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J Neurol (2001) 248:522–524 © Steinkopff Verlag 2001

Eva Schielke Christian Nolte Wolf Müller Wolfgang Brück

Sarcoidosis presenting as rapidly progressive dementia: clinical and neuropathological evaluation

JON 450

Received: 6 March 2000 Received in revised form: 28 November 2000 Accepted: 27 December 2000

Sirs: Sarcoidosis is a multisystemic granulomatous disease of unknown aetiology. In approximately 5 % of patients neurological involvement is found, but dementia as the presenting manifestation is rare. A 63-year-old man was admitted to our hospital with an 8-month history of progressive cognitive impairment, involuntary weight loss and recent complaints of headache. He was awake and orientated but apathetic and markedly slowed, showing verbal perseveration and constructive apraxia. Attention and immediate memory were markedly impaired, as were spontaneity and fluency of speech. During his stay he developed a paranoid-hallucinatory episode which resolved with haloperidol. Neurological examination revealed paratonic rigidity, grasping reflex, motor perseveration and a bilateral postural and action tremor. He was of normal weight and body temperature was 37.5 °C. Magnetic resonance imaging (MRI) of the brain revealed diffuse non-enhancing periventricular and frontal white matter lesions. Cerebrospinal fluid (CSF) showed 293 WBC per mm3, elevated protein (4380 mg/l), intrathecal synthesis of


immunoglobulin A and M, and elevated angiotensin converting enzyme (ACE). Computerized tomography of thorax and abdomen demonstrated numerous enlarged lymph nodes. The tuberculin skin test was positive, but M. tuberculosis was not found in CSF, sputum, gastric juice or urine. Open frontal brain biopsy revealed an inflammatory central nervous system (CNS) lesion within the grey and white matter. The inflammatory infiltrates consisted of non-necrotizing granulomas composed of lymphocytes, epitheloid histiocytes and giant cells which were located in the perivascular space and within the parenchyma (Fig. 1). Vessel walls were not infiltrated. Immunocytochemistry showed CD3-positive T cells dominating the lymphocytic infiltrate. There were also numerous CD68 positive macrophages present within the granulomas. Within the meningeal biopsy specimen, granulomas or inflammatory infiltrates were not observed. Neither fungi nor mycobacteria could be detected.

Thus, diagnosis of neurosarcoidosis was confirmed and prednisolone treatment was started. Within two weeks the patient’s condition dramatically improved. He remained slightly facetious but was fully able to look after himself. CSF examination showed a decrease of the white blood cell count to 122/mm3 and of protein to 1720 mg/l. More than one year later, he still is doing well with a daily maintenance therapy of 20 mg prednisolone. Abnormal mental states have been reported with a frequency of 0–26 % in neurosarcoidosis and may be caused by parenchymal inflammation, hypercalcaemia or increased intracranial pressure due to space-occupying granulomas [1, 9, 13, 15]. Dementia as the presenting manifestation of sarcoidosis, however, is rare. Table 1 summarizes the cases reported so far. Notably, seven of the twelve reviewed patients were older than 50 years, whereas the median age at onset of sarcoidosis is about 35 years. Periventricular and multifocal non-enhancing white matter le-

Fig. 1 Typical intracerebral non-necrotizing granuloma with lymphocytes, multinucleated giant cells and epitheloid cells characteristic for sarcoidosis. The granuloma is located within the cerebral subcortical white matter (H&E stain, x40).


Tab. 1 Dementia as the presenting manifestation of sarcoidosis – review of the literature Authors


age (years)

confirmation of diagnosis

cranial CT/MRI

CSF protein (mg/l)

CSF WBC other (per mm3) manifestations

treatment/ outcome

Mehraein & Jamada 19676



post mortem histology

not available




Hahn 19713



not available



Cordingley et al 19812



clinical features liver biopsy post mortem histology

markedly elevateda 1250

steroids/ improved nil/died

Hier et al 19834



Mitchell et al 198514


Scully et al 199011




post mortem histology

CT: mild ventricular enlargement with periventricular contrast enhancement CT: normal



nil/died nil/died


clinical features

not reported





mediastinal lymph node biopsy brain biopsy



Sommer et al 199112



clinical features

markedly elevatedb


spastic tetraparesis, diabetes insipidus

steroids/ improved

Mendez & Zander 19927



brain biopsy

not done

not done none

steroids/ improved

Vanhoof et al 199214



clinical features bronchial biopsy nasal mucosa biopsy



loss of visual fields, hypopituitarism

steroids/ improved

Sanson et al 199610



post mortem histology



peripheral neuropathy


present case



brain biopsy

MRI: periventricular white matter lesions, moderate ventricular enlargement MRI: multiple enhancing granulomas at the base of the brain MRI: dural enhancing lesion over frontal convexities MRI: periventricular frontotemporal white matter lesions, enhancing granulomas at the base of the brain CT: multiple white matter hypodensities, ventricular enlargement, no enhancement MRI: multiple whitematter lesions, no enhancement

dysarthria, hypopituitarism bilat VIth nerve palsy, hemiparesis gait ataxia




steroids/ improved

nil/slowly worsenedc

a CSF protein concentration was measured in so called Kafka units and was 3,8 which is approximately 3 times beyond the normal range b

