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Delirium and Lyme Disease
Case Reports
Delirium and Lyme Disease V. CALIENDO, M.D. DONALD 1. KUSHON, M.D. JEAN W. HELZ, M.D.
MARK
D
elirium is often a presenting feature of acute physical illness and has been reported to occur in nearly 10% of all hospitalized patients.1-J As defined by DSM-IV,4 delirium is a cognitive disorder characterized by dysfunction of attention and consciousness, disturbance of the sleep-wake cycle, and altered psychomotor activity. The clinical signs and symptoms of delirium vary widely from a subtle confusional state to one in which severe agitation places the patient at risk for serious self-injury. Nonspecific changes in a patient's mood, thought, and behavior often represent the first and only signs of an undetected medical illness. Therefore, early recognition of delirium and treatment of its underlying cause is essentia1. 1 In addition to delirium's high mortality, if untreated it places the patient at higher risk for the development of residual cognitive impairments and progression ofthe underlying disease process. 5- 7 Lyme disease, which is caused by the tickborne spirochete, Borrelia burgdoiferi, is endemic along the northeastern coast of the United States, from Maryland to Massachusetts, and in parts of Wisconsin, Minnesota, Oregon, and Calg ifornia. The illness usually begins in summer or early fall, 3-21 days after a tick bite (Ixodes dammini, known colloquially as the bear tick or deer tick, in the Northeast and Midwest and Ixodes pacificus in the West) with a characteristic expanding skin lesion, erythema chronica migrans (ECM), accompanied by flu-like or meningitis-like symptoms (stage I). Systemic symptoms (arthralgias, chills, fever, malaise, and fatigue) may accompany the erythema. 9 This phase of the disease may be followed by cranial VOLUME 36' NUMBER I • JANUARY - FEBRUARY 1995
or peripheral neuritis, carditis, or painful radiculitis (stage 2), or by intermittent or chronic arthritis or chronic neurologic or skin abnormalities (stage 3). Cases of Lyme disease are often reported in association with hiking, camping, or hunting trips or among people living in wooded or rural areas, with patients of any age and both sexes being affected. It has been determined recently that more than 1,000 people now acquire the infection in the United States each summer. IO Little has been published in the psychiatric literature regarding Lyme disease, yet a diversity of neuropsychiatric manifestations has been described in patients with known B. burgdoiferi infection, including lethargy, decreased concentration, poor memory, emotional lability, irritability, sleep disturbances, and personality changes, as well as instances of dementia, frank psychoses with auditory hallucinations, and a single episode of an anorexia nervosa-type illness. I I Although some of the clinical phenomena caused by this infection are almost pathognomonic (e.g., heart block in an otherwise healthy adult, bilateral facial palsy, painful radiculitis), others are completely nonspecific. 12 Reports have suggested that the nervous system Received May 20. 1992; revised June 2. 1993; accepted June 10. 1993. From the Depanment of Mental Health Sciences. Division of Consultation and Liaison Psychiatry. Hahnemann University School of Medicine. Address correspondence to Dr. Kushon. Col Psychiatry. Hahnemann University Hospital. Broad and Vine. Philadelphia. PA 19102. Copyright © 1995 The Academy of Psychosomatic Medicine.
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Case Reports
is involved in 15-40% of patients with Lyme disease. '3 .'4 Among patients with neurologic involvement, nearly 40% recall an initial tick bite, while 80% had a preceding ECM. 14.15 Neuropsychiatric symptomatology often appears during the second stage of infection, characteristically dominated by more prominent neurological signs, such as meningitis, radiculitis, and neuritis, often accompanied by cardiologic features, such as cardiac conduction defects and left ventricular dysfunction. I 1.16-18 Clinical presentation may range from severe focal signs to a mild delirium. 11.19 Pachner and Steere J7 concluded that II of their 38 patients (29%) experienced subtle encephalopathic symptoms, including sleep disturbances, difficulty concentrating, poor memory, irritability, and emotional lability. Additionally, they noted that although several patients made mistakes in their mental status testing, none had a definite organic brain syndrome, obtundation, or coma. J7 Moreover, 9 of the II patients had abnormal electroencephalograms (EEGs), demonstrating focal abnormalities, while computerized tomographic (CT) scans of the head done with and without contrast were normal in 8 of these patients. 17 Bendig and Ogilvie 20 previously reported one case of a child with severe delirium associated with positive serology to B. burgdoiferi but without a known preceding tick bite or ECM. Halperin et al. 19 found that cognitive function was impaired on bedside testing of 15 of 30 seropositive patients, with significant cognitive impairment in 4 of 5 patients with intrathecal antibody production to B. burgdorferi. Similarly, Reik et al. 14 reported 4 patients with elevated titers to B. burgdoiferi with signs of delirium, including somnolence, confusion, disorientation, poor memory, impaired calculation and abstraction, decreased attention span, and irritability. We report on a patient who developed a rapidly fluctuating delirium associated with positive serology to B. burgdorferi, without a known preceding tick bite or ECM, persisting several days until responding to antibiotic therapy. This case illustrates that psychiatrists who work in endemic areas need to include Lyme disease in the differential diagnosis of delirium. 70
Case Report A 64-year-old woman, who was previously active and in good health, returned from a trip to Princeton, NJ, in late summer, when she suddenly began to experience tingling paresthesias in her hands and feet along with ascending bilateral leg weakness that progressed to involve her arms. She was admitted to a neurology service 5 days later when the weakness progressed asymmetrically to involve her arms and she lost her ability to ambulate. On admission, she was afebrile and without other specific complaints, although she felt unwell. On neurological examination, she was areflexive and had a profound vibratory loss, bilateral facial palsy, and marked, asymmetrical diffuse weakness. She denied any recent headache or neck pain. At the time of admission, she appeared exhausted but was awake and able to follow commands. She was able to lift her left arm but was unable to lift her other extremities or support her head. A lumbar puncture performed the next day revealed a protein level of 38 mg/dl (normal = 15-45 mg/dl) in the cerebrospinal fluid. The diagnostic impression of the primary service was that she suffered from an acute inflammatory polyradiculoneuropathy [Guillain-Barre Syndrome (GBS)]. The plan was