J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

Journal of Neurology, , and Psychiatry, 1974, 37, 879-887

Jakob-Creutzfeldt disease Modification of clinical and electroencephalographic activity with methylphenidate and diazepam F. ELLIOTT1, C. GARDNER-THORPE2, D. D. BARWICK, AND J. B. FOSTER3 From the Regional Neurological Centre, Newcastle General Hospital, Newcastle upon Tyne

SYNOPSIS The electroencephalogram in three patients with Jakob-Creutzfeldt disease showed two separate abnormalities-namely, progressive background suppression and periodic generalized synchronous triphasic sharp wave complexes which evolve to a uniform morphology and periodicity. The abnormalities, when found in the EEG of a patient in middle-age with a dementing illness, should not be confused with other periodic electroencephalographic phenomena. Since the neuro- pathological abnormalities of Jakob-Creutzfeldt disease are non-specific, the electroencephalogram is essential for the recognition of this disorder, although serial recordings may be necessary to guest. Protected by copyright. establish the diagnosis. Modification of the electroencephalographic abnormalities occurs with afferent stimuli and with methylphenidate or diazepam, suggesting that the phenomenon of back- ground suppression is independent ofthe presence ofthe periodic complexes. Modification ofclinical activity with methylphenidate suggests that some degree of reversibility of function exists in this inexorably fatal disorder. Further detailed studies of the electroencephalogram in cases of Jakob- Creutzfeldt disease are indicated.

Creutzfeldt (1920) and Jakob (1921, 1923) primates after the instillation of homogen- described a rare form of progressive ate from cases of Jakob-Creutzfeldt disease has associated with a variable clinical picture of been demonstrated (Gajdusek et al., 1966; Gibbs corticospinal and striatal abnormalities and with et al., 1968). pathological findings of widespread neuronal The electroencephalographic (EEG) abnor- loss and either focal or generalized astrocytic mality of periodic sharp wave complexes, origin- proliferation. Variations in these features have, ally described by Jones and Nevin in 1954, has in the past, resulted in diverse terminology for been observed in a high proportion of patients this condition which is now termed Jakob- (Kirschbaum, 1968; Siedler and Malamud, 1963;

Creutzfeldt disease. It is thought to be more May, 1968) but controversy still exists regarding http://jnnp.bmj.com/ prevalent than was originally supposed and may the specificity of the EEG in this condition be at least as common as Pick's disease (Torvik, (Gubbay and Barwick, 1966; Kiloh et al., 1972; 1970; Barrett, 1972). Jakob-Creutzfeldt disease Forster and Kugler, 1970). Similar EEG dis- (including its variants) has generated widespread charges may be seen with other subacute afflic- interest since clinicopathological correlates have tions of cortical and subcortical grey matter been observed with certain endemic disorders of (Gloor et al., 1968) but the configuration, dura-

the of New Guinea tion, and periodicity of the sharp wave com- on September 29, 2021 by (Klatzo et al., 1964; Neumann et al., 1964) and plexes in the recordings in Jakob-Creutzfeldt of Guam (Hirano et al., 1961; Hirano et al., disease appear, nevertheless, to constitute the 1961; Hirano et al., 1966), and especially since most useful clues towards the diagnosis of this serial transmissibility of a similar disorder in condition (Gloor et al., 1968; Hauser-Dumur and Radvanyi, 1970; Goldhammer et al., 1972), 1 Present address: c/o Permanente Medical Group, 900 Kiely Boule- vard, Santa Clara, California 95051, U.S.A. especially since the neuropathological 'spongi- 2 Present address: Department of Neurology, Royal Devon and Exeter Hospital, Devon. form' abnormalities are now thought by most 3 Reprint requests: Dr J. B. Foster, at above address. authorities to be non-specific (Torvik, 1970; 379 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

880 F. Elliott, C. Gardner-Thorpe, D. D. Barwick, and J. B. Foster

Robinson, 1969; British Medical Journal, 1972). complexes in a patient with the disease and, in Jones and Nevin (1954) in their original paper addition, showed that the periodic complexes described the characteristic morphology, period- were enhanced by the intravenous administration icity, and waxing and waning quality of the of chlorpromazine or pentazol. Fdrster in 1970 periodic discharges seen in the electroencephalo- used massive doses of intravenous diazepam in grams of their patients with subacute vascular patients with the disease and reported only slight encephalopathy, a condition which is now and short-lived suppression of the EEG sharp generally regarded as a variant of Jakob- potentials. Recent publications (Goldhammer Creutzfeldt disease. They also showed that the and Braham, 1969; Burger et al., 1971) have intravenous administration of short-acting bar- stressed the need for further analysis of the EEG biturate suppressed the spike or sharp wave abnormalities of Jakob-Creutzfeldt disease and component of the periodic complexes. Nelson the present paper reviews such findings in three and Leffman in 1963 also demonstrated the sup- cases of this disorder studied during the past five pression by barbiturate of the EEG periodic years. The results of clinical and electro- guest. Protected by copyright.

