the atrophic muscle fibres show FIG. 5. The groups of atrophic fibres also con-dark, increased staining in the DPNH reaction tain type IIB fibres with intermediate staining.X 120. Myofibrillar A TP-ase reaction with preincubation

at pH 4, X120.

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muscle fibres. Nerve bundles were not present inthe specimen. These morphological abnormalitiesin the left quadriceps muscle were thought to besimilar to those of acute denervation, althoughthe electromyogram of the same muscle did notshow electrophysiological evidence of suchdenervation.

DISCUSSION

The patient described here presented with clinicalevidence of polyneuropathy after three months ofsymptomatic hyperthyroidism and four weeksbefore treatment started. The clinical evidence forpolyneuropathy consisted of marked distal, in ad-dition to proximal, muscle weakness, muscleatrophy, almost absent tendon reflexes, and sen-sory deficit as described above. The legs were sopredominantly involved that the clinical picturestrongly resembled that of flaccid paraparesis.

The first electrophysiological evidence ofnerve involvement was obtained in the initialstudies nine days after admission and medicaltreatment. Frank electrical denervation of distalleg muscles and marked slowing in conduction ofperoneal, tibial and sural nerves were demon-strated 20 days later, two weeks after the first'thyroid storm'. The time course of these electro-physiological abnormalities indicated the presenceof an initial polyneuropathy and a subsequentacute exacerbation coincident with the worseningof the thyrotoxicosis.Follow-up clinical and electrophysiological

observations after subtotal thyroidectomy andcure of thyrotoxicosis showed further slowing ofnerve conduction in the legs and new abnormali-ties in the arms, despite definite improvement inmuscle strength and sensory deficit. This lack ofcorrelation betwen nerve conduction velocitiesand clinical recovery has also been observed inthe Guillain-Barre syndrome (Bannister andSears, 1962; Pleasure et al., 1968) and probablyrepresents changes in myelin thickness duringremyelination.

Histochemical studies in a biopsy specimenfrom a proximal leg muscle showed severe musclefibre atrophy which, like denervation, wasgrouped or scattered throughout the specimen andinvolved all histochemical fibre types. Theabsence of electrical denervation in this proximalmuscle, although suggesting that the muscle in-volvement was not classical denervation, does notexclude other nerve-mediated mechanism, orearly stages of denervation. Furthermore, thepresence of fully developed electromyographicdenervation in the distal leg muscles of our

patient indicates that the same neuropathic pro-cess might have affected his proximal musculature.The alternative of an independent proximal myo-pathy was not supported by our histochemical orelectromyographic studies except for a 'myo-pathic EMG'. In our view, a 'myopathic EMG'does not necessarily mean primary muscle diseasesince it has been frequently associated withseveral types of muscle fibre atrophy of undeter-mined nature (Warmolts and Engel, 1970).

Since the initial electrophysiological evidenceof frank denervation occurred several weeks aftertreatment began, the possibility that propylthiou-racil may have aggravated an already existingpolyneuropathy cannot be ignored. However,neurological disorders complicating therapy withpropylthiouracil are rare. Vertigo, paraesthesias,and dysaesthesias have been reported (Vanderlaanand Storrie, 1955; Crile and McCullagh, 1951).To our knowledge, objective neuropathy has notbeen described after its use.

Propylthiouracil, a thionamide, inhibits the in-corporation of iodide into the precursors of thethyroid hormones (Solomon, 1973). The precisemode of action of this drug is unknown (Burgiand Labhart, 1974), but no direct neurotoxiceffect has been described. However, adverse side-effects, including agranulocytosis, are well known(McGavack and Chevalley, 1954). In our patient,bone-marrow toxicity causing leucopenia followedhigh-dose therapy with propylthiouracil; hence,the drug, acting in concert with the worsening ofthyrotoxicosis and subsequent 'thyroid storm',may have had a similar adverse effect on neuraltissue.