to treat with plasmapheresis. The same evening, however, the patient developed decreasing pulmonary vital capacities and was intubated. Her condition continued to deteriorate; I week later she developed cardiac bundle branch block and supraventricular tachycardia and was unable to receive plasmapheresis, although her pulmonary function returned to normal and she was extubated. A psychiatric consultation was requested on the 13th hospital day regarding a change in mental status. Her husband noted that over the prior 3 days she exhibited a sudden state of confusion that continued to worsen. During this time, she was also noted by her nurse to be confused and agitated at night, yelling at imaginary people. Her mental status examination revealed the patient to be restless, inattentive, requiring questions to be repeated, and maintaining poor eye contact throughout the interview. At times she became agitated but was generally somnolent and had difficulty keeping awake throughout the examination. Her speech rambled and often was incoherent. She appeared irritable and her thought process was disorganized. She also displayed several episodes of echolalia. She appeared to be responding to hallucinations of "angels" appearing outside of PSYCHOSOMATICS
Case Reports
her window. She was disoriented to time and place and her concentration was poor. Her short-term memory was likewise poor, as evidenced by her inability to repeat the names of several unrelated objects after 5 minutes, but her long-term memory was intact. She responded concretely to proverbs and her insight and judgment were deemed poor as she was clearly unable to understand her condition or recognize the need for treatment. Her Mini-Mental State Examination score was 20/30. 11 Laboratory evaluation at the time of our initial consultation revealed body temperature, vital signs, serum electrolytes (Na+, K+, cr, C0 1), blood urea nitrogen, serum creatinine, and blood glucose all to be within normal limits. A complete blood count, prothrombin time, partial thromboplastin time, as well as serum levels of calcium and magnesium were also unremarkable. Plain films of the chest revealed right lower lobe atelectasis, although pulmonary function tests, as well as arterial blood gases-performed at this time to rule out hypoxia as a cause of altered mental status-were normal. In addition, erythrocyte sedimentation rate, monospot test, serum protein electrophoresis, immunoelectrophoresis, test for myelin basic protein, hepatitis screen, heavy metal screen, test for antinuclear antibodies, and gram stain of the cerebrospinal fluid (CSF) yielded no significant findings. Cultures for CSF syphilis, fungus, and acid-fast bacilli did not reveal any microorganisms. Electrocardiogram revealed left bundle branch block unchanged from admission, and echocardiography revealed no findings consistent with a cause of her delirium. Her medications at the time included digoxin and sucralfate but offered no additional etiology for her delirium. An EEG performed in response to her change in mental status revealed an abnormal tracing, including continuous generalized theta and intermittent triphasic delta activity with preserved reactivity and no localizing or epileptiform features, indicative of a moderate diffuse disturbance of cerebral function. A CT scan of the head with IV contrast revealed mild cortical and central atrophy with no evidence of focal abnormality. including cardiovascular accident, recognized. Magnetic resonance imaging of the head was unremarkable. Laboratory studies revealed a positive serum Lyme antibody titer with I: 12 IgG/lgM and 1.2 IgM in serum with 1.1 being the high level of normal (personal correspondence with HUH lab). A repeat lumbar puncture revealed mildly elevated CSF protein and positive IgM Lyme titer in CSF. Reduced ability to maintain attention. disorga-
VOLUME 36· NUMBER I • JANUARY - FEBRUARY 1995
nized thinking, reduced level of consciousness, increased psychomotor activity, memory impairment, and perceptual disturbances in the presence of evidence of an organic cause (progressive polyneuropathy and heart block) indicated the organic mental syndrome delirium. The possibility of Lyme disease was raised after the onset of the heart block. History exploring this possibility revealed no preceding tick bite or ECM, but a geographic location, time of year, and clinical features of the illness (e.g., ascending asymmetrical polyradiculopathy. bilateral facial palsy. and heart block) were compatible and treatment with intravenous ceftriaxone was begun. Haloperidol (0.5 mg q 30 min) was given that evening to control agitation but was discontinued due to extrapyramidal effects. The next morning she became lethargic, offering single-word responses, and was oriented to self only. During the evening she appeared more alert, offering immediate responses in a coherent fashion. The following morning she had again become lethargic, opening her eyes only to painful stimuli. neither communicating nor responding to verbal commands. Once again that afternoon she was alert. following commands and communicating freely, although she remained confused and agitated. Her mental state was unchanged and continued to fluctuate throughout the evening and the following day. She began to improve by the 3rd day of treatment. becoming more coherent and attentive. She was now easily awakened and well oriented to self, time, and place but was still intermittently confused. Several days later she remained more alert and coherent. Although still disoriented to her surroundings and confused by her condition, she was no longer agitated. Finally, by the 8th day of treatment, movement in her extremities had improved and she was alert, coherent. and well oriented, with proper insight into her condition and treatment. Her mental state at this time had returned to normal. A repeat EEG the following day revealed no evidence of focal abnormality. The patient gradually regained partial strength in her upper and lower extremities. and the paresthesias and facial dysplegia resolved. She continued to receive intravenous ceftriaxone for a full 30-day course, and her condition upon leaving the hospital was much improved. She exhibited no further symptoms of delirium, although she remained partially weak in her extremities for which she continued to receive physical therapy. We telephoned the patient for follow-up 6 months after discharge. At this time we could assess no deficits of mental status, including orientation,
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Case Reports
concentration, mood, affect, short- and long-term recall, language, and sleep patterns. She was attentive and pleasant upon questioning, offering appropriate responses with good insight and judgment. Moreover, neither the patient nor her husband noticed any changes in her mental status throughout the period following discharge. She also reported full recovery of strength in her extremities and was delighted to have returned to her usual lifestyle.