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FIG. 1. (a) Case L.H. Patient in terminal quiescent state. EEG shows repetitive generalized synchronous spike and sharp wave triphasic complexes at a repetition rate of approximately one per second. Intervening back- ground rhythms markedly suppressed. (b) Case R.M. EEG shows generalized synchronous triphasic periodic sharp wave complexes at repetition rate of 0 6 per second. Morphology of periodic complexes, which occur intermittently in short runs, is characteristic of the early stage of Jakob-Creutzfeldt disease. (Calibrations 100 KvV; I s.) J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

Jakob-Creutzfeldt disease 881 encephalographic monitoring during the ad- was transferred from the Darlington Memorial ministration of parenteral methylphenidate and Hospital to the Regional Neurological Centre on 28 diazepam in one patient (K.D.) are discussed in June 1968 in a grossly demented state with inter- detail. mittent myoclonic jerking of her extremities, a right spastic hemiplegia, right homonymous visual field METHODS defect, primitive facial reflexes, and truncal ataxia. Three patients with Jakob-Creutzfeldt disease were Extensive investigations of blood, urine, and cerebro- studied. EEGs were recorded on an Offner TC 16- spinal fluid (CSF) showed no abnormality. Pneumo- channel or on a SLE 18-channel machine; in all encephalography revealed generalized ventricular cases bipolar montages (as in Fig. 1) were used with a dilatation with widening of cortical sulci; EEG sensitivity of 100 ,uV/cm and an amplifier time con- showed generalized periodic complexes, and brain stant of 1 s, except Fig. 2b in which the calibration revealed neuronal loss with spongiform astro- was 56 ,uV/cm and the time constant was 0 3 s. cytic proliferation. Serial electroencephalograms indicated that the generalized synchronous periodic CASE REPORTS triphasic sharp wave discharges, which showed a CASE L.H. (N28547) This 64 year old female patient repetition rate of about one per second, became per- guest. Protected by copyright.

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4.1 (ai) (b) FIG. 2. Montages as in Fig. 1. Case K.D. (a) EEG performed on admission and while patient awake shows generalized slowing of background rhythms below 8 Hz. (Calibrations 100 ,uV; 1 s.) (b) Two weeks after admission. EEG shows intermittent periodic complexes at repetition rate ofone per second which are generalized but more prominent over the left anterior head region. Background activity has become less abundant (compare (a)). (Calibrations 56 V; I s.) J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from 882 F. Elliott, C. Gardner-Thorpe, D. D. Barwick, and J. B. Foster sistent and stereotyped in wave form as the patient's driving on the autobahn in Germany, an incident clinical condition deteriorated. This increase in the throughout which he remained unperturbed even abundance of the electroencephalographic periodic though his passengers were alarmed and distressed. discharges coincided with a progressive diminution For three weeks before his admission to hospital he of background rhythms in the intervals between the had become forgetful, apathetic, and at times discharges so that by the time the patient reached a irrationally suspicious so that he was already a state of inanition the background activity showed source of concern and embarrassment both at home almost complete suppression (Fig. la). The patient and at work. His past history revealed that he had died on 19 November 1968. entered England involuntarily as a prisoner of war in 1944 but had remained in this country after his first CASE R.M. (N28719) This 56 year old female patient marriage in 1948 and had developed a responsible was admitted to the Regional Neurological Centre position as an industrial equipment export executive. on 2 December 1970 with a four week history of General physical examination of D.K. on admis- forgetfulness and lethargy. After admission she sion was unremarkable except for self-inflicted super- developed progressive myoclonic jerking and rigidity ficial excoriations over the extensor surfaces of both of her limbs, hyper-reflexia, and extensor plantar upper extremities. He was disorientated in time and responses, and she became unresponsive to verbal recent memory was impaired. Throughout the stimuli. Routine investigations of blood, urine, and examination he exhibited constant psychomotor cerebrospinal fluid and radiographs were within restlessness as indicated by distractability and inter- normal limits but demon- mittent twitchings of his face, arms, and legs. He

