Psychiatric Features and Disturbance of Circadian Rhythm of Temperature, Pulse, And Blood Pressure in Wilson's Disease

7/28/2019 Psychiatric Features and Disturbance of Circadian Rhythm of Temperature, Pulse, And Blood Pressure in Wilson's Disease

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J Neuropsychiatry Clin Neurosci 14:3, Summer 2002 335

Psychiatric Features and

Disturbance of CircadianRhythm of Temperature,Pulse, and Blood Pressurein Wilsons DiseaseEneida B. Matarazzo, M.D., Ph.D.

Received September 20, 2000; revised January 5, 2001; accepted January10, 2001. From the Institute of Psychiatry, School of Medicine, Universityof Sao Paulo, Brazil. Address correspondence requeststo Dr. Matarazzo,Departamento de Psiquiatria, Faculdade de Medicina, USP, Caixa Postal3671, Sao Paulo, SP, Brazil. E-mail: [email protected].

Copyright 2002 American Psychiatric Publishing, Inc.

Wilsons disease (hepatolenticular degeneration), adisease of genetic origin, is due to abnormal cop-per metabolism affecting many organs and sys-tems, especially the liver and the nervous system.The initial symptoms can be exclusively or pre-dominantly psychiatric, including psychotic fea-tures. Three cases are reported in which the clini-cal picture at the beginning was compatible with apsychiatric diagnosis. During hospitalization, be-

fore treatment, there were abnormal and spontane-ous changes in the circadian rhythm of tempera-ture, pulse, and blood pressure, recorded every 6hours, with febrile peaks in the absence of infec-tious focus. Because the hypothalamus is impor-tant in the regulation of these autonomic func-tions, the hypothesis of a possible hypothalamicdysfunction was made, justifying a wide clinicaland laboratory investigation that allowed the di-agnosis of Wilsons disease. Alertness to circadianrhythm abnormalities in such cases may help the

psychiatrist avoid an erroneous diagnosis.(The Journal of Neuropsychiatry and ClinicalNeurosciences 2002; 14:335339)

Wilsons disease (WD), or hepatolenticular degen-eration, an inherited disorder of autosomal trans-mission, is due to an abnormality of copper metabolismthat affects many organs and systems, especially theliver and the central nervous system. In most cases it

begins in childhood or adolescence, rarely starting inadulthood; the onset is generally insidious, and the clini-cal course is difficult to predict, varying from weeks toyears.1 According to Bearn,2 in 40% of the cases the firstsymptoms are related to the liver (jaundice, hepatomeg-aly); in 40% they are neurologic (rigidity, athetosic

movements, tremors, abnormal postures, dysarthria,dysphagia, epileptic seizures); and in 20% of the casesthe illness begins with behavioral disorders or psychi-atric diseases. Akil et al.,3 in a study of 31 patients withWD, concluded that about 50% of them displayed someevidence of psychopathology, and about 20% had seena psychiatrist before the diagnosis was reached. Similarresults were found by Dening and Berrios,4 who veri-fied, in a study of 195 cases of WD, that an organic con-dition had not been suspected in 50% of 20 patients whowere first seen by a psychiatrist. The initial clinical pic-ture may be similar to schizophrenia, depression, or be-havioral disorders.1,47 Cartwright8 reminds us that

when psychiatric symptoms exist in WD, if neurolepticsare prescribed, abnormal liver function and motor dis-


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336 J Neuropsychiatry Clin Neurosci 14:3, Summer 2002

FEATURES OF WILSONS DISEASE

orders may be misinterpreted as side effects. Hoogen-raad1 also notes that neuroleptic treatment is usually in-advisable for patients with WD because even in smalldoses it can cause side effects.