Discussion The case presented here is a rather dramatic one with acute delirium developing in a patient admitted with a number of neurological and cardiac signs consistent with the second stage of Lyme disease. Despite the relatively characteristic picture of second-stage Lyme disease, this condition is often misdiagnosed, especially in the absence of a history suggestive of Lyme disease (i.e., the occurrence ofECM, an antecedent tick bite, other family members affected, or flu-like illness). Areflexia, profound vibratory loss, and ascending diffuse weakness in a patient with Lyme radiculitis are often reminiscent of GBS. 17 Initially, this patient's illness resembled GBS; however, a subtle differentiation must be made. Lyme disease commonly progresses asymmetrically, as demonstrated in this patient, whereas GBS is generally a symmetric progressive weakness. Furthermore, Lyme disease often causes a painful radiculitis, as in this patient. 17 As mentioned previously, symptoms of bilateral facial palsy and cardiac conduction defects in an otherwise healthy patient, in conjunction with radiculitis, are almost pathognomonic for Lyme disease. '9 Finally, this patient presented in late summer with a history of recent travel to an area where Ixodes tick bites and Lyme disease are endemic. Therefore, despite the lack of an antecedent tick bite or ECM, a geographical location, time of year, ascending asymmetrical polyradiculoneuropathy, bilateral facial palsy, and heart block, combined with positive antibody titers for B. burgdorferi in serum and CSF, should clue the astute consultant to a diagnosis of Lyme disease as a cause for delirium in the patient presented. Diagnosis of Lyme disease was essential in the 72
rapid treatment and alleviation of her delirium. Likewise, it is important to recognize the variety of manifestations of Lyme disease described in the literature. Patients with B. burgdorferi infection may have presentations ranging from a subtle delirium to major neurological features such as meningitis, radiculitis, and neuritis. Often these symptoms occur without knowledge of an antecedent tick bite or ECM and may mimic many of the classic manifestations of syphilis, multiple sclerosis, brain tumors, or better-known psychiatric disturbances.'4.,~ Steere and Logigian 22 report that most of their patients had symptoms of both an encephalopathy and a polyneuropathy, manifested primarily by memory impairment, distal paresthesias, or radicular pain. However, neuropsychiatric symptomatology may manifest more discretely and without the more characteristic neurological and cardiac findings of the second stage of Lyme disease as in this patient. Of those less characteristic findings, decreased concentration, irritability, emotional lability, and sleep disorders are more usually noted. 11.14.17 These subtle features of delirium, particularly in a patient who displays other neurological signs consistent with a central nervous system infection, or several risk factors consistent with B. burgdorferi infection (such as ECM, antecedent tick bite, other family members affected, or migratory arthralgias) should also alert the consulting physician of the possibility of Lyme disease. The diagnosis of central nervous system Lyme disease may be confirmed by the presence of elevated titers of serum and intrathecal antibodies specific for B. burgdorferi. 14 •1K.2.1 However, Steere and Logigian 22 caution that demonstration of an intrathecal antibody response is an inconsistent finding among patients they have studied with central nervous system abnormalities secondary to Lyme borreliosis. Moreover, other studies have demonstrated considerable interlaboratory (and sometimes intralaboratory) variability in results, potentially invalidating conclusions from a negative serology .19 This suggests that the variability of laboratory findings in patients with Lyme disease requires the physician to rely more heavily on clinical presentation. PSYCHOSOMATICS
Case Reports
Nonetheless. intrathecal antibody determinations are the most specific diagnostic test currently available for central nervous system B. burgdorferi infection. 2.1 Halperin et al. 19 report that in their patient population with intrathecal antibody production to B. burgdorferi. almost all had antibiotic-responsive impairments in cognitive function. suggesting that cerebrospinal fluid examination is important in patients with presumptive Lyme disease and compromised cognitive function on objective testing. Furthermore. prompt treatment with intravenous ceftriaxone is imperative to alleviate the central nervous system manifestations of Lyme disease. including delirium. as in the case presented. Chronic neurologic abnormalities have also been noted months to years after the initial infection with B. burgdorferi. Logigian et al. 24 report that 24 of 27 patients (89%) studied had a mild encephalopathy that began I month to 14 years after the onset of the disease and was characterized by memory loss. mood changes. or sleep disturbance and usually improved with antibiotic therapy. The pathogenesis of parenchymal neurologic abnormalities in acute and chronic B.
burgdorferi infection is less certain. The role of immune complex vasculitis. in which circulating immune complexes resemble the diffuse and multifocal central and peripheral neurologic abnormalities of serum sickness. has been suggested as a potential mechanism and continues to serve as a topic of further study.25 Likewise. the association between misdiagnosis and untimely treatment of B. burgdorferi infection and persistent neuropsychiatric deficits in chronic Lyme disease remains to be determined. Similarly. the incidence of patients with Lyme disease who present initially with more subtle neuropsychiatric symptoms or who were previously misdiagnosed with other neurological "imitators" is unclear. However. one thing is certain: Unexplained neuropsychiatric symptoms. particularly in a patient with known risk factors. should lead to a consideration of Lyme disease in a differential diagnosis. The authors thank Mary McCabe jor her assistance in editing and preparing this manuscript.
