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Clinical Case Conference   |    
Neurosarcoidosis as a Cause of Refractory Psychosis: A Complicated Case Report
Joseph R. Bona, M.D., M.B.A.; Sondralyn M. Fackler, M.D.; Morris J. Fendley; Charles B. Nemeroff, M.D., Ph.D.
Am J Psychiatry 1998;155:1106-1108.

This report describes the psychiatric presentation and clinical course of a man who was eventually diagnosed with neurosarcoidosis. He presented with a past history of depressive symptoms and intermittent psychosis. His previous psychiatric diagnoses included schizophrenia, schizoaffective disorder, and dementia. He had been hospitalized numerous times before the establishment of his diagnosis, with multiple unsuccessful attempts at psychiatric management of symptoms that included hallucinations, disorganization, and confusion.

Sarcoidosis is a rare disorder (10.9–35.5 cases per 100,000) and involves the central nervous system (CNS) in approximately 5% of cases. In addition to neurologic signs and symptoms, psychiatric presentations of neurosarcoidosis may include symptoms of delirium, dementia, depression, personality changes, and psychosis. Because CNS sarcoidosis is a treatable disease that may present with psychiatric symptoms, it is important that mental health professionals become aware of the neuropsychiatric manifestations of this disease. The complexity of this illness and difficulties in differential diagnosis are described in this report.

Mr. A, a 36-year-old African American man, presented to Emory University Hospital with a 9-year history of multiple psychiatric admissions to his local community hospital that began with an amitriptyline overdose attempt in 1987. Over the subsequent 6 years, Mr. A was diagnosed with and treated for a number of psychiatric disorders including major depression, substance abuse, and "bizarre behavior." In 1993, Mr. A presented with a new onset of psychotic symptoms that included auditory and visual hallucinations, disorganized thoughts, and combative and sexually inappropriate behavior. Medical workup at that time did not reveal a clear causative organic etiology; results of brain computed tomography (CT), EEG, and serum chemistries were reported as normal. Chest radiograph revealed a "chronic pulmonary disease pattern" without other abnormalities. Mr. A was treated by community physicians with a high-potency antipsychotic for a presumptive diagnosis of schizophrenia.

Later that year, Mr. A was readmitted to a community hospital with similar symptoms. A more extensive workup was performed, including head magnetic resonance imaging (MRI) and lumbar puncture. The MRI revealed "diffuse meningeal and perivascular enhancement," while the lumbar puncture revealed increased cellularity and protein. Results were within normal limits for all remaining tests (i.e., CBC, SMA-18, VDRL, antinuclear antibody titer, thyroid panel, thyroid-stimulating hormone, angiotensin converting enzyme level, cardiolipin antibodies, HIV, rheumatoid factor, and lupus anticoagulant). An extensive differential diagnosis was considered at that time, including neurosarcoidosis; however, Mr. A was again discharged with a presumptive diagnosis of schizophrenia and "rule out CNS problem." Treatment with high-potency antipsychotic drugs was continued.

Mr. A was followed by his outpatient psychiatrist over the next 2 years and managed symptomatically until he was again readmitted to the inpatient service of the local community hospital because of exacerbation of bizarre and disorganized behavior. These behaviors included wandering from home, disorientation, agitation, combativeness, and inappropriate, public urination. Continued diagnostic workup and psychopharmacological management at Mr. A's community hospital failed to provide any novel information or significant relief. Repeat lumbar puncture and brain MRI (with and without gadolinium contrast) revealed no new findings. Chest radiograph did reveal "questionable hilar adenopathy" consistent with previous findings dating as far back as 1989, and chest CT showed "prominent hilar structures bilaterally." An extensive neurologic and psychiatric differential diagnosis was entertained during the patient's complicated, month-long hospitalization. Brief trials of traditional doses of oral and intravenous glucocorticosteroids were attempted, without noticeable improvement. In addition, numerous psychopharmacological interventions were tried alone and in combination, with little positive, therapeutic response. Ultimately, Mr. A's symptoms appeared controlled with haloperidol, and he was discharged from the regional hospital with a working diagnosis of "probable organic brain disorder with psychotic features—etiology undetermined."