Lishman9 states that in the beginning, symptomssuch as tremors, athetosic movements, and rigidity can

be influenced by emotion, leading to an erroneous im-pression of conversion hysteria. The diagnosis of WDis confirmed when the total serum level of copper orceruloplasmin is low and the naked eye or an ophthal-mologic examination detects the presence of the Kayser-Fleischer ring in the cornea; however, in the earlierstages these findings may be absent or spontaneous re-mission may be seen, and even thereafter, marked fluc-tuations in severity may occur. Intellectual deteriorationis common in the later stages, and the prognosis is worsethe younger the age at onset; death usually occurs fromliver failure, rupture of esophageal varices, inhalation,or intercurrent infections.9

Electroencephalographic changes are common in WD,taking the form of decreased alpha activity and in-creased beta and theta activities, with a low voltage

background.10 Computed tomography (CT) and mag-netic resonance may indicate enlarged ventricles and

both cortical and brainstem atrophy.6

Malaspina et al.11 estimate the frequency of WD at10 in 100,000. Despite the severity and importance ofmental symptoms in WD, most of the psychiatric text-

books, including those dealing with child and adoles-cent psychiatry,12,13 give brief or even no informationabout this disease. On the other hand, in the biblio-graphic review the author did not find any referenceto abnormal circadian rhythms of temperature, pulse,and blood pressure as possible symptoms of Wilsonsdisease. However, abnormal changes in these functionswere found in the three cases that will be described,and these changes may be of help in making an earlydiagnosis of WD.

METHODS

In the Child and Adolescent Psychiatry Service (CAPS)of the Institute of Psychiatry, temperature (T), pulse (P),

and blood pressure (BP) of the inpatients were recordedjust once a day, in the morning, unless the child had aninfection and was febrile. However, since 1964, as partof a research project on the etiology of mental diseases,it became a norm applied to all inpatients that T, P, andBP would be recorded every 6 hours and that, unlessurgent therapeutic measures were necessary, no treat-ment would be prescribed for at least 2 weeks after hos-pitalization, inasmuch as there could be a spontaneous

remission. This would help to ensure that the correctdiagnosis was made before introducing treatment. Re-cording of T, P, and BP every 6 hours revealed abnormalcircadian rhythm of these autonomic functions in somepatients; febrile peaks also appeared in the absence ofinfection and ceased spontaneously without use of an-

tipyretics. Because the hypothalamus plays an impor-tant role in the regulation of blood pressure, heart rate,and temperature,14,15 when the abnormalities in theseautonomic functions were detected the hypothesis of apossible hypothalamic dysfunction was adopted, justi-fying deeper laboratory investigation that led to the di-agnosis of encephalopathies of different etiologies, in-cluding WD.

The author made a search of the diagnoses of the pa-tients who have been hospitalized in CAPS, to look forthose that received the diagnosis of WD. Three caseswere found, and the symptoms that justified the initialdiagnosis of a psychiatric disease, and later of WD, are

described below.

RESULTS

Case 1. A., 15 years old, had a normal development and be-havior until the age of 15, when, after an emotionally trau-matic experience, she manifested quick involuntary move-ments, first of the right arm and progressively extending toother parts of the body, which disappeared spontaneouslyafter 2 months. About 3 months later, she started avoidingsocial contact, had no spontaneous speech, and often re-ported auditory hallucinations. The diagnosis of schizophre-nia was made and she was treated with chlorpromazine by apsychiatrist, with slight improvement in the first months, butlater the symptoms reappeared. Eight months after the be-ginning of the disease, she was examined in CAPS and washospitalized in April 1963. In the ward, she maintained theclinical picture described above. However, the intensity ofthe symptoms was reduced when she was alone and in-creased significantly in the presence of members of CAPSstaff. In addition to the involuntary movements, neurologicalexamination revealed only a mild generalized hypertonia,and these symptoms were attributed to the recent use ofneuroleptic. Even so, A. was administered some laboratoryexaminations, including EEG and cerebrospinal fluid (CSF),and the results were normal. The daily temperature, re-corded only in the morning, remained in the range of 36.4to 37.8 Celsius; P ranged from 80 to 100 per minute, and BP

remained between 120/70 and 140/80. On the basis of theseresults, the characteristics of her behavior, and the fact thatthe disease had appeared after an emotional trauma, diagno-sis of hysterical conversion was made. She was treated withpsychotherapy and tranquilizers and showed great improve-ment. Involuntary movements seldom appeared in the arms;she had normal behavior, no longer reported hallucinations,seemed happy, and was discharged after 2 months of hospi-talization.

