If a patient after midlife presents with a progressive disorder of the central and peripheral nervous system of unknown origin, an APBD should be suspected. In our experience, although sural nerve biopsy is reliable in APBD [ 3 , 61, an axilla skin biopsy is preferable because it is more comfortable for the patient and is less complicated to perform.

We are grateful to Mrs M. W. Janssen-van Kempen for technical assistance, and to the staff of both the Department of Pathology of the Canisius-Wiihelmina Hospital and the Institute of Pathology of the University Hospital Nijmegen for taking the axilla skins at autopsy.

References 1. Suzuki K, David E, Kutschman B. Presenile dementia with “Lafora-like” intraneuronal inclusions. Arch Neurol 197 1; 25169-80 2. Peress NS, DiMauro S. Roxburg V. Adult polysaccharidosis: clinicopathological, ultrastructural and biochemical features. Arch Neurol 1979;36:840-845 3. Robitaille Y ,Carpenter S, Karpati G, DiMauro S. A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes: a report of four cases and a review of the occurrence o i polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing. Brain 1980;103:315-336 4. Stam FC, Wigboldus JM, Bots GThAM. Presenile dementia: a form of Lafora disease. J Am Geriatr Soc 1980;28:237-240 5. Okan~otoK, Llena JF, Hirano A. A type of adult polyglucosan body disease. Acta Neuropathol 1982;58:73-77 6. Vos AJIM, Joosten LAG, Gabreek-Festen AAWM. Adult polyglucosan body disease: clinical and nerve biopsy findings in two cases. Ann Neurol 1983;13:440-444 7. Cafferty MS, Hays A, DiMauro S, et al. Adult polyglucosan body disease. Muscle Nerve 1986;59:134 (Abstract) 8. Taboada E, Suzuki K, Traugott U, et al. Adult polyglucosan body disease. X. International Congress of Neuropathology, Stockholm, 1986. Stockholm: GOTAB, 1986:392 (Abstract) 9. Gray F, Gherardi R, Marshall A, et al. Adult polyglucosan body disease (APBD). J Neuropathol Exp Neurol 1088;47:459-474 10. Karpati G, Carpenter S. The clinical spectrum of adult polyglucosan body disease. Neurology 1983;33(suppl2):246(Abstract) 11. Busard HLSM, Gabreels-Festen AAWM, Renier WO, et al. Axilla skin biopsy: a reliable test for the diagnosis of Lafora’s disease. Ann Neurol 1987;21:599-601 12. Bemsen RAJAM, Busard HLSM, Ter Laak HJ, et al. Polyglucosan bodies in intramuscular motor nerves. Acta Neuropathol 1989;77:629-633 13. Busard HLSM, Gabreels-Festen AAWM, van ’t Hof MA, et al. Polyglucosan bodies in sural nerve biopsies. Acta Neuropathol 1990;80:554-5 5 7 14. A n d AP, Herrlinger H, Blinzinger K, Kronski D. Intraneuritic corpora amylacea:demonstration in orbital cortex of elderly subjects by means of early postmortem brain sampling and electron microscopy. Virchows Arch [A] 1974;364:297-301 15. Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology 1981;31:1564-1568 16. Weis J, Schroder JM. Adult polyglucosan body myopathy with subclinicalperipheral neuropathy: case report and review of diseases associated with polyglucosan body accumulation. Clin Neuropathol 1988;6:27 1-279

Cranial Newopathy Associated with Primary Amyloidosis Ann E. Traynor, MD, Morie A. Gertz, MD, and Robert A. Kyle, MD

We report 6 patients for whom cranial neuropathy was a major manifestation of primary amyloidosis, In 3 of the 6, multiple cranial nerves were involved. All had tissue biopsy documentation of amyloidosis. In 2, nerve biopsy also confirmed amyloidosis. All had renal involvement manifested by proteinuria. Primary systemic amyloidosis must be considered in the differential diagnosis of cranial neuropathy, especially when proteinuria is present. Traynor AE, Gertz MA, Kyle RA. Cranial neuropathy associated with primary amyloidosis. Ann Neurol 1991;29:451-454