Mr. A's psychiatrist struggled over the next 2 years to help Mr. A maintain outpatient stability, as his symptoms worsened. Mr. A's family was resistant to more invasive or aggressive treatment alternatives. However, after three subsequent short community hospital inpatient stays for symptom stabilization, the family agreed to transfer Mr. A to the Emory University Hospital Neurology Service for further evaluation. Consultations were obtained from both the Pulmonary Service and the Psychiatry Consultation-Liaison Service. An open-lung biopsy was performed, and histopathology revealed noncaseating granulomas. Repeat MRI of the brain, with and without contrast, revealed diffuse abnormal leptomeningeal enhancement. Given Mr. A's history, previous workup, and current findings, a diagnosis of neurosarcoidosis was supported, and a course of high-dose steroids was initiated. At the recommendation of the Psychiatry Consultation-Liaison Service, Mr. A was transferred to the Emory University Hospital Medical-Psychiatric Inpatient Unit for further treatment of his neuropsychiatric symptoms.

At the time of his transfer to the Inpatient Psychiatric Service, Mr. A presented with acute symptoms that included disorganized thought processes, auditory and visual hallucinations, paranoid ideation, delusions, and bizarre behaviors. These symptoms represented a 4-year exacerbation that was previously treated without success and included diagnoses of refractory depression, schizophrenia, schizoaffective disorder, presenile dementia, mixed substance abuse (with positive urine toxicology screens for marijuana and cocaine), and mixed personality disorder.

Although the diagnosis of neurosarcoidosis had been made and Mr. A was treated with relatively high-dose glucocorticoids (prednisone, 60 mg daily) for 4 days, his behavioral symptoms remained largely unchanged. He was intermittently agitated, threatening, bizarre, and paranoid. He was noted to be pacing the hallways at night, checking doors and laughing inappropriately. At the time of transfer to the medical psychiatry unit, Mr. A was treated with the previously noted medications, as well as with divalproex sodium (500 mg in the morning and 1000 mg at bedtime). Olanzapine, which had been initiated by the psychiatric consultation service, was increased in dose to 10 mg every morning and 20 mg at bedtime. Both olanzapine and divalproex were administered in divided doses in an attempt to reduce Mr. A's flagrant agitation and psychosis. Mr. A also required haloperidol, on an as-needed basis (4 mg, up to three times per day), for management of acute agitation. Repeated initial attempts to taper the haloperidol yielded escalation of bizarre behaviors, with agitation and insomnia. On several occasions, physical restraint was required in order to control Mr. A's threatening and wandering behaviors.

Over the course of 7 days, Mr. A began to respond to the psychopharmacological regimen of prednisone, olanzapine, valproate, and haloperidol. He seemed to be more alert, oriented, and appropriately responsive to peers and staff. He was noted to quietly tolerate group and milieu therapy while occasionally participating appropriately. Individual supportive therapy also seemed useful with Mr. A's increasing self- and environmental awareness. Haloperidol was gradually tapered without adverse effect. Mr. A's thought processes and behaviors continued to improve. His sleep, energy, mood, and appetite all normalized as well.

In coordination with the neurology consultation team, Mr. A's outpatient community psychiatrist, and his family, it was decided that discharge from the hospital was appropriate. To reflect the diagnostic evaluation, his final discharge diagnosis was changed to psychotic disorder secondary to a general medical condition (neurosarcoidosis) with hallucinations. His outpatient medications included prednisone, 60 mg/day, olanzapine, 10 mg p.o. every morning and 20 mg p.o. every day at bedtime, and divalproex sodium, 500 mg every morning and 1000 mg every day at bedtime. Mr. A returned home to his family with arranged aftercare.

Ten-week follow-up with Mr. A, his family, and his outpatient psychiatrist and neurologist indicated that he continued to improve without any further episodes. No further medication changes were made.