References I. Lipowski ZJ: Delirium (acute confusional states). JAMA 1987:258:1789-1792 2. Lipowski ZJ: Transient cognitive disorders (delirium. acute confusional states) in the elderly. Am J Psychiatry 1983; 140: 1426-1436 3. Hodkinson HM: Common Symptoms of Disease in the Elderly. Boston. Blackwell Scientific. 1976 4. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 4th Edition. Revised. Wa~hington. DC. American Psychiatric Association. 1994 5. Murray GB: Confusion. delirium and dementia. in Massachusetts General Hospital Handbook of General Hospital Psychiatry. 3rd Edition. edited by Cassem NH. St. Louis. MO. Mosby- Yearbook. 1991. pp 89-120 6. Weddington WW: The monality of delirium: an underappreciated problem'! Psychosomatics 1982; 23:12321235 7. Adams F: Neuropsychiatric evaluation and treatment of delirium in the critically ill cancer patient. The Cancer Bulletin 1984; 36: 156-160 8. Steere AC, Malawista SE: Cases of Lyme disease in the United States: locations correlated with distribution of Ixodes dammini. Ann Intern Med 1979; 91 :730-733
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9. Steere AC, Malawista SE. Hardin JA. et al: Erythema chronica migrans and Lyme anhritis: the enlarging clinical spectrum. Ann Intern Med 1977; 86:685"'()98 10. Steere AC: Lyme borreliosis. in Principles and Prdctice of Infectious Diseases. 3rd Edition. edited by Mandell GL et al. New York. Churchill-Livingstone. 1990 II. Finkel MF: Lyme disease and its neurologic complications. Arch Neurol 1988; 45:99-104 12. Halperin JJ. Krupp LB. Golightly MG. et al: Lyme borreliosis-associated encephalopathy. Neurology 1990; 40: 1340-1343 13. Steere AC, Broderick TF. Malawista SE: Erythema chronica migrans and Lyme anhritis: epidemiologic evidence for a tick vector. Am J Epidemiol1978; 108:312-321 14. Reik L: Lyme Disease and the Nervous System. New York. Thieme. 1992 15. Reik L. Steere AC. Banenhagen NH. et al: Neurologic abnormalities of Lyme disease. Medicine (Baltimore) 1979;58:281-294 16. Lane KL. Parker JC. Jr: Lyme disease: a confusing muhisystem Borreliosis. South Med J 1989; 82: 1147-1152 17. Pachner AR. Steere AC: The triad of neurologic manifestations of Lyme disease: meningitis. cranial neuritis and
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Case Reports
radiculoneuritis. Neurology 1985; 35:47-53 18. Pachner AR: Neurologic manifestations of Lyme disease. the new "great imitator:' Rev Inf Disease 1989: II (suppl 16): 1482-1486 19. Halperin JJ. Krupp LB. Golightly MG. et al: Lyme borreliosis-associated encephalopathy. Neurology 1990; 40: 1340--1343 20. Bendig JWA. Ogilvie D: Severe encephalopathy associated with Lyme disease. Lancet 1987: March 21 :681-682 21. Folstein MF. Folstein SE. McHugh PR: Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975: 12: 189198
22. Steere AC. Logigian EL: Chronic neurologic manifestations of Iyme disease. N Engl J Med 1991: 324: 1137 23. Steere AC. Berardi VP. Weeks KE. et al: Evaluation of the intrathecal antibody response to Borrelia burgdoiferi as a diagnostic test for Lyme Neuroborreliosis. J Infect Dis 1990; 161:1203-1209 24. Logigian EL. Kaplan RF. Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990: 323:1438-1444 25. Brogan GX. Homan CS. Viccellio P: The enlarging clinical spectrum of Lyme disease: Lyme Cerebral Vasculitis. a new disease entity. Ann Emerg Med 1990; 19:572-576
H2 Blocker Delirium DAWN PICOTTE-PRILLMAYER, M.D. JOSEPH
R.
WALTER
H
DIMAGGIO, M.D.
F.
histamine antagonists are frequently used in the medically ill for stress ulcer prophylaxis. These commonly used drugs include cimetidine, ranitidine, and famotidine. Cimetidine-induced mental status changes have been documented in more than 30 cases. I Although less common, ranitidine has been implicated in several cases of delirium. v Delirium associated with famotidine has been reported only twice. 4 This report describes a case of delirium associated with ranitidine that resolved completely and then recurred with initiation of famotidine therapy. To our knowledge. this represents the only case of delirium that recurred with initiation of an alternate histamine blocker and only the third case of famotidine-induced delirium. 2
Received March 5. 1993; revised May 24. 1993; accepted June 10. 1993. From H. Lee Moffitt Cancer Center & Research Institute. Address correspondence to Dr. Baile. MD Anderson Cancer Center. Box 100. 1515 Holcombe. Houston. TX77030. Copyright © 1995 The Academy of Psychosomatic Medicine.
74
BAILE, M.D.
Pharmacology Ranitidine hydrochloride (Zantac) is a reversible H 2 blocking agent that is a competitive antagonist of histamine-induced gastric acid secretion. It is four to thirteen times more potent than cimetidine in antagonizing pentagastrin-stimulated acid secretion. Like cimetidine, ranitidine acts by inhibiting the volume and concentration of gastric acid induced nocturnally and by food. The oral bioavailability of ranitidine is 50%. Serum protein binding averages 15%. The plasma half-life is approximately 1.7-3.0 hours in adults and is prolonged in geriatric patients and those with impaired renal or hepatic function. Ranitidine undergoes significant first-pass metabolism in the liver after oral administration, and its metabolites are pharmacologically inactive. It is excreted primarily through the urine. Adverse CNS reactions. including malaise. dizziness, somnolence, and headache, occur in less than 3% of patients. Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been reponed. predominantly in PSYCHOSOMATICS
Delirium and Lyme Disease V. CALIENDO, M.D. DONALD 1. KUSHON, M.D. JEAN W. HELZ, M.D.