Neurological involvement in primary amyloidosis (AL) is characterized by a sensorimotor peripheral neuropathy with prominent autonomic features. Peripheral neuropathy can also be seen in familial amyloidosis (AF). One key feature distinguishing the neuropathy associated with AL from that associated with AF has been the absence of cranial neuropathy in AL. Review [I) of 31 patients with peripheral neuropathy associated with primary amyloidosis revealed one patient with anosmia as the sole manifestation of cranial neuropathy. We reviewed our experience with cranial nerve deficits as a manifestation of AL.

Case Report A 58-year-old woman was referred for evaluation of progressive neurological deficits. She had experienced dilatation of her right pupil. During the next several months, right-sided ptosis and diplopia developed. She had noted left facial weakness with numbness around her left upper lip and cheek. Distal lower extremity weakness developed and numbness without dysesthesia developed in her toes. There was no family history of amyloidosis. Physical evaluation detected total nerve I11 palsy on the right. There was numbness in the maxillary distribution of the left trigeminal nerve (V2),pronounced weakness of the left facial musculature (VII), and sensory loss in the ulnar

From the Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN. Received Aug 1, 1990, and in revised form Oct 28. Accepted for publication Oct 29, 1990. Address correspondence to Dr Gern, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Copyright 0 1091 by the American Neurological Association 451

Table I. Summaly of Cranial Neuropathy in Primay Amyloidosis

Positive Biopsy Sites

Negative Biopsy Sites Fat aspirate, bone marrow Rectum

Patient No.

Age (yr) Sex

1

5 8lF

Surd nerve, rectum

2

66iF

Lung

3

5 91M

Liver, None pancreas

4

60lM

Bone marrow, fat aspirate Kidney, right thigh Kidney

67iF

4 7iF

Equivocal rectal biopsy

Peripheral Neuropathy

Electromyogram

Transthyretin (Prealbumin) Stain

Sural RIII, positive LV,, LVII

Present

Abnormal

Negative

Not done

Present

Abnormal

Negative

Present

Abnormal

Negative

Absent

Not done

Negative

Nerve Biopsy

Annals of Neurology

RIII, NV, L& RVl.7,33 RVI, R& LVII RVII

Brachial and sciatic plexi positive postmortem Not RIV done

&one

h-ot done

LVII

Present

Abnormal

Negative

Bone marrow, rectum

Not done

LVII, LV2.3

Present

Abnormal

Negative

distribution on the left with interosseous muscle atrophy. Major weakness was noted in the gastrocnemius, soleus, tibid, and peroneal muscles on the left. Deep tendon reflexes were absent in all four extremities. Serum protein electrophoresis revealed a discrete band equivalent to 1.47 d d l ( l 4 . 7 gm/L) (Table 1). Immunoelectrophoresis showed a monoclonal immunoglobulin M-A (IgM-A) protein. Immunofixation of urine revealed a monoclonal A protein. An electromyogram revealed diffuse sensorimotor peripheral neuropathy. A computed tomographic scan showed no evidence of periorbital amyloid. Magnetic resonance imaging showed scattered, localized white matter changes in the cerebral hemispheres and a prominent area of abnormality just opposite the anterior horn of the right lareral ventricle. A bone marrow aspirate and biopsy revealed no abnormalities, and amyloid stains were negative. An amyloid stain on a subcutaneous fat aspirate was negative, but a rectal biopsy was positive, that is, showing green birefringence of the Congo red-stained specimen when viewed under polarized light. A sural nerve biopsy revealed a normal density of myelin fibers. Some of the endoneural vessels were surrounded by amyloid deposits. Small amyloid globules were seen among the myelin fibers. Amyloid was identified

452

Cranial Nerves Involved

VoI 29 N o 4

April 1991

both by green birefringence and by its metachromasia with methyl violet. The rates of remyelination (23%) and axonal degeneration (1 0%) observed in teased fiber preparations were greater than normal. Therapy with prednisone (60 mg every other day) for 6 months produced no improvement in her cranial neuropathy.