In summary, we believe that our patient hada covert sensorimotor polyneuropathy as a pre-senting manifestation of his hyperthyroidism. Thecontinued worsening to a 'thyroid storm' and per-haps the treatment with propylthiouracil resultedin an overt acute polyneuropathy. This polyneuro-pathy involved both proximal and distal legmuscles with different severity. A concomitantthyrotoxic proximal myopathy could not beseparated from the muscle involvement by thepolyneuropathy.

THYROTOXIC NEUROPATHY IN LITERATURE Para-plegia-like weakness during severe hyperthyroid-ism was first described by Charcot in one of hisLeCons du Mardi (1888). In the paper, 'Nouveauxsignes de la maladie de Basedow' (1889) hedescribed the clinical findings as follows:'Cette paraplegie est flasque, sans aucun pheno-mene spasmodique; elle ne s'accompagne pas de

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douleurs fulgurantes, les reflexes sont absents. I1n'y a aucun trouble de la sensibilite, il n'y a pasde participation de la vessie. Elle ne peut seconfrondre avec la paraplegie hysterique. I1 sembledonc qu'il y ait un type particular de paraplegiedans la maladie de Basedow, dont le premierphenomene serait l'effondrement des jambes, quin'en est qu'une forme attenuee'.This flaccid paraplegia with absent reflexes,without sphincter disturbances but occasionallywith some sensory deficit, was reported at least13 times by early European authors (Sattler,1908). The condition was called 'Basedow'sparaplegia' by Joffroy (1894). After these earlyreports, the term 'Basedow's paraplegia', to ourknowledge, has been mentioned only twice injournal titles since 1940 (Sanghvi et al., 1959;Fridberg and Egart, 1970) and also by Tyler andAdams in Harrison's Principles of InternalMedicinie (1974). We believe our patient to beanother example of this rare condition.Neural involvement in severe thyrotoxicosis

is supported by Jan Waldenstrom's review ofacute thyrotoxic myopathy (Waldenstrom, 1945),a condition described by Russell Brain (Brain andTurnbull, 1938) that Waldenstrom preferred tocall 'acute thyrotoxic encephalo- or myopathy'.Waldenstrom described it as'usually associated with signs of thyrotoxic crisisor thyrotoxic coma and the most striking symp-toms are those of bulbar palsy. Muscular weak-ness of the limbs and loss of reflexes also occur.Severe cerebral symptoms, such as paraphasia,acalculia and psychosis with hallucinations seemto indicate that the disorder is often either accom-panied (or caused?) by a real encephalopathy. Itmay be very difficult to determine if the causesare of cerebral or muscular origin'.This condition was distinguished from that ofmyasthenia gravis associated with thyrotoxicosis(Millikan and Haines, 1953).More recently, Ludin et al. (1969) revived

interest in neuropathic involvement in hyper-thyroidism by reporting eight patients with a'neurogenic' electromyogram in distal legmuscles. They postulated that their patients had asubclinical polyneuropathy. Later, Chollet et al.(1971) mentioned two cases of thyrotoxic goitreand polyneuropathy with definite slowing ofnerveconduction. Previously reported electrophysio-logical studies in thyrotoxic myopathy (Harvardet al., 1963; Ramsey, 1965) were not sufficiently

complete to rule out the presence of peripheralnerve involvement. Studies of multiple nerves andsequential determinations, as done in our patient,are often necessary to demonstrate a conductiondefect in peripheral nerves.

In conclusion, peripheral nerve involvementin hyperthyroidism is a rarely reported, butpossible, manifestation of severe thyrotoxicosis.In these situations the commonly reported muscleweakness may change to a frank polyneuropathy.It is also possible that what we call thyrotoxicmyopathy is actually a neuropathic or nerve-mediated process not fully expressed as classicaldenervation. The effect of thyroid hormones onperipheral nerve function appears to be apertinent subject of appropriate investigation.

REFERENCES

Bannister, R. G., and Sears, T. A. (1962). The changesin nerve conduction in acute idiopathic poly-neuritis. Journal of Neurology, Neurosurgery, andPsychiatry, 25, 321-328.