This case illustrates the complex clinical presentation of psychotic symptoms in a patient with a past history of depression and substance abuse and a strong family history suggestive of a thought disorder. The patient subsequently had a several-year history of psychiatric illness associated with multiple hospitalizations and misdiagnoses before a definite diagnosis of neurosarcoidosis. Neurosarcoidosis is one of the many medical illnesses that may present with psychiatric symptoms requiring an aggressive and persistent search for organic etiologies when clinical suspicion conflicts with normal results on medical evaluation.

Sarcoidosis is a systemic disease of unknown etiology that is characterized pathologically by the presence of noncaseating granulomas (R1558201). The diverse manifestations of the disorder contribute to the hypothesis that sarcoidosis has more than one cause. Some of the multiple posited etiologies include infectious, environmental, genetic, and immunologic causes (R1558202). The prevalence of sarcoidosis is 10.9 cases per 100,000 lives in the Caucasian population and 35.5 cases per 100,000 lives in African Americans. For reasons that remain obscure, African Americans seem more acutely and severely affected than other ethnic groups (R1558203). Neurosarcoidosis is found in only 5% of patients with sarcoidosis, and only half of these patients will present with neurologic symptoms (R1558204). The most frequent neurologic manifestations of sarcoidosis involve cranial nerve neuropathies; peripheral seventh nerve palsy is the single most common cranial nerve abnormality. Other neurologic manifestations of this disease include aseptic meningitis, hydrocephalus, myopathy, peripheral neuropathy, CNS parenchymatous disease, and seizures (R1558205).

Psychiatric disease is a relatively rare presentation of neurosarcoidosis. Of the 5% of sarcoid patients who develop neurosarcoidosis, up to 20% will display psychiatric symptoms (R1558206). Reports of CNS sarcoidosis have described mental status changes associated with delirium or dementia and a diversity of psychiatric symptoms that includes hallucinations, delusions, euphoria, depressive personality changes, aggressiveness, apathy, and cognitive deficits (R1558207).

Neurosarcoidosis should be suspected in patients with neurologic or psychiatric symptoms or both and with previous diagnoses of sarcoidosis, as well as in symptomatic patients with abnormal results on radiologic or laboratory studies consistent with this diagnosis. Diagnosis is based on the clinical or radiographic picture of sarcoidosis with histological evidence of noncaseating granulomas (R1558208). Chest radiograph is abnormal in over 90% of patients and represents the first tool in the differential diagnosis of sarcoidosis. Serum angiotensin converting enzyme levels, a gallium 67 lung scan, bronchoalveolar lavage, and chest MRI may be of help in supporting the diagnosis. However, sarcoidosis remains a diagnosis of exclusion in the absence of a known causative agent (R1558203). A head MRI scan with contrast is the most sensitive radiologic procedure for suspected CNS involvement; a CT scan is only slightly less sensitive (R1558209). Results of CSF examination are normal in patients with localized space-occupying lesions; elevated protein levels, pleocytosis, and increased spinal pressure have been reported in approximately half of patients with meningitis, peripheral nerve palsies, and cranial nerve palsies (R1558208).

Oral corticosteroids, with or without immunosuppressive drugs, remain the treatment of choice for neurosarcoidosis. Steroids work to suppress the cellular immune and inflammatory processes that are believed to cause organ dysfunction in the affected areas. Doses of prednisone range from 40 to 80 mg/day, and treatment may continue for periods of 8 to 12 weeks with a gradual taper over several months (R1558208). Most patients respond to treatment and are able to tolerate steroid withdrawal over several months. Approximately one-third will relapse, however, and may require low-dose glucocorticoid maintenance therapy between exacerbations. There is evidence to suggest that disease limited to the cranial and peripheral nerves may have a more favorable response to glucocorticoids, whereas patients with intracranial neurosarcoidosis may have a more malignant course and higher rate of relapse (R1558204, R15582010).

In summary, it is important to consider the diagnosis of neurosarcoidosis in a patient with a known diagnosis of sarcoidosis who develops new neurologic or psychiatric symptoms or in a patient with refractory psychosis without established sarcoidosis in whom an organic etiology is suspected. Despite the relatively rare presentation of this disease, it is essential that clinicians consider this diagnosis in tertiary-care psychiatric settings.