In October 1964, A. returned to CAPS outpatient service,


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MATARAZZO

FIGURE 1. Wilsons disease patient, 15 years old (Case 1):temperature and pulse, recorded at 6, 12, 18, and 24hours, at her second hospital admission and duringthe first 15 days without treatment thereafter.

120

100

80

Day

60

401 2 3 4 5 6 7 8 9 10 11 12 13 14 15

39

38

37

36

35

Pulse (bpm) Temperature (C)

FIGURE 3. Wilsons disease patient, 13 years old (Case 2):temperature and pulse, recorded at 6, 12, 18, and 24hours, during 15 days without treatment.


120

100

80

Day

60

401 2 3 4 5 6 7 8 9 10 11 12 13 14 15

39

38

37

36

35

FIGURE 2. Wilsons disease patient, 15 years old (Case 1):

temperature and pulse, recorded at 6, 12, 18, and 24hours, during the 15 days preceding her death. Noinfectious focus was detected. Antipyretics weregiven every 4 hours.


Patient's death

120

140

100

80

Day

60

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

39

40

38

37

36

and her parents reported that she had been well until thepreceding week, when the symptoms had reappeared. Onceagain she was hospitalized. On this occasion, she was dysar-thric, had involuntary movements in the upper and lowerlimbs, and walked with difficulty, tracking to the left side;she exhibited hypertonia alternating with normal tonus inseveral muscular groups, and Babinski sign in the right foot.

A discrete cognitive impairment in comparison with the pre-ceding examination was detected. No hallucinations werethen reported. Autonomic functions were recorded every 6hours and revealed abnormal changes: BP oscillated between100/60 and 150/100; T and P changes are shown in Figure 1.

Pneumoencephalography of the brain was then per-formed, revealing a ventricular dilatation and cortical atro-phy. This time, EEG showed diffuse slow-wave discharges.The total serum copper level was low (30 lg/dl, vs. normal70160 lg/dl), and the ophthalmologic examination detectedthe presence of Kayser-Fleischer rings. The diagnosis of Wil-sons disease was now evident, but her physical conditionquickly deteriorated; she became semicomatose and died afew days later, in December 1964. During the days precedingdeath, BP oscillated between 140/100 and 180/120. Eventhough no infectious focus was detected, she had almost con-

tinuous high fever that did not cease with antipyretics, andthe changes in T and P also increased, as shown in Figure 2.

Case 2. B. had normal behavior, was healthy, and was agood student until the beginning of her illness. When shewas 13 years old, there appeared a slow and progressivechange of behavior: she became very quiet, stopped speak-ing spontaneously, gave laconic answers in a very low voice,had unmotivated crises of laughing, crying, or aggressive-ness, was inattentive, and had almost no initiative. Fourmonths later she was examined by a psychiatrist, who diag-nosed schizophrenia and prescribed chlorpromazine. A fewdays later B. developed difficulty swallowing and tremors inthe extremities, which were attributed to a side effect of theneuroleptic.

As she did not improve with treatment, she was broughtto CAPS in 1969 and hospitalized 10 months after the begin-ning of the disease. In the ward, she maintained the same

behavior described above. On clinical and neurological ex-amination the only abnormalities were a discrete hypertoniaof the extremities and slight reduction of the stretch reflexes,which could be attributed to the recent use of neuroleptic.However, BP, recorded every 6 hours, oscillated between100/60 and 140/100; T and P also showed abnormal changes,and febrile peaks appeared in absence of infection, as shownin Figure 3.

