Leukoencephalopathy in multiple myeloma: Two case reports

Annals of Oncology 10: 1515-1517, 1999. © 1999 Klmver Academic Publishers. Primed in the Netherlands.

Clinical case Leukoencephalopathy in multiple myeloma: Two case reports C. Lebrun,1 S. Chanalet,2 M. Frenay3 & M. Chatel1 Service de Neurologie, 'Service de Radiologie, Pr Padovani, Hopital Pasteur; 3Centre Antoine Lacassagne, Nice, France

Background: No case of leukoencephalopathy has been reported associated with multiple myeloma. Patients: We report on two patients with a very rare association of leukoencephalopathy and multiple myeloma revealed by cognitive impairment.

Results: Chemotherapy has improved neurological and biological signs. Radiological abnormalities have been stabilized. Conclusion: The authors suggest that leukoencephalopathy is probably a direct cerebral expression of malignant gammopathy. Key words: leukoencephalopathy, MRI, myeloma, polyneuropathy

touch, pinprick, vibration and joint position) were normal. Laboratory tests showed a normal blood count Neurological complications of multiple myeloma include with a high sedimentation rate (50/70-Normal <5) and spinal cord or root compressions, cranial nerve palsies increased P2 microglobulin (5-Normal < 3). There was and peripheral neuropathies related to nerve ischemia no renal insufficiency or hypercalcemia. Serum immuand myelomatous or amyloid infiltration. Leukoencephal- noelectrophoresis showed a monoclonal IgG-A. gammaopathy has been described as a paraneoplastic syndrome globulin peak (21.6g/l-Normal = 6.5-14), with low IgA in association with chronic lymphocytic leukemia, and IgM fractions. Urine analysis revealed a monoclonal Hodgkin's disease or lymphosarcoma, but has not been Bence Jones proteinuria. Chemical and bacteriological found to be associated with multiple myeloma. We re- examinations of cerebrospinal fluid (CSF) obtained by port two cases with these two associated pathologies lumbar puncture were normal, and cellular analysis which probably constitute a cerebral localization of found only 4 leukocytes/mm3 with 44% of lymphocytes malignant dysglobulinemia. (Table 1). CSF electrophoresis isolated the same intrathecal secretion of monoclonal IgG-A. protein, excluding a transudate (qualitative and quantitative levels). Polymerase chain reaction for JC virus was negative. AntiCase report 1 bodies to myelin associated protein were negative. ElecA 66-year-old man was admitted to the neurological tromyographic studies showed a significant slowing down department for distal weakness of upper limbs and of motor and sensory nerve conduction velocities in paresthesia. He had no medical history (i.e., hyperten- median and sural nerves, reduction in amplitude and sion, diabetes) or neurological symptoms. He presented, increased distal latencies. Taken together, these measurewith a two-month history, a diffuse amyotrophia and a ments confirmed a generalized peripheral mixed polymild proprioceptive ataxia. The patient complained of a neuropathy. Sural nerve biopsy showed subacute myelin discreet impairment of higher cortical functions, espe- degeneration without amyloid component deposit. Howcially memory loss and difficulties of concentration ever, an immunofluorescence study revealed binding of (Mini Mental State 28/30). Tendon reflexes were absent anti-IgG and anti-X. antibodies to myelin sheaths. The in the arms but present and symmetrical in his legs. diagnosis of multiple myeloma was confirmed by the There was no Babinski sign and sensory testing (i.e., presence of a bone marrow plasma cell infiltrate (45%). Introduction

Table I. Patients data

Gender

Age

Symptom

PNS

MMS

Renal failure/ HCa

EP serum

EPU

EP CSF

CSF protein (g/1)

CSF Bone marrow cells (plasmocytes) (mm3)

MRI months 3,6, 12

Evolution

Male Female

66 70

Disorientation Disorientation

Yes Yes

28/30 24/30

No Yes

IgG-?. IgG-?.

Bence Jones Bence Jones

IgG-/. IgG->.

0.62 0.31

4 3

Stable Stable

Remitting Remitting

Abbreviations: MMS - Mini Mental State; PNS - peripheral nervous system symptoms.

45% 38%

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Summary

1516 Table 2. Main clinical features of leukoencephalopathies and polyneuropathies in multiple myeloma.

Accessory salivary gland and rectal biopsies failed to detect associated amyloidosis. Computerized tomographic scan of the brain, performed to explain the mild changes in mental status and the intrathecal IgGA secretion, showed diffuse white matter abnormalities. Magnetic resonance imaging (MRI) revealed a diffuse leukoencephalopathy with the presence in the T2-weighted sequence of numerous bihemispheric hypersignals (Figure la). There was no enhancement after Gadolinium injection in Trweighted sequences. No other pathology was found to explain the leukoencephalopathy. Treatment with Melphalan (10 mg/d for four days/month) and prednisone (1 mg/kg/day) was started. After three courses of treatment, his subjective sensory disorders and ataxia had disappeared; all his tendon reflexes had also reappeared. Biological tests showed normal CSF values and serum IgG levels, with diminution of the bone marrow plasmocytosis (19%). Further MRI studies performed 3, 6 and 12 months later confirmed stabilization of the white matter lesions.