MARK
D
elirium is often a presenting feature of acute physical illness and has been reported to occur in nearly 10% of all hospitalized patients.1-J As defined by DSM-IV,4 delirium is a cognitive disorder characterized by dysfunction of attention and consciousness, disturbance of the sleep-wake cycle, and altered psychomotor activity. The clinical signs and symptoms of delirium vary widely from a subtle confusional state to one in which severe agitation places the patient at risk for serious self-injury. Nonspecific changes in a patient's mood, thought, and behavior often represent the first and only signs of an undetected medical illness. Therefore, early recognition of delirium and treatment of its underlying cause is essentia1. 1 In addition to delirium's high mortality, if untreated it places the patient at higher risk for the development of residual cognitive impairments and progression ofthe underlying disease process. 5- 7 Lyme disease, which is caused by the tickborne spirochete, Borrelia burgdoiferi, is endemic along the northeastern coast of the United States, from Maryland to Massachusetts, and in parts of Wisconsin, Minnesota, Oregon, and Calg ifornia. The illness usually begins in summer or early fall, 3-21 days after a tick bite (Ixodes dammini, known colloquially as the bear tick or deer tick, in the Northeast and Midwest and Ixodes pacificus in the West) with a characteristic expanding skin lesion, erythema chronica migrans (ECM), accompanied by flu-like or meningitis-like symptoms (stage I). Systemic symptoms (arthralgias, chills, fever, malaise, and fatigue) may accompany the erythema. 9 This phase of the disease may be followed by cranial VOLUME 36' NUMBER I • JANUARY - FEBRUARY 1995
or peripheral neuritis, carditis, or painful radiculitis (stage 2), or by intermittent or chronic arthritis or chronic neurologic or skin abnormalities (stage 3). Cases of Lyme disease are often reported in association with hiking, camping, or hunting trips or among people living in wooded or rural areas, with patients of any age and both sexes being affected. It has been determined recently that more than 1,000 people now acquire the infection in the United States each summer. IO Little has been published in the psychiatric literature regarding Lyme disease, yet a diversity of neuropsychiatric manifestations has been described in patients with known B. burgdoiferi infection, including lethargy, decreased concentration, poor memory, emotional lability, irritability, sleep disturbances, and personality changes, as well as instances of dementia, frank psychoses with auditory hallucinations, and a single episode of an anorexia nervosa-type illness. I I Although some of the clinical phenomena caused by this infection are almost pathognomonic (e.g., heart block in an otherwise healthy adult, bilateral facial palsy, painful radiculitis), others are completely nonspecific. 12 Reports have suggested that the nervous system Received May 20. 1992; revised June 2. 1993; accepted June 10. 1993. From the Depanment of Mental Health Sciences. Division of Consultation and Liaison Psychiatry. Hahnemann University School of Medicine. Address correspondence to Dr. Kushon. Col Psychiatry. Hahnemann University Hospital. Broad and Vine. Philadelphia. PA 19102. Copyright © 1995 The Academy of Psychosomatic Medicine.
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Case Reports
is involved in 15-40% of patients with Lyme disease. '3 .'4 Among patients with neurologic involvement, nearly 40% recall an initial tick bite, while 80% had a preceding ECM. 14.15 Neuropsychiatric symptomatology often appears during the second stage of infection, characteristically dominated by more prominent neurological signs, such as meningitis, radiculitis, and neuritis, often accompanied by cardiologic features, such as cardiac conduction defects and left ventricular dysfunction. I 1.16-18 Clinical presentation may range from severe focal signs to a mild delirium. 11.19 Pachner and Steere J7 concluded that II of their 38 patients (29%) experienced subtle encephalopathic symptoms, including sleep disturbances, difficulty concentrating, poor memory, irritability, and emotional lability. Additionally, they noted that although several patients made mistakes in their mental status testing, none had a definite organic brain syndrome, obtundation, or coma. J7 Moreover, 9 of the II patients had abnormal electroencephalograms (EEGs), demonstrating focal abnormalities, while computerized tomographic (CT) scans of the head done with and without contrast were normal in 8 of these patients. 17 Bendig and Ogilvie 20 previously reported one case of a child with severe delirium associated with positive serology to B. burgdoiferi but without a known preceding tick bite or ECM. Halperin et al. 19 found that cognitive function was impaired on bedside testing of 15 of 30 seropositive patients, with significant cognitive impairment in 4 of 5 patients with intrathecal antibody production to B. burgdorferi. Similarly, Reik et al. 14 reported 4 patients with elevated titers to B. burgdoiferi with signs of delirium, including somnolence, confusion, disorientation, poor memory, impaired calculation and abstraction, decreased attention span, and irritability. We report on a patient who developed a rapidly fluctuating delirium associated with positive serology to B. burgdorferi, without a known preceding tick bite or ECM, persisting several days until responding to antibiotic therapy. This case illustrates that psychiatrists who work in endemic areas need to include Lyme disease in the differential diagnosis of delirium. 70
Case Report A 64-year-old woman, who was previously active and in good health, returned from a trip to Princeton, NJ, in late summer, when she suddenly began to experience tingling paresthesias in her hands and feet along with ascending bilateral leg weakness that progressed to involve her arms. She was admitted to a neurology service 5 days later when the weakness progressed asymmetrically to involve her arms and she lost her ability to ambulate. On admission, she was afebrile and without other specific complaints, although she felt unwell. On neurological examination, she was areflexive and had a profound vibratory loss, bilateral facial palsy, and marked, asymmetrical diffuse weakness. She denied any recent headache or neck pain. At the time of admission, she appeared exhausted but was awake and able to follow commands. She was able to lift her left arm but was unable to lift her other extremities or support her head. A lumbar puncture performed the next day revealed a protein level of 38 mg/dl (normal = 15-45 mg/dl) in the cerebrospinal fluid. The diagnostic impression of the primary service was that she suffered from an acute inflammatory polyradiculoneuropathy [Guillain-Barre Syndrome (GBS)]. The plan was to treat with plasmapheresis. The same evening, however, the patient developed decreasing