These abnormalities suggested a hypothalamic dysfunc-tion and the need of a broader laboratory investigation. Ahemogram demonstrated eosinophilia. All other results, in-cluding EEG, CSF with protein electrophoresis, urine and

feces analyses, glycemia, and levels of bilirubin, antistreptoli-sin, and immunoglobulin (IgG, IgA, IgM), were normal.However, an ophthalmic examination detected the presenceof Kayser-Fleischer rings, the total serum copper level waslow (50 lg/dl), and a diagnosis of Wilsons disease wasmade. For this reason, she was transferred to the NeurologicClinic for treatment.

Case 3. C. had a normal development, was calm and socia-ble, and was a good student. When she was 12 years old, her


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338 J Neuropsychiatry Clin Neurosci 14:3, Summer 2002

FEATURES OF WILSONS DISEASE

FIGURE 4. Wilsons disease patient, 12 years old (Case 3):temperature and pulse, recorded at 6, 12, 18, and 24hours, during 15 days without treatment.

120

100

80

Day

60

401 2 3 4 5 6 7 8 9 10 11 12 13 14 15

39

38

37

36

35


behavior changed, with a progressive reduction of initiative,daily activity, and verbal communication, in addition to cri-ses of aggressiveness. Two months later, she experienced dif-ficulty in swallowing and developed hand tremors. She wasexamined by a clinician who prescribed glutamic acid andphosphate. According to the parents information, dysphagiaand tremors disappeared but psychiatric symptoms per-

sisted. For this reason, she was brought to CAPS 10 monthsafter the beginning of the disease. The psychiatric examina-tion indicated reduced attention, slow movements with ten-dency to immobility, and inexpressive mimicry. She did notspeak spontaneously and gave laconic answers to somequestions, in a very low voice. Sometimes she cried withouttears, but this ceased abruptly. No delusions or hallucina-tions were reported. Her nutritional condition was good, andneurological examination detected only slight intentionaltremors of both hands.

In 1975, C. was hospitalized and maintained the same be-havior described above, which was compatible with the di-agnosis of schizophrenia. However, during her first days ofhospitalization, and without any treatment, instability of au-tonomic functions was detected: BP oscillated between 90/60and 160/120; changes in T and P were also abnormal, as

shown in Figure 4.Because of a hypothesized hypothalamic dysfunction, lab-

oratory examinations were then done: the hemogram re-vealed eosinophilia. Feces, urine, EEG, and CSF examina-tions gave normal results. However, computed tomographyshowed a cortical atrophy and enlarged ventricular system.The total serum copper level was below normal (30 lg/dl),and the ophthalmologic examination detected the presenceof Kayser-Fleischer rings. While lab results were pending,the patient developed dysphagia and involuntary tremors ofthe extremities. The diagnosis of Wilsons disease was made,and the patient was transferred to the Neurologic Clinic fortreatment.

DISCUSSION

The cases herein reported confirm the description ofWilsons disease, in which the initial symptoms may be

behavioral and may even mimic psychiatric diseases.Making the correct diagnosis is therefore difficult, par-ticularly because laboratory and clinical examinationmay be normal at the beginning of the disease.

In Case 3, the improvement in the initial phase of thedisease could hardly be related to the use of glutamic

acid or phosphate prescribed by a clinician; probably itwas coincident with a phase of transitory and sponta-neous remission of the motor symptoms, a possibilitymentioned in the literature.9

In Cases 2 and 3, when only psychiatric symptomsexisted and were compatible with the diagnosis ofschizophrenia, the instability of the circadian rhythmsof T, P and BP, when recorded several times a day,alerted medical personnel to the possibility of an en-cephalopathy and to the need of a deeper laboratory andclinical investigation, thus averting an incorrect psychi-atric diagnosis and revealing that both patients had WD.