Review of the Institutional Experience We conducted a review of patients seen at the Mayo Clinic with a diagnosis of amyloidosis who also had cranial neuropathy. We found 5 additional patients with cranial neuropathy associated with AL seen between 1974 and 1989 (see Table 1). In each patient, the diagnosis was confirmed by biopsy. In 4 of the 6 patients, the cranial neuropathy was a chief complaint at the time that amyloidosis was diagnosed. Nerve tissue from 2 of our 6 patients contained amyloid. In 3 of our 6 patients, multiple cranial nerves were involved. Because 2 patients had isolated nerve VII deficits, the possibility of nonrelated Bell's palsy cannot be excluded. Three patients had nephrotic-range proteinuria. Immunoelectrophoresis of urine revealed a monoclonal light chain in 4 of 5 patients examined. Serum immunoelectrophoresis revealed IgM-A in 2, 1gG-A in 1, and no monoclonal protein in 2. The serum

Table 1. Continued Survival from Onset of CraResponse nial Nerve of Cranial Symptoms Neuropathy (mo)

Urine Protein, mgi24 hr (gdd)

Urine Protein Imrnunoelectrophoresis/immunofixation

Serum Protein Immunoelectrophoresis

Therapy

A

124 (0.124)

A

IgM A

Prednisone

6

None

30 +

A

760

No monoclonal protein

IgM A

Melphalan, 1 prednisone

None

72

Not done Not done, 3+ protein on urinalysis

Not don=

Prednisone

'i,

None

2

9,800 (9.800)

K

Negative

Melphalan, 1 prednisone, colchicine

None

17

4,500 (4.500)

A

Negative

Melphalan

1

Partial with melphalan

5

5,900 (5.900)

A and IgG A

IgG A

Colchicine

14

Neuropathy appeared

1

Tissue Immunostain

(0.760)

K

Duration of ?'herapy (mo)

+

while receiving

colchicine and urine immunoglobulin light chains represent the precursor of the tissue amyloid deposit. One patient was treated with melphalan and 2, with melphalan and prednisone. Two patients were treated with highdose prednisone. One was treated with colchicine alone. In general, there was no significant improvement noted with therapy (see Table 1).

Discussion Review of our experience suggests that cranial neuropathy is a rare but definite manifestation of AL (Table 2). The neuropathy of AL typically is distal, symmetrical, and progressive. Pain and temperature sensations are typically affected earlier and to a greater degree than proprioception. Autonomic involvement may be prominent early in the course. Diagnosis of amyloid neuropathy depends on the identification of amyloid deposits, usually around capillaries in the endoneurium and in the walls of small blood vessels in the epineurium. Teased fiber preparations typically show axonal degeneration with different components of segmental demyelination [l-31. There are several aspects of our

index patient's presentation that are unusual for AL. She did not have peripheral neuropathy but did have prominent cranial nerve involvement. Of the 5 patients with cranial nerve involvement reported in the literature in association with plasma cell dyscrasias, only 3 appear to be patients with AL-related cranial neuropathy f1, 4-61, In a review of 31 patients with amyloid-associated neuropathy, Kelly and colleagues f lJ mentioned only one patient with anosmia. This is the only other reported patient with biopsyconfirmed AL associated with cranial neuropathy. There was no family history of amyloidosis in any of our patients. Cranial neuropathy as the presenting and dominant feature of AF has been well described in Finnish families E7-10) (see Table 2). Autosomal dominant transmission is characteristic. Clearly, our patients are distinct from these patients. Immunostains of biopsy tissues revealed that all of our patients had amyloid composed of immunoglobulin light chains (AL). Amyloid may be localized to the extraocular muscles, the orbit, or the conjunctiva. Magnetic resonance