pulmonary vital capacities and was intubated. Her condition continued to deteriorate; I week later she developed cardiac bundle branch block and supraventricular tachycardia and was unable to receive plasmapheresis, although her pulmonary function returned to normal and she was extubated. A psychiatric consultation was requested on the 13th hospital day regarding a change in mental status. Her husband noted that over the prior 3 days she exhibited a sudden state of confusion that continued to worsen. During this time, she was also noted by her nurse to be confused and agitated at night, yelling at imaginary people. Her mental status examination revealed the patient to be restless, inattentive, requiring questions to be repeated, and maintaining poor eye contact throughout the interview. At times she became agitated but was generally somnolent and had difficulty keeping awake throughout the examination. Her speech rambled and often was incoherent. She appeared irritable and her thought process was disorganized. She also displayed several episodes of echolalia. She appeared to be responding to hallucinations of "angels" appearing outside of PSYCHOSOMATICS
Case Reports
her window. She was disoriented to time and place and her concentration was poor. Her short-term memory was likewise poor, as evidenced by her inability to repeat the names of several unrelated objects after 5 minutes, but her long-term memory was intact. She responded concretely to proverbs and her insight and judgment were deemed poor as she was clearly unable to understand her condition or recognize the need for treatment. Her Mini-Mental State Examination score was 20/30. 11 Laboratory evaluation at the time of our initial consultation revealed body temperature, vital signs, serum electrolytes (Na+, K+, cr, C0 1), blood urea nitrogen, serum creatinine, and blood glucose all to be within normal limits. A complete blood count, prothrombin time, partial thromboplastin time, as well as serum levels of calcium and magnesium were also unremarkable. Plain films of the chest revealed right lower lobe atelectasis, although pulmonary function tests, as well as arterial blood gases-performed at this time to rule out hypoxia as a cause of altered mental status-were normal. In addition, erythrocyte sedimentation rate, monospot test, serum protein electrophoresis, immunoelectrophoresis, test for myelin basic protein, hepatitis screen, heavy metal screen, test for antinuclear antibodies, and gram stain of the cerebrospinal fluid (CSF) yielded no significant findings. Cultures for CSF syphilis, fungus, and acid-fast bacilli did not reveal any microorganisms. Electrocardiogram revealed left bundle branch block unchanged from admission, and echocardiography revealed no findings consistent with a cause of her delirium. Her medications at the time included digoxin and sucralfate but offered no additional etiology for her delirium. An EEG performed in response to her change in mental status revealed an abnormal tracing, including continuous generalized theta and intermittent triphasic delta activity with preserved reactivity and no localizing or epileptiform features, indicative of a moderate diffuse disturbance of cerebral function. A CT scan of the head with IV contrast revealed mild cortical and central atrophy with no evidence of focal abnormality. including cardiovascular accident, recognized. Magnetic resonance imaging of the head was unremarkable. Laboratory studies revealed a positive serum Lyme antibody titer with I: 12 IgG/lgM and 1.2 IgM in serum with 1.1 being the high level of normal (personal correspondence with HUH lab). A repeat lumbar puncture revealed mildly elevated CSF protein and positive IgM Lyme titer in CSF. Reduced ability to maintain attention. disorga-
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nized thinking, reduced level of consciousness, increased psychomotor activity, memory impairment, and perceptual disturbances in the presence of evidence of an organic cause (progressive polyneuropathy and heart block) indicated the organic mental syndrome delirium. The possibility of Lyme disease was raised after the onset of the heart block. History exploring this possibility revealed no preceding tick bite or ECM, but a geographic location, time of year, and clinical features of the illness (e.g., ascending asymmetrical polyradiculopathy. bilateral facial palsy. and heart block) were compatible and treatment with intravenous ceftriaxone was begun. Haloperidol (0.5 mg q 30 min) was given that evening to control agitation but was discontinued due to extrapyramidal effects. The next morning she became lethargic, offering single-word responses, and was oriented to self only. During the evening she appeared more alert, offering immediate responses in a coherent fashion. The following morning she had again become lethargic, opening her eyes only to painful stimuli. neither communicating nor responding to verbal commands. Once again that afternoon she was alert. following commands and communicating freely, although she remained confused and agitated. Her mental state was unchanged and continued to fluctuate throughout the evening and the following day. She began to improve by the 3rd day of treatment. becoming more coherent and attentive. She was now easily awakened and well oriented to self, time, and place but was still intermittently confused. Several days later she remained more alert and coherent. Although still disoriented to her surroundings and confused by her condition, she was no longer agitated. Finally, by the 8th day of treatment, movement in her extremities had improved and she was alert, coherent. and well oriented, with proper insight into her condition and treatment. Her mental state at this time had returned to normal. A repeat EEG the following day revealed no evidence of focal abnormality. The patient gradually regained partial strength in her upper and lower extremities. and the paresthesias and facial dysplegia resolved. She continued to receive intravenous ceftriaxone for a full 30-day course, and her condition upon leaving the hospital was much improved. She exhibited no further symptoms of delirium, although she remained partially weak in her extremities for which she continued to receive physical therapy. We telephoned the patient for follow-up 6 months after discharge. At this time we could assess no deficits of mental status, including orientation,
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concentration, mood, affect, short- and long-term recall, language, and sleep patterns. She was attentive and pleasant upon questioning, offering appropriate responses with good insight and judgment. Moreover, neither the patient nor her husband noticed any changes in her mental status throughout the period following discharge. She also reported full recovery of strength in her extremities and was delighted to have returned to her usual lifestyle.