In Case 1, the morning temperature during the first

hospitalization was always under 37 C, and the clinicalpicture induced to the diagnosis of hysteria. Febrilepeaks occurred at 6:00 A.M. only during the second hos-pitalization, when neurological signs were already evi-dent. It is probable that if the CAPS procedure duringthe first hospitalization had included recording T, P, andBP not only in the morning, but four times a day, theabnormal changes in these autonomic functions wouldhave been seen to exist already, and once they had beendetected, the hypothesis of an encephalopathy wouldhave been investigated and WD diagnosed. In this case,an early and correct treatment could have been pre-scribed, probably averting the patients death.

Abnormal changes of T, P, and BP have not been ob-served in patients hospitalized in CAPS for treatment ofendogenous psychosis or severe behavior disorders;however, they were present not only in WD, but also inother encephalopathies, such as acute sclerosing pan-encephalitis, neurocysticercosis, and encephalitisrelatedto immune process, all of which began with the mani-festation of psychiatric symptoms.

Wilsons disease requires lifelong therapy, and the re-sources for treatment are expanding,1,1619 mainlythrough the use of chelating agents. However, as Chowand Cummings20 comment, WD is an inevitably pro-

gressive fatal disease; the earlier treatment is initiated,the better for preventing or reducing damage. This pa-per may be a contribution to an earlier diagnosis of thissevere disease, especially when it starts with psychiatricsymptoms.

The author is grateful to Dr. Cesar Timo-Iaria, Professor ofPhysiology, for his help in interpreting the results of this re-search.


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References

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8. Cartwright GE: Diagnosis of treatable Wilsons disease. N EnglJ Med 1978; 298:13471350

9. Lishman A: Organic Psychiatry: The Psychological Conse-quences of Cerebral Disorders, 3rd edition. Oxford, UK, Black-well Scientific, 1998, pp 639687

10. Nazer A, Ede RJ, Mowat AP, et al: Wilsons disease in childhood:variability of clinical presentation. Clin Pediatr 1983; 22:755757

11. Malaspina D, van Kammen M, Johnson J, et al: Epidemiologicand genetic aspects of neuropsychiatric disorders, in The Amer-ican Psychiatric Press Textbook of Psychiatry, 3rd edition, editedby Yudofsky SC, Hales RE. Washington, DC, American Psychi-atric Press, 1997, pp 271329

12. Rutter M, Taylor E, Gottersov L (eds): Child and Adolescent Psy-chiatry. London, Blackwell Scientific, 1994

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14. Patton HD: Higher control of autonomic outflows: the hypo-thalamus, in Neurophysiology, 19th edition, edited by Ruch TC,Patton HD, Woodbury JW, et al. Philadelphia, WB Saunders,1965, pp 238251

15. Gelb D: Abnormalities of thermal regulation and the nervoussystem, in Neurology and General Medicine, 2nd edition, editedby Aminoff MJ. New York, Churchill Livingstone, 1995, pp 931932

16. Denny-Brown D, Porter H: The effect of BAL(2,3-dimercapto-propanol) on hepatolenticular degeneration (Wilsons disease).N Engl J Med 1951; 241:917925

17. Adams DA, Goodman R, Maxwell MH, et al: Nephrotic syn-drome associated with penicillamine therapy of Wilsons dis-

ease. Am J Med 1964; 36:33033618. Sternlieb I, Scheinberg IH: Penicillamine therapy in hepatolen-

ticular degeneration JAMA 1964; 189:74875419. Starosta-Rubenstein S: Treatment of Wilsons disease, in Treat-

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20. Chow TW, Cummings L: Neuropsychiatry: clinical assessmentand approach to diagnosis, in Kaplan and Sadocks Comprehen-sive Textbook of Psychiatry, 7th edition, vol 1, edited by SadockBJ, Sadock VA. Philadelphia, Lippincott Williams and Wilkins,2000, pp 221241

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Psychiatric Features and Disturbance of Circadian Rhythm of Temperature, Pulse, And Blood Pressure in Wilson's Disease