Brief Communication: Traynor et al: Cranial Neuropathy and AL 453

Table 2. Clinical Charactmitics of Amyloid Neuropathy

Neuropathy Type

Biochemical Structure

Peripheral

Autonomic

Cranial

Renal Involvement

Primary

Monoclonal Ig Light chain K or X

2+

2+

1+

3+

Mutant prealbumin (Met3",Ile33,GIY*~) Mutant prealbumin (His58) Apolipoprotein A1

4+

4+

0

1+

4+

0

0

0

4+

2+

0

4+

Gelsolin

0

0

4+

0

Familial Type 1 Portuguese Type I1 Maryland Type 111 Rukavina Type IV Finnish

imaging or biopsy reveals direct muscle infiltration with amyloid {11-14}. Our index patient showed no evidence of extraocular muscle infiltration. Our 6 patients are added to the 3 previously reported associations of documented AL with cranial neuropathy. They include the first 2 patients with nerve biopsy confirmation of that diagnosis. Review of our experience suggests that cranial neuropathy may be the initial manifestation of AL and that it is underdiagnosed and underreported. AL should be considered in the differential diagnosis of cranial neuropathy when proteinuria is noted on urinalysis or when a monoclonal protein is found in serum or in urine. Alkylating agent-based chemotherapy has been used with some success in AL, but its value in treating neuropathic manifestations of the disease is unproved. This work was supported in part by the Quade Amyloidosis Research Fund.

References 1. Kelly JJ Jr, Kyle RA, OBrien PC, Dyck PJ. The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann

Neurol 1979;6:1-7 2. Dayan AD, Urich H, Gardner-Thorpe C. Peripheral neuropathy and myeloma. J Neurol Sci 1971;14:21-35

454 Annals of Neurology Vol 29 No 4 April 1991

3. Kelly JJ Jr. Polyneuropathies associated with plasma cell dyscrasias. Semin Neurol 1987;7:30-39 4. Little KH, Lee EL, Frenkel EP. Cranial nerve deficits due to amyloidosis associated with plasma cell dyscrasia. South Med J 1986;79:677-681 5 . Massey EW, Massey JM. Facial diplegia due to amyloidosis. South Med J 1986;79:1458-1459 6. Davies-Jones GAB, Esiri MM. Neuropathy due to amyloid in myelomatosis. Br Med J 1971;2:444 7. Kelly JJ, Adelman LS, Berkman E, Bhan I. Polyneuropathies associated with IgM monoclonal gammopathies. Arch Neurol 1988;45:1355-1359 8. Meretoja J, Teppo L. Hiscoparhologicalfindings of familial amyloidosis with cranial neuropachy as principal manifestation: report on three cases. Acta Pathol Microbiol Immunol Scand [A] 1971;79:432-440 9. Meretoja J. Genetic aspects of familial amyloidosis with corneal lartice dystrophy and cranial neuropachy. Clin Genet 1973; 4:173-185 10. Maury CPJ, Teppo A-M, Karinemi A-L, Koeppen AH. Amyloid fibril protein in famhal amyloidosis with cranial neuropathy and corneal lattice dystrophy (FAP type IV) is related to transthyretin. Am J Clin Pachol 1988;89:359-364 11. Katz B, k j a S, Melles RB, Press GA. Amyloid ophchalmoplegia: ophthalmoparesis secondary to primary systemic amyloidosis. J Clin Neurol Ophthalmol 1989;9:39-42 12. R d o GT, Farrell TA, Sioussac RS. Complete ophchalmoplegia secondary to amyloidosis associated with multiple myeloma. Am J Ophthalmol 1981;92:221-224 13. Holstrom GE, Nyman KG. Primary orbital amyloidosis localised to an extraocular muscle. Br J Ophthalmol 198?;71:32-33 14. Brownstein MH, Elliott R, Helwig EB. Ophthalmologic aspects of amyloidosis. Am J Ophthalmol 1970;69:423-430