strated generalized ventricular dilatation with widen- denied hallucinatory sensations but admitted that heguest. Protected by copyright. ing of cortical sulci. Serial EEGs showed generalized felt 'someone is out to get me'. Abstraction and synchronous triphasic sharp and slow wave com- abilities of judgment were impaired but intelligence plexes with a periodicity of 0-6-0-7 seconds (Fig. lb) as assessed by arithmetical problem solving seemed but with subsequent recordings occurred persistently to be intact. Nominal dysphasia was present. His with a periodicity of one per second. These changes gait was unstable in an apraxic fashion; dressing in the abundance and periodicity of the sharp wave apraxia was present. Bilateral anosmia and a right complexes coincided with a progressive diminution homonymous visual field defect were demonstrated. of background EEG activity. Brain biopsy showed External ocular movements showed paresis of up- neuronal degeneration with a proliferative vacuolar ward conjugate gaze. Brisk jaw jerk and snout astrocytosis. The patient's clinical condition deterior- reflexes were present. A slight drift of the right upper ated to a rigid immobile state with prominent suck- extremity with incoordination of the extremities on ing, grasp, and startle responses. She died on 13 finger-nose and heel-shin testing were demonstrated. March 1971. Deep tendon reflexes were brisk but the plantar responses were flexor. No obvious abnormalities of CASE D.K. (N44714) This 53 year old German male muscle tone or of superficial or deep sensation were patient was admitted to the Regional Neurological found. The initial clinical impression was of a mid- Centre on 28 November 1972 and was able, with the line parietal space-occupying lesion: the time course help of some prompting by his young wife, to relate suggested a glioblastoma as the most likely possi- the details of his present illness. He had always bility. Routine radiography of , cervical spine, http://jnnp.bmj.com/ enjoyed robust health with wide interests in outdoor and chest were unremarkable, as were blood and sport and international travel until April 1972 when urine counts and serum chemistry. An EEG (33031) he developed an irritable 'tingling' across his back, performed on the day of admission showed general- neck, and shoulders associated with an ill-defined ized slowing a background rhythms to 6 Hz without sense of malaise. These sensations were especially lateralizing or projected abnormalities and the troublesome at night and had precipitated numerous changes suggested a diagnosis of dementia (Fig. 2a). medical consultations in England and Germany. Brain scan and bilateral carotid angiography were

Multiple prescriptions of medications failed to pro- unremarkable. A pneumoencephalogram (6 Decem- on September 29, 2021 by vide significant relief from his symptoms but his ber 1972) revealed generalized ventricular dilatation condition did not seem severe enough to prevent his and widening of cortical sulci compatible with a marriage in September 1972. During his honeymoon, diagnosis of cerebral atrophy with compensatory his wife related, he experienced two 'spells' each hydrocephalus. Examination of CSF showed normal characterized by the adoption of a blank facial values for pressure, cells, protein, and sugar. By 12 expression, a strange look in his eyes, and verbal December 1972, two weeks after his admission, the unresponsiveness. During one such episode he was patient had deteriorated to the point where he did involved in a minor automobile accident while not speak and responded only to simple commands J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

Jakob-Creutzfeldt disease 883 such as 'open your mouth'. He had developed a marked rigidity of the head, trunk and limbs, and generalized increase of muscle tone and held his fists bilateral extensor plantar responses. By 29 December clenched and his upper extremities flexed in decorti- 1972 spontaneous myoclonic movements had ceased: cate posture. Occasional myoclonic jerking of all when approached, he responded by abducting his limbs was noted. On 12 December 1972 a repeat arms briskly and opening his eyes and mouth widely, EEG (33091, Fig. 2b) revealed generalized inter- the response being somewhat like the Moro reflex in mittent triphasic sharp wave complexes of 400 ms children. At this time EEG (33143, Fig. 3a) showed duration and with a periodicity of about one per generalized periodic triphasic sharp wave complexes second. At this stage, a clinical diagnosis of Jakob- but with modulation of amplitude in a waxing and Creutzfeldt disease was made. Brain biopsy was per- waning fashion. No clinical accompaniments to the formed on 18 December 1972 and revealed neuronal periodic discharges were observed. The amplitude loss with astrocytic proliferation of the 'spongiform' and amount of the background rhythms between the variety. By this time the patient had become mute complexes was reduced in comparison with the pre- and unresponsive to painful stimuli; he showed vious recordings. On 10 January 1973, paraplegia