Polyneuropathies

1. — Demyelination of white matter as complication of circulating immunoglobulin. — Cognitive dysfunction with memory loss — Stabilization with cytotoxic agents.

1. - Symmetrical axonal sensory, axonal sensorimotor or or chronic motor neuropathy. - Reversible with cytotoxic agents, plasmapheresis.

2. - Progressive multifocal leukoencephalopathy: disappearance of myelin sheaths with preservation of axis cylinders due to JC virus (cytopathic infection of oligodendrocytes). — Altered mentation or behavior, hemiplegia, cerebellar syndrome, cortical blindness, ataxia. — Asymmetrical clinical course — Possible stabilization with cidofovir

2. - Sensorimotor mononeuropathy multiplex - Reversible with irradiation of bony lesion 3. - Small-fiber sensory neuropathy, marked loss pain, weakness, dysautonomia in case of amyloidosis. 4 - POEMS distal symmetrical sensonmolor polyneuropathy with both axonal degeneration and segmental demyelination.

demonstrated a proprioceptive ataxia without Babinski sign. There were no signs of intracranial hypertension; her ankle jerks were absent and the other reflexes were symmetrical in both lower and upper limbs. She did not complain of loss of strength or motor failure. There was no evidence of sensory deficit and her Mini Mental State was 26/30. T2-weighted MRI showed diffuse bilateral hypersignals suggesting leukoencephalopathy, without stroke (Figure lb). After six courses of treatment, examination showed normal serum and CSF IgG levels. Her headaches and vertigo disappeared within 10 days.

Discussion

In these two cases, the association of diffuse leukoencephalopathy, myelinic polyneuropathy and multiple myeCase report 2 loma suggests a probable relationship between all features, which appears to be unusual in multiple myeloma A 70-year-old woman was admitted to the neurological as no similar case has been reported in the literature. department of the Pasteur Hospital for asthenia, disori- Leukoencephalopathy is characterized by widespread entation, headaches and vertigo. She had chronic renal lesions of demyelination, mainly of the cerebral hemifailure (urea: 20 mmol/1-Normal: 2.5-7.5; creatinin: 220 spheres but also of the brainstem and cerebellum, rarely umol/1-Normal: 45-90) without hypertension or other of the spinal cord (Table 2). It is more often associated medical history. Three months previously, she had been with chronic neoplasia: chronic lymphocytic leukemia, initially treated for a proplasmacytic multiple myeloma. Hodgkin's disease, lymphosarcoma and, more rarely, She had already had three cycles of Melphalan (10 myeloproliferative disease [1]. The use of prednisone mg/d; four days/month) and prednisone (1 mg/kg/day) and alkylating agents sometimes leads to an improvewhen her neurological symptoms appeared. Blood count ment in the general and neurological symptoms, but showed mild thrombopenia (110,000/mm3; Normal: with incomplete recovery. In cases of solitary plasmacy140,000-440,000) and anemia (Hb: 7 mmol/1-Normal: toma, radiotherapy may result in prolonged remission 7.4-9). Sedimentation rate was increased (30/80-Normal of both the myeloma and neuropathy [2]. < 5). Serum immunoelectrophoresis showed a monoThe first case reported here fits with the diagnosis of clonal IgG-?.. gammaglobulin (20.3 g/1-Normal: 6.5-14). an associated myelomatous neuropathy. Subacute or Urine analysis isolated Bence Jones proteinuria. CSF chronic distal sensorimotor polyneuropathies (PN) are values were within normal range and electrophoresis of common in multiple myeloma and have a high associathe CSF isolated the same intrathecal secretion of IgG-?. tion with the osteosclerotic form. These clinical forms of gammaglobulin (Table 1). Neurological examination PN are seen clinically in 5% to 14% of myeloma [3, 4].

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Figure 1. T2-weighted MRI showing diffuse bilateral hypersignals characterizing leukoencephalopathy. (a) Case report 1 (b) Case report 2.

Leukoencephalopathies

1517 Table 3 Neurological symptoms described with multiple myeloma.

The incidence increases significantly (40%) when subclinical neuropathy based on nerve conduction studies is included. Histologic examination of peripheral nerves demontrates that the primary pathologic lesions are axonal degeneration and demyelination. Numerous theories exist as to the origin of neurologic changes in cases where there is no evidence of anatomical involvement between the tumor mass and neighbouring neural structures. These theories include amyloidosis, ischemia, toxic metabolic factors (circulating abnormal protein or immunoglobulin fragment) and myelin antibodies. Other neurological syndromes have been reported in multiple myeloma such as motor neuropathies [5], Guillain-Barre syndrome, isolated or multiple cranial nerve palsies [6, 7], benign intracranial hypertension [8], spinal cord compressions [9], meningeal involvement [10] or strokes due to rheologic abnormalities (Table 3). Myelomatous PN are predominantly distal, characterized by severe weakness, ataxia and sensory loss in the upper and lower limbs. Usually, they are characterized by alternating remissions and relapses with muscular atrophy increasing over a period of several months. Ataxia can be pronounced when sensory loss exceeds paresis. Few patients with myeloma have osteosclerotic lesions, but over half of those with sclerotic lesions have neuropathy. Furthermore, the paraprotein is usually an IgA or IgG in small concentrations, almost always with a lambda light chain [11]. The neuropathies associated with sclerotic myeloma are likely to become severe and the cerebrospinal fluid protein level tends to be very high. Although multiple myeloma can be associated with amyloidosis or with paraneoplastic neuropathy [12], amyloid neuropathy is seen in approximately 10% to 15% of patients. In the first case report , chemotherapy improved the neurological and biological signs and MRIs