Received Feb. 3, 1998; revision received May 7, 1998; accepted May 18, 1998. From the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine. Address reprint requests to Dr. Nemeroff, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Dr., Atlanta, GA 30322.

Stern BJ, Schonfeld SA, Sewell C, Krumholz A, Scott P, Belendiuk G: The treatment of neurosarcoidosis with cyclosporine. Arch Neurol  1992; 49:1065–1072
[PubMed]
 
Stoudemire A, Linfors E, Houpt JL: Central nervous system sarcoidosis. Gen Hosp Psychiatry  1983; 5:129–132
[PubMed]
[CrossRef]
 
Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med  1997; 336:1224–1234
[PubMed]
[CrossRef]
 
Scott TR: Neurosarcoidosis: progress and clinical aspects. Neurology  1993; 43:8–12
[PubMed]
 
Stern BJ, Krumholz A, Johns C, Scott P, Nissim J: Sarcoidosis and its neurological manifestations. Arch Neurol  1985; 42:909–917
[PubMed]
 
O'Brien GM, Baughman RP, Broderick JP, Arnold L, Lower EE: Paranoid psychosis due to neurosarcoidosis. Sarcoidosis  1994; 11:34–36
[PubMed]
 
Sabaawi M, Gutierrez-Nunez J, Fragala MR: Neurosarcoidosis presenting as schizophreniform disorder. Int J Psychiatry Med  1992; 223:269–274
 
Sharma OP, Sharma AM: Sarcoidosis of the nervous system. Arch Intern Med  1991; 151:1317–1321
[PubMed]
[CrossRef]
 
Miller DH, Kendall BE, Barter S, Johnson G, MacManus DG, Logsdail SJ, Ormerod IE, McDonald WI: Magnetic resonance imaging in central nervous system sarcoidosis. Neurology  1988; 38:378–383
[PubMed]
 
Luke RA, Stern BJ, Krumholz A, Johns CJ: Neurosarcoidosis: the long-term clinical course. Neurology  1987; 37:461–463
[PubMed]
 
+

References

Stern BJ, Schonfeld SA, Sewell C, Krumholz A, Scott P, Belendiuk G: The treatment of neurosarcoidosis with cyclosporine. Arch Neurol  1992; 49:1065–1072
[PubMed]
 
Stoudemire A, Linfors E, Houpt JL: Central nervous system sarcoidosis. Gen Hosp Psychiatry  1983; 5:129–132
[PubMed]
[CrossRef]
 
Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med  1997; 336:1224–1234
[PubMed]
[CrossRef]
 
Scott TR: Neurosarcoidosis: progress and clinical aspects. Neurology  1993; 43:8–12
[PubMed]
 
Stern BJ, Krumholz A, Johns C, Scott P, Nissim J: Sarcoidosis and its neurological manifestations. Arch Neurol  1985; 42:909–917
[PubMed]
 
O'Brien GM, Baughman RP, Broderick JP, Arnold L, Lower EE: Paranoid psychosis due to neurosarcoidosis. Sarcoidosis  1994; 11:34–36
[PubMed]
 
Sabaawi M, Gutierrez-Nunez J, Fragala MR: Neurosarcoidosis presenting as schizophreniform disorder. Int J Psychiatry Med  1992; 223:269–274
 
Sharma OP, Sharma AM: Sarcoidosis of the nervous system. Arch Intern Med  1991; 151:1317–1321
[PubMed]
[CrossRef]
 
Miller DH, Kendall BE, Barter S, Johnson G, MacManus DG, Logsdail SJ, Ormerod IE, McDonald WI: Magnetic resonance imaging in central nervous system sarcoidosis. Neurology  1988; 38:378–383
[PubMed]
 
Luke RA, Stern BJ, Krumholz A, Johns CJ: Neurosarcoidosis: the long-term clinical course. Neurology  1987; 37:461–463
[PubMed]
 
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