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(a) (b) FIG. 3. Montages as in Fig. 1. Case D.K. (a) Four weeks after admission. EEG shows that periodic triphasic sharp wave complexes of400 ms duration and with a repetition rate of 1J05 per second have become persistent and stereotyped. Interval background activity is markedly suppressed. (b) Six weeks after admission. EEG shows persistent generalized and stereotyped periodic discharges at repetition rate of 1J28 per second with marked suppression of intervening background rhythms. (Calibrations 100 ,u V; 1 s.) J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

884 F. Elliott, C. Gardner-Thorpe, D. D. Barwick, and J. B. Foster in-flexion with marked truncal and limb rigidity was rhythms showed further suppression (Fig. 3b). found. A sucking reflex was now present and tapping Negligible alteration of the periodic complexes the lips, which elicited the snout reflex, also preci- occurred during an adversive seizure. Needle stimula- pitated myoclonic jerks of the patient's limbs. His tion of the left ulnar nerve, however, was followed by eyes and head periodically deviated to the right side partial suppression of the complexes (Fig. 4a). Slow with myoclonic jerking of his eyes that suggested an intravenous injection of methylphenidate (40 mg) adversive seizure. A grasping reaction of the feet was was followed almost immediately by flattening of the found on stimulation of the plantar areas but tonic periodic discharges (Fig. 5) but little alteration of the neck reflexes could not be demonstrated, indicating background rhythms occurred. The ECG showed an that decortication was present without decerebra- increased heart rate but did not otherwise change tion. On 11 January 1973 EEG was performed with significantly. The patient, who had been unresponsive monitoring of the electrocardiograph (ECG) (73/ for the previous month, directed his gaze in the direc- 0060). The periodic complexes were uniform with tion of the intravenous needle, tried to get off the diminished modulation of amplitude as compared examination table, attempted to remove the intra- with the previous recordings, while background venous needle, successfully pulled out his nasogastric

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FIG. 4. Montages as in Fig. 1. Case D.K. Electrocardiographic (lead 1) monitor on channel 17. (a) EEG shows partial suppression ofperiodic complexes following mechanical stimulation of the left ulnar nerve with a needle. (b) EEG shows suppression ofperiodic complexes and enhancement of background rhythms after intravenous injection of diazepam (10 mg). The changes lasted for several minutes (compare Fig. 3b). (Calibrations 100 VP; 1 S.) J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

Jakob-Creutzfeldt disease 885 tube, called out repeatedly 'No, no, no' and re- recording and the procedure was then terminated. sponded to simple commands. Within 20 minutes of The patient died on 4 February 1973. the injection he settled back into his previously un- Brain biopsy was performed and reported (Pro- responsive state and the EEG resumed its periodic fessor B. E. Tomlinson) as follows: Histological activity, at first in a modulating fashion similar to examination shows a cortical and, to a lesser extent, that noted with the earlier recordings. At this time, white matter abnormality. In the cortex there is diazepam (10 mg) was administered intravenously, almost certainly a considerable loss of neurones which caused no alteration in the patient's quiescent affecting particularly the deep layers. This is not clinical state but which suppressed the periodic EEG accompanied by gross evidence of spongiosis but activity and, in addition, showed an enhancement of occasional neurones in the more superficial cortex the EEG background rhythms to such a degree that are associated with a clear-cut small vacuole adjacent abundant medium amplitude alpha activity, which to the perikaryon which does not appear to be arte- had been virtually absent at the onset of the record- fact. The most prominent change, however, is an in- ing, appeared over the posterior head regions (Fig. crease ofastrocytes and also probably of oligodendro- 4b). This alteration of the EEG towards an almost cytes in the deep white matter, the latter forming normal state persisted for a further 10 minutes of numerous clusters in places, often in the vicinity of

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( a (h FIG. 5. Montages as in Fig. 1. Case D.K. Electrocardiographic (lead 1) monitor on channel 17. EEG shows suppression of periodic complexes (compare Fig. 3b) after intravenous administration of methylphenidate (40 mg). At this time the patient responded verbally to his name and also responded appropriately to simple commands. (Calibrations 100 , V; I s.) J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