CSF total protein concentration is not reported, but albumin was elevated with defaults between 862 and1250 mg/l

c The authors considered to start steroid treatment in their discussion but did not report on the patient’s further course.

sions are the most common MRI pattern of neurosarcoidosis, followed by leptomeningeal contrast enhancement. Brain MRI may be normal in about 20 % of patients with clinical evidence of CNS sarcoidosis [1, 5, 15]. CSF examination reveals raised protein level and/or pleocytosis in 60–80 % of patients with neurosarcoidosis [9, 13, 15]. CSF levels of angiotensin converting enzyme (ACE) are elevated in 33 to 58 % [9, 15]. However, this is not specific for sarcoidosis and can be detected in several other CNS diseases. A definite diagnosis of cerebral sarcoidosis should be established only with positive histology and

the exclusion of other granulomatous diseases. The most important differential diagnosis is CNS tuberculosis. Corticosteroids are the cornerstone of therapy for neurosarcoidosis, and improvement was achieved in the vast majority of reported patients with dementia whereas nearly all of those who did not receive therapy had a fatal course [2, 3, 4, 6, 7, 8, 10, 11, 12, 14]. However, steroid treatment would be devastating if CNS tuberculosis was missed. We therefore emphasize the importance of brain biopsy to confirm cerebral sarcoidosis early in the course of disease.

■ Acknowledgements The authors wish to thank Professor Hans Förstl, Dept. of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität, Munich, for helpful review, and Dr. Katrin Wetzel, Dept. of Neurology, Charité University Hospital, Berlin, for neuropsychological assessment.

References 1. Christoforidis GA, Spickler EM, Recio MV, Mehta BM (1999) MR of CNS sarcoidosis: correlation of imaging features to clinical symptoms and response to treatment. AJNR 20: 655–669 2. Cordingley G, Navarro C, Brust JC, Healton EB (1981) Sarcoidosis presenting as senile dementia. Neurology 31: 1148–1151 3. Hahn R (1971) Unusual forms of sarcoidosis. South Med J 64: 541–545


4. Hier DB, Thomas C, Shindler AG (1983) A case of subcortical dementia due to sarcoidosis of the hypothalamus and fornices. Brain Cogn 2: 189–198 5. Lexa FJ, Grossmann RI (1994) MR of sarcoidosis in the head and spine: spectrum of manifestations and radiographic response to steroid therapy. AJNR 15: 973–982 6. Mehraein P, Jamada M (1967) Amnestisches Syndrom bei einem Fall mit isolierter cerebraler BesnierBoeck-Schaumannscher Erkrankung. Arch Psychiatr Z Neurol 210: 89–96 7. Mendez MF, Zander B (1992) Frontal lobe dysfunction from meningeal sarcoidosis. Psychosomatics 33: 215–217 8. Mitchell JD, Yap PL, Milne LA, Lachmann PJ, Pentland B (1985) Immunological studies on the cerebrospinal fluid in neurological sarcoidosis. J Neuroimmunol 7: 249–253

9. Oksanen V (1986) Neurosarcoidosis: clinical presentations and course in 50 patients. Acta Neurol Scand 73: 283–290 10. Sanson M, Duyckaerts C, Thibault JL, Delattre JY (1996) Sarcoidosis presenting as late-onset dementia. J Neurol 243: 484–487 11. Scully RE, Mark EJ, McNeely WF, McNeely BU (1990) Case records of the Massachusetts General Hospital. Case 6–1990. N Engl J Med 322: 388–396 12. Sommer N, Weller M, Petersen D, Wiethölter H, Dichgans J (1991) Neurosarcoidosis without systemic sarcoidosis. Eur Arch Psychiatry Clin Neurosci 240: 334–338 13. Stern BJ, Krumholz A, Johns C, Scott P, Nissim J (1985) Sarcoidosis and its neurological manifestations. Arch Neurol 42: 909–917 14. Vanhoof J, Wilms G, Bouillon R (1992) Hypothalamic hypopituitarism with hyperphagia and subacute dementia due to neurosarcoidosis: case report and literature review. Acta Clin Belg 47: 319–328

15. Zajicek JP, Scolding NJ, Foster O, Rovaris M, Evanson J, Moseley IF, Scadding JW, Thompson EJ, Chamoun V, Miller DH, McDonald WI, Mitchell D (1999) Central nervous system sarcoidosis – diagnosis and management. Q J Med 92: 103–117 Dr. med. E. Schielke () · C. Nolte Department of Neurology Charité University Hospital Campus Charité Mitte Humboldt-University Schumannstr. 20/21 10117 Berlin, Germany Tel.: +49-30-28 02-32 85 Fax: +49-30-28 02-50 47 e-mail:[email protected] W. Müller · W. Brück Department of Neuropathology Charité University Hospital Campus Virchow-Klinikum Humboldt-University Augustenburger Platz 1 13353 Berlin, Germany

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