Brain, W. R., and Turnbull, H. M. (1938). Exopthal-mic ophthalmoplegia. Quarterly Journal ofMedicine, 7, 292-323.

Burgi, H., and Labhart, A. (1974). The thyroid gland.In Clinical Endocrinology, 2nd edn, p. 190. Editedby A. Labhart. Springer: New York.

Charcot, J. (1888-1889). Le9ons du mardi. Poly-clinique, 239-243.

Charcot, J. (1889). Nouveaux signes de la maladie deBasedow. Le Bulletin Medical, 3, 147-149.

Chollet, P. H., Rigal, J. P., and Pigniole, L. (1971).Une complication meconnue de l'hyperthyroidie: laneuropathie peripherique. Presse Medicale, 79, 145.

Crile, G., and McCullagh, E. P. (1951). The treat-ment of hyperthyroidism. Annals of Surgery, 134,18-28.

Fridberg, D. I., and Egart, F. M. (1970). A case ofBasedow's paraplegia. Problemy Endokrinology(Mosk), 16, 38-40.

Harvard, C. W. H., Campbell, E. D. R., Ross, H. B.,and Spence, A. W. (1963). Electromyographic andhistological findings in muscles of patients withthyrotoxicosis. Quiarterly Journal of Medicine, 32,145.

Joffroy, M. A. (1894). Hospice de la Salpetriere,Clinique Nerveuse, Legons faites en decembre,1891 (1). Le Progres Medical, 22, 2nd series, 61-62.

Ludin, H. P., Spiess, H., and Koenig M. P. (1969).Neuromusclar dysfunction associated with thyro-toxicosis. European Neurology, 2, 269-278.

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McGavack, T. H., and Chevalley. J. (1954). Untowardhematologic responses to the antithyroid com-pounds. American Journal of Medicine, 17, 36-40.

Millikan, C. H., and Haines, S. F. (1953). The thyroidgland in relation to neuromusclar disease. Archivesof Internal Medicine, 92, 5-39.

Pleasure, D. E., Lovelace. R. E., and Duvoisin, R. C.(1968). The prognosis of acute polyradiculo-neuritis. Neurology (Minneap.), 18, 1143-1148.

Ramsey, I. D. (1965). Electromyography in thyro-toxicosis. Quarterly Journal of Medicine, 34, 255-267.

Ramsey, I. C. (1968). Thyrotoxic muscle disease. Post-graduate Medical Journal, 44, 385-397.

Ramsey, I. D. (1974). Thyroid DIsease and MuscleDysfunction. Yearbook Medical Publishers:Chicago.

Sanghvi, L. M., Gupta, K. D., Banerjee, K., and Bose,K. (1959). Paraplegia, hypokalemia, and nephro-pathy with muscle lesions of potassium deficiencyassociated with thyrotoxicosis. A merican Journalof Medicine, 27, 817-823.

Sattler, H. (1952). Basedow's Disease. English transla-tion of 1908 edition by G. W. Marchand, and J. F.Marchland. Grune and Stratton: New York.

Solomon, D. H. (1973). Antithyroid drugs. In TheThyroid, 3rd edn, p. 689. Edited by S. C. Wernerand S. H. Ingbar. Harper and Row: New York.

Tyler, F. H., and Adams, R. D. (1974). Acute andsubacute myopathic paralysis. In Harrison's Prin-ciples of Internal Medicine, 7th edn, p. 1924.McGraw-Hill: New York.

Vanderlaan, W. P., and Storrie, V. M. (1955). Asurvey of the factors controlling thyroid functionwith especial reference to newer views on anti-thyroid substances. Pharmacological Reviews, 7,301-334.

Waldenstrom, J. (1945). Acute thyrotoxic encephalo-or myopathy, its cause and treatment. A cta MedicaScandinavica, 121, 251-294.

Warmolts, J. R., and Engel, W. K. (1970). A critiqueof the myopathic electromyogram. Transactions ofthe A merican Neurological Association, 95, 173-177.

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