Discussion The case presented here is a rather dramatic one with acute delirium developing in a patient admitted with a number of neurological and cardiac signs consistent with the second stage of Lyme disease. Despite the relatively characteristic picture of second-stage Lyme disease, this condition is often misdiagnosed, especially in the absence of a history suggestive of Lyme disease (i.e., the occurrence ofECM, an antecedent tick bite, other family members affected, or flu-like illness). Areflexia, profound vibratory loss, and ascending diffuse weakness in a patient with Lyme radiculitis are often reminiscent of GBS. 17 Initially, this patient's illness resembled GBS; however, a subtle differentiation must be made. Lyme disease commonly progresses asymmetrically, as demonstrated in this patient, whereas GBS is generally a symmetric progressive weakness. Furthermore, Lyme disease often causes a painful radiculitis, as in this patient. 17 As mentioned previously, symptoms of bilateral facial palsy and cardiac conduction defects in an otherwise healthy patient, in conjunction with radiculitis, are almost pathognomonic for Lyme disease. '9 Finally, this patient presented in late summer with a history of recent travel to an area where Ixodes tick bites and Lyme disease are endemic. Therefore, despite the lack of an antecedent tick bite or ECM, a geographical location, time of year, ascending asymmetrical polyradiculoneuropathy, bilateral facial palsy, and heart block, combined with positive antibody titers for B. burgdorferi in serum and CSF, should clue the astute consultant to a diagnosis of Lyme disease as a cause for delirium in the patient presented. Diagnosis of Lyme disease was essential in the 72
rapid treatment and alleviation of her delirium. Likewise, it is important to recognize the variety of manifestations of Lyme disease described in the literature. Patients with B. burgdorferi infection may have presentations ranging from a subtle delirium to major neurological features such as meningitis, radiculitis, and neuritis. Often these symptoms occur without knowledge of an antecedent tick bite or ECM and may mimic many of the classic manifestations of syphilis, multiple sclerosis, brain tumors, or better-known psychiatric disturbances.'4.,~ Steere and Logigian 22 report that most of their patients had symptoms of both an encephalopathy and a polyneuropathy, manifested primarily by memory impairment, distal paresthesias, or radicular pain. However, neuropsychiatric symptomatology may manifest more discretely and without the more characteristic neurological and cardiac findings of the second stage of Lyme disease as in this patient. Of those less characteristic findings, decreased concentration, irritability, emotional lability, and sleep disorders are more usually noted. 11.14.17 These subtle features of delirium, particularly in a patient who displays other neurological signs consistent with a central nervous system infection, or several risk factors consistent with B. burgdorferi infection (such as ECM, antecedent tick bite, other family members affected, or migratory arthralgias) should also alert the consulting physician of the possibility of Lyme disease. The diagnosis of central nervous system Lyme disease may be confirmed by the presence of elevated titers of serum and intrathecal antibodies specific for B. burgdorferi. 14 •1K.2.1 However, Steere and Logigian 22 caution that demonstration of an intrathecal antibody response is an inconsistent finding among patients they have studied with central nervous system abnormalities secondary to Lyme borreliosis. Moreover, other studies have demonstrated considerable interlaboratory (and sometimes intralaboratory) variability in results, potentially invalidating conclusions from a negative serology .19 This suggests that the variability of laboratory findings in patients with Lyme disease requires the physician to rely more heavily on clinical presentation. PSYCHOSOMATICS
Case Reports
Nonetheless. intrathecal antibody determinations are the most specific diagnostic test currently available for central nervous system B. burgdorferi infection. 2.1 Halperin et al. 19 report that in their patient population with intrathecal antibody production to B. burgdorferi. almost all had antibiotic-responsive impairments in cognitive function. suggesting that cerebrospinal fluid examination is important in patients with presumptive Lyme disease and compromised cognitive function on objective testing. Furthermore. prompt treatment with intravenous ceftriaxone is imperative to alleviate the central nervous system manifestations of Lyme disease. including delirium. as in the case presented. Chronic neurologic abnormalities have also been noted months to years after the initial infection with B. burgdorferi. Logigian et al. 24 report that 24 of 27 patients (89%) studied had a mild encephalopathy that began I month to 14 years after the onset of the disease and was characterized by memory loss. mood changes. or sleep disturbance and usually improved with antibiotic therapy. The pathogenesis of parenchymal neurologic abnormalities in acute and chronic B.
burgdorferi infection is less certain. The role of immune complex vasculitis. in which circulating immune complexes resemble the diffuse and multifocal central and peripheral neurologic abnormalities of serum sickness. has been suggested as a potential mechanism and continues to serve as a topic of further study.25 Likewise. the association between misdiagnosis and untimely treatment of B. burgdorferi infection and persistent neuropsychiatric deficits in chronic Lyme disease remains to be determined. Similarly. the incidence of patients with Lyme disease who present initially with more subtle neuropsychiatric symptoms or who were previously misdiagnosed with other neurological "imitators" is unclear. However. one thing is certain: Unexplained neuropsychiatric symptoms. particularly in a patient with known risk factors. should lead to a consideration of Lyme disease in a differential diagnosis. The authors thank Mary McCabe jor her assistance in editing and preparing this manuscript.