References 1. Bellan ID, CoxTA, Cascoyne RD. Parasellar syndrome caused by plasma cell leukemia. Can J Ophtalmol 1989; 24 (7): 331-4. 2. SinoffCL, Blumsohn A. Spinal cord compression in myelomatosis: Response to chemotherapy alone. Eur J Cancer Clin Oncol 1989; 25 (2): 197-200. 3 Dimopoulos MA, Moulopoulos A, Smith Tet al. Risk of disease progression in asymptomatic multiple myeloma. Am J Med 1993; 94: 57-61. 4. Vrethem M, Cruz M, Wen-Xin H et al. Clinical, neurophysiological and immunological evidence of polyneuropathy in patients with monoclonal gammopathies. J Neurol Sci 1993; 114. 193-9. 5. Delattre JY. Said G. Neuropathies penpheriques au cours des dysglobuhnemies. Rev Prat 1991; 15: 41 (24): 2476-81. 6. Forret-KaminskyMC, Sherer C, Platini C, Boujan F. Paralysie isolee du nerf grand hypoglosse revelant un myelome multiple. Rev Neurol 1991; 147 (3): 238-9. 7. Ennouri A, Moalla M, Hajri H et al. Atteintes des paires craniennes revelatrices de la maladie de Kahler. Ann Otolaryngol Chir Cervicofac 1990; 107: 141-3 8. Wasan H, Mansi JL. Benjamin S et al. Myeloma and benign intracranial hypertension. BMJ 1992; mar 14-304 (6828): 685. 9. Spiess JL, Adelstein DJ. Hines JD. Multiple myeloma presenting with spinal cord compression. Oncology 1988; 45 (2). 88-92. 10. Oda K, Egawa H, Okuhara T et al. Meningeal involvement in Bence-Jones multiple myeloma. Cancer 1991; 67 (7): 1990-2. 11. Scully RE, Mark EJ, McNeely WF, McNeely BU. Case report of the Massachusetts General Hospital. N Engl J Med 1993; 328: 1550-8. 12. Samanta A, Hilton D, Roy S. Peripheral neuropathy, polymyalgia and arthralgia: A paraneoplastic syndrome syndrome associated with myeloma. Clin Rheumatol 1990; 9 (2): 246-8. Received 16 October 1998; accepted 26 January 1999. Correspondence to: Dr C. Lebrun Service de Neurologie, Pavilion D Hopital Pasteur 30 av. Voie Romaine, BP 69 F 06002, Nice Cedex France

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Peripheral nervous system Subacute sensorimotor neuropathy Chronic distal neuropathy Motor neuropathy Sensitive distal neuropathy Chronic polyradiculoneuritis Compressive neuropathy, carpal tunnel syndrome Acute polyradiculoneuritis (Guillain-Barre syndrome) Multiple cranial nerve palsies (II, V, VI, VII, VIII, XI) Collet-Sicard syndrome (IX, X, XI, XII) Optic neuropathy Paraneoplastic neuropathy (Denny Brown) POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) Crow-Fukase syndrome (including polyneuropathy. mild lamda paraproteinemia level, mild bone marrow plasmocytosis) Amyotrophic lateral sclerosis-like syndrome Central nervous system Benign intracranial hypertension (pseudotumor cerebri) Spinal cord compression Meningeal involvement Leukoencephalopathy Ischemic stroke Intracranial hemorrhages Encephalopathies (hypercalcaemia)

performed 3, 6 and 12 months later showed stabilization of the leukoencephalopathy. Serial electromyographic studies confirmed an increase in nerve conduction velocities concurrently with the clinical improvement. Although an IgG-?*. component was isolated in CSF, the etiology of the white matter changes seen on MRI is unclear without histopathological proof. The fact that leukoencephalopathy and cognitive impairment did not worsen or were stabilized by prompt specific treatment for multiple myeloma strengthens the hypothesis that the leukoencephalopathy is directly related to myeloma. We venture to suggest that the leukoencephalopathy is probably a direct cerebral expression of malignant gammopathy. In both cases, absence of Gadolinium enhancement in Trweighted MRI reflects blood brain barrier integrity. Intrathecal secretion of monoclonal protein could be responsible for the leukoencephalopathy. However, we cannot exclude the possibility that it represents a combined paraneoplastic syndrome or a fortuitous association. While the development of the different neurological symptoms may vary, prompt systemic treatment is necessary in all cases in order to achieve stabilization or improvement of neurological symptoms.

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