Brain Pathology Case of the Month - November 1999

FINAL DIAGNOSIS:

Clinical Course

The patient was treated with oral prednisone and her symptoms resolved except for residual facial weakness.

Discussion

The patient developed multiple cranial and limb mononeuropathies. In addition, there were cerebral white matter abnormalities on MR imaging in a pattern suggestive of multiple sclerosis. However, the multiple (peripheral) mononeuropathies are not consistent with multiple sclerosis. Acquired disorders associated with multiple mononeuropathies and cerebral white matter abnormalities include vasculitis, Sjogren's syndrome, Lyme disease, sarcoidosis, cancer (including lymphoma), and viral infections (such as herpesviruses). Despite the lack of systemic features of sarcoidosis, the biopsy findings are characteristic of neurosarcoidosis.

The prevalence of sarcoidosis is 3 per 100,000 in North American whites and 47 per 100,000 in African Americans. In Europe, the prevalence is 10-53 per 100,000 with whites more commonly affected.3 The disorder usually presents between 20-40 years of age or thereafter and is more common in women. "Isolated" neurosarcoidosis tends to present later. Clinical courses may be acute, subacute, and intermittent.

As in our patient, neurologic features, which occur in 5-14% of patients with sarcoidosis, can be the only and presenting manifestation. In fact, half of the patients with neurologic involvement have no other organs affected at the time of presentation.6,10 Often, other organs (especially lung), become involved. In fact, of all patients with sarcoidosis, ninety percent have pulmonary involvement with lymphadenopathy detected by chest X-ray, CT scan, or Gallium scan.1,3,5,9 Of the neurologic features, cranial neuropathies, especially of CN VII and VIII and less often II and others, are common. Patients may also have pituitary and hypothalamic dysfunction, meningitis, hydrocephalus, seizures, and mass lesions in the brain or spinal cord.2 Associated white matter signal changes on MR scanning may occur.1 Peripheral neuropathy occurs in about 8.5% of patients with neurosarcoidosis.12 Mononeuropathies with or without vasculitis, polyradiculopathies, and diffuse sensorimotor polyneuropathies that may or may not simulate Guillain-Barre Syndrome may be present. Symptomatic myopathy sometimes occurs, but asymptomatic muscle granulomas are more common.

Diagnostic findings are variable. The cerebrospinal fluid (CSF) reveals a mild mononuclear pleocytosis and a mild elevation in protein in 50-70% of patients. Eighteen percent have a low glucose. The CSF ACE is elevated in 50%, but this finding is non-specific. Increased IgG synthesis and oligoclonal bands are present in about 50% as in our patient.7 Serologic laboratory abnormalities may be absent. When present, they include lymphocytopenia, hyperglobulinemia, elevated erythrocyte sedimentation rate, hypercalcemia (rare), and elevated serum ACE (65%). The Kveim-Siltzbach antigen is not readily available and in not always productive of a skin reaction. Ultimately, diagnosis usually rests upon identification of granulomas is the affected tissue in the appropriate setting.1,5

Indeed, the pathologic hallmark is the non-caseating granuolma with T-cells and epithelioid histiocytes which secrete cytokines and ACE.9 The autoimmune response is due to an undefined antigenic trigger. The various types of nervous system dysfunction may be due to effects of cytokines and, in some instances, vasculitis. Mass effect from granulomas may play a role. In peripheral nerve, granulomas may occur in and potentially injure the endoneurial components, but they usually occur in the epineurium or perineurium adjacent to blood vessels.4,11 In our patient, the multiple mononeuropathies may have been due to vasculitis, but we did not identify accompanying nerve infarction in the biopsy specimen.

Most (90%) with neurosarcoidosis improve with corticosteroid therapy. Alternative therapies have not been well-studied and include hydroxychloroquine, cyclosporin, azathioprine, and methotrexate.7,8,10 The prognosis is good, but relapses may occur.

References

  1. Chapelon C, Ziza JM, Piette JC, et al. Neurosarcoidosis: Signs, course and treatment in 35 confirmed cases. Medicine 1990; 69:261-276.
  2. Delaney P. Neurologic manifestations of sarcoidosis. Review of the literature, with a report of 23 cases. Ann Int Med 1977;87:336-345.
  3. Muller-Quernheim J. Sarcoidosis: clinical manifestations, staging and therapy (part II). Resp Med 1998;92:140-149.
  4. Nemni R, Galassi G, Cohen M, et al. Symmetric sarcoid polyneuropathy: Analysis of a sural nerve biopsy. Neurology 1981;31:1217-1223.
  5. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997;17:1224-1234.
  6. Oskanen V. Neurosarcoidosis: clinical presentations and course in 50 patients. Acta Neurol Scand 1986;73:283-290.
  7. Scott TF. Neurosarcoidosis: Progress and clinical aspects. Neurology 1993;43:8-12.
  8. Sharma OM. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement. Arch Neurol 1998;55:1248-1254.
  9. Sheffield EA. Pathology of sarcoidosis. Clinics in Chest Med 1997;18:741-754.
  10. Stern BJ, Krumholz, Johns C, et al. Sarcoidosis and its neurological manifestations. Arch Neurol 1985;42:909-917.
  11. Vital C, Aubertin J, Ragnault JM, Amigues H, et al. Sarcoidosis of peripheral nerve: A histological and ultrastructural study of two cases. Acta Neuropathol 1982;58:111-114.
  12. Zuniga G, Ropper AH, Frank J. Sarcoid peripheral neuropathy. Neurology 1991; 41:1558- 1561.

Contributed by David Lacomis, M.D and Rock A. Heyman, M.D

International Society of Neuropathology