886 F. Elliott, C. Gardner-Thorpe, D. D. Barwick, and J. B. Foster neurones and creating the appearance of neurono- Methylphenidate was also observed to create a phagia. This latter phenomenon is very difficult to transient alerting phenomenon in the clinical assess because of its variability in different parts of response of one patient. Thus, this patient, who the cerebral cortex with increasing age, but it does was mute and immobile for several weeks, was appear to be considerably in excess of normal in this show appropriate motor re- case. Astrocytic increase is probably also present in able to speak and the white matter, but no gross gliosis, no demyelina- sponses to simple commands after intravenous tion and no vascular lesions. injection of methylphenidate. The appearances are consistent with Jakob- We do not propose to speculate upon the Creutzfeldt disease. involvement of neuronal pathways in Jakob- Postmortem examination was performed and the Creutzfeldt diseases which results in the develop- histological features were in agreement with those ment of electroencephalographic abnormalities, found in the brain biopsy. nor can we explain how such abnormalities can be modified by afferent stimulation or by various DISCUSSION drugs. The alteration of clinical and electro- encephalographic activity, albeit transient, which We have studied three cases ofJakob-Creutzfeldt occurs in the presence of cerebral atrophy and disease with serial and neuronal degeneration (as demonstrated by have observed, in one patient, the clinical and pneumoencephalography and brain biopsy), effects of the intra- electroencephalographic nevertheless indicates that some element ofguest. Protected by copyright. venous administration of methylphenidate and reversibility of function exists in Jakob- diazepam. Our observations show two distinct Creutzfeldt disease. electroencephalographic abnormalities develop- ing in patients with this disorder. The first We are grateful to Miss B. P. Longely, who recorded abnormality noted was a progressive slowing the EEGs and kindly prepared the illustrations, and and eventual suppression ofbackground rhythms also to Mr J. Osselton who read the manuscript and and the second was the evolution of periodic made many helpful suggestions. sharp wave complexes. These complexes first occurred intermittently with a varying mor- phology but later became persistent with stereo- REFERENCES The development of the dis- Barrett, R. E. (1972). Dementia in adults. Medical Clinics of typed morphology. North America, 56, 1405-1418. tinctive one per second generalized synchronous British Medical Journal (1972). Spongy change in the brain, triphasic sharp wave complexes occurred fairly 3, 433-434. late in the course ofthe disease and this observa- Burger, L. J., Goldensohn, E. S., and Fisher, W. (1971). The EEG Creutzfeldt-Jakob disease. (Abstract.) Electro- tion indicates that, if serial electroencephalo- encephalography and Clinical Neurophysiology, 31, 420. graphy is not performed, the diagnosis of this Creutzfeldt, H. G. (1920). tUber eine eigenartige herdformige Erkrankung des Zentralnervensystems. Zeitschrift fur die

condition may be missed. http://jnnp.bmj.com/ gesamte Neurologie und Psychiatrie, (Orig.), 57, 1-18. Our observations also suggest that the electro- Forster, C. (1970). EEG changes in Jakob-Creutzfeldt's encephalographic abnormalities of background disease under the influence of diazepam. (Abstract.) suppression and of periodic complexes are inde- Electroencephalography and Clinical Neurophysiology, 29, 218. pendent phenomena, since afferent stimuli (ulnar Forster, C., and Kugler, J. (1970). EEG differential diagnosis nerve stimulation) and methylphenidate sup- of Jakob-Creutzfeldt disease. (Abstract.) Electroencephalo- pressed the periodic discharges without altera- graphy and Clinical Neurophysiology, 28, 327. tion of background activity whereas diazepam Gajdusek, D. C., Gibbs, C. J., Jr, and Alpers, M. (1966).

Experimental transmission of a kuru-like syndrome to on September 29, 2021 by suppressed the periodic discharges but enhanced chimpanzees. Nature, 209, 794-797. background activity. This background activity Gibbs, C. J., Jr, Gajdusek, D. C., Asher, D. M., Alpers, be slow 'fast activity' due to the M. P., Beck, E., Daniel, P. M., and Matthews, W. B. might simply (1968). Creutzfeldt-Jakob disease (spongiform encephalo- diazepam since it was seen in channel 5 as clearly pathy): transmission to the chimpanzee. Science, 161, 388- as in many of the posterior derivations and it 389. was asymmetrical. Similar changes Gloor, P., Kalabay, O., and Giard, N. (1968). The electro- appreciably encephalogram in diffuse encephalopathies: electro- may be seen in the EEGs of severely brain encephalographic correlates of grey and white matter damaged children sedated with trimeprazine. lesions. Brain, 91, 779-802. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.879 on 1 August 1974. Downloaded from

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