References I. Lipowski ZJ: Delirium (acute confusional states). JAMA 1987:258:1789-1792 2. Lipowski ZJ: Transient cognitive disorders (delirium. acute confusional states) in the elderly. Am J Psychiatry 1983; 140: 1426-1436 3. Hodkinson HM: Common Symptoms of Disease in the Elderly. Boston. Blackwell Scientific. 1976 4. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 4th Edition. Revised. Wa~hington. DC. American Psychiatric Association. 1994 5. Murray GB: Confusion. delirium and dementia. in Massachusetts General Hospital Handbook of General Hospital Psychiatry. 3rd Edition. edited by Cassem NH. St. Louis. MO. Mosby- Yearbook. 1991. pp 89-120 6. Weddington WW: The monality of delirium: an underappreciated problem'! Psychosomatics 1982; 23:12321235 7. Adams F: Neuropsychiatric evaluation and treatment of delirium in the critically ill cancer patient. The Cancer Bulletin 1984; 36: 156-160 8. Steere AC, Malawista SE: Cases of Lyme disease in the United States: locations correlated with distribution of Ixodes dammini. Ann Intern Med 1979; 91 :730-733
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9. Steere AC, Malawista SE. Hardin JA. et al: Erythema chronica migrans and Lyme anhritis: the enlarging clinical spectrum. Ann Intern Med 1977; 86:685"'()98 10. Steere AC: Lyme borreliosis. in Principles and Prdctice of Infectious Diseases. 3rd Edition. edited by Mandell GL et al. New York. Churchill-Livingstone. 1990 II. Finkel MF: Lyme disease and its neurologic complications. Arch Neurol 1988; 45:99-104 12. Halperin JJ. Krupp LB. Golightly MG. et al: Lyme borreliosis-associated encephalopathy. Neurology 1990; 40: 1340-1343 13. Steere AC, Broderick TF. Malawista SE: Erythema chronica migrans and Lyme anhritis: epidemiologic evidence for a tick vector. Am J Epidemiol1978; 108:312-321 14. Reik L: Lyme Disease and the Nervous System. New York. Thieme. 1992 15. Reik L. Steere AC. Banenhagen NH. et al: Neurologic abnormalities of Lyme disease. Medicine (Baltimore) 1979;58:281-294 16. Lane KL. Parker JC. Jr: Lyme disease: a confusing muhisystem Borreliosis. South Med J 1989; 82: 1147-1152 17. Pachner AR. Steere AC: The triad of neurologic manifestations of Lyme disease: meningitis. cranial neuritis and
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radiculoneuritis. Neurology 1985; 35:47-53 18. Pachner AR: Neurologic manifestations of Lyme disease. the new "great imitator:' Rev Inf Disease 1989: II (suppl 16): 1482-1486 19. Halperin JJ. Krupp LB. Golightly MG. et al: Lyme borreliosis-associated encephalopathy. Neurology 1990; 40: 1340--1343 20. Bendig JWA. Ogilvie D: Severe encephalopathy associated with Lyme disease. Lancet 1987: March 21 :681-682 21. Folstein MF. Folstein SE. McHugh PR: Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975: 12: 189198
22. Steere AC. Logigian EL: Chronic neurologic manifestations of Iyme disease. N Engl J Med 1991: 324: 1137 23. Steere AC. Berardi VP. Weeks KE. et al: Evaluation of the intrathecal antibody response to Borrelia burgdoiferi as a diagnostic test for Lyme Neuroborreliosis. J Infect Dis 1990; 161:1203-1209 24. Logigian EL. Kaplan RF. Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990: 323:1438-1444 25. Brogan GX. Homan CS. Viccellio P: The enlarging clinical spectrum of Lyme disease: Lyme Cerebral Vasculitis. a new disease entity. Ann Emerg Med 1990; 19:572-576
H2 Blocker Delirium DAWN PICOTTE-PRILLMAYER, M.D. JOSEPH
R.
WALTER
H
DIMAGGIO, M.D.
F.
histamine antagonists are frequently used in the medically ill for stress ulcer prophylaxis. These commonly used drugs include cimetidine, ranitidine, and famotidine. Cimetidine-induced mental status changes have been documented in more than 30 cases. I Although less common, ranitidine has been implicated in several cases of delirium. v Delirium associated with famotidine has been reported only twice. 4 This report describes a case of delirium associated with ranitidine that resolved completely and then recurred with initiation of famotidine therapy. To our knowledge. this represents the only case of delirium that recurred with initiation of an alternate histamine blocker and only the third case of famotidine-induced delirium. 2
Received March 5. 1993; revised May 24. 1993; accepted June 10. 1993. From H. Lee Moffitt Cancer Center & Research Institute. Address correspondence to Dr. Baile. MD Anderson Cancer Center. Box 100. 1515 Holcombe. Houston. TX77030. Copyright © 1995 The Academy of Psychosomatic Medicine.
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BAILE, M.D.
Pharmacology Ranitidine hydrochloride (Zantac) is a reversible H 2 blocking agent that is a competitive antagonist of histamine-induced gastric acid secretion. It is four to thirteen times more potent than cimetidine in antagonizing pentagastrin-stimulated acid secretion. Like cimetidine, ranitidine acts by inhibiting the volume and concentration of gastric acid induced nocturnally and by food. The oral bioavailability of ranitidine is 50%. Serum protein binding averages 15%. The plasma half-life is approximately 1.7-3.0 hours in adults and is prolonged in geriatric patients and those with impaired renal or hepatic function. Ranitidine undergoes significant first-pass metabolism in the liver after oral administration, and its metabolites are pharmacologically inactive. It is excreted primarily through the urine. Adverse CNS reactions. including malaise. dizziness, somnolence, and headache, occur in less than 3% of patients. Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been reponed. predominantly in PSYCHOSOMATICS