28 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 8, NO.1, 1995

Clinico-pathological Conference

An adult male with myeloradiculopathy and cranial nerve palsy

POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH,CHANDIGARH

THE CASEA 49-year-old male was admitted to our institute on7 January 1994with progressive weakness in his right lowerlimb for 14 weeks, followed 2 weeks later by weakness inhis left lower limb and deviation of the angle of the mouthto the right side. He, subsequently, developed flexor spasmsin the lower limbs and a vague pain and dysaesthesia belowthe knees. He then had diplopia and drooping of his lefteyelid. At the time of admission there was no history ofimpaired vision or hearing, bowel or bladder involvement,decreased sensation over his face, dysphagia, nasal regur-gitation or a nasal twang to his speech, impotence, sweatingabnormalities and back pain. There was also no historyof fever, abdominal pain, toxin ingestion, dog bite orvaccination. He had mild to moderate hypertension forwhich he had been on irregular treatment.

On examination he was afebrile with a blood pressure of170/100mm.Hg.All his peripheral pulses were palpable. Thechest, cardiovascular and abdominal examinations werenormal. Examination of the central nervous system (CNS)revealed the patient had normal higher mental functionsand speech. Fundoscopy showed early papilloedema and healso had bilateral (right greater than left) third cranialnerve palsy, left fourth nerve palsy, right sixth nerve paresisand left seventh nerve palsy. The other cranial nerves werenormal. The motor system examination revealed normalupper limbs, a decreased tone in both lower limbswith grade3/5 power proximally at the hips, 4/5 at the knees and 2/5at the ankles. No fasciculation was seen. The deep tendonjerks were normal in the upper limbs with absent knee andankle jerks and abdominal and cremasteric reflexes. Pinprick and touch sensation were decreased from the L3 toS5 dermatomes and the position and vibration sense wereimpaired upto the knees. There were no signs of cerebellaror extrapyramidal involvement nor were there any signs ofmeningeal irritation. The straight leg raising test was positivebilaterally.

Investigations showed a normal haemogram andnormocytic, normochromic red blood cells (RBCs) on bloodfilm examination. There were no blast cells and the plateletswere adequate in number. Urine examination was normal.The serum sodium was 140 mEqlL, potassium '3.8 mEqlL,blood urea 50 mg/dl and serum creatinine 0.8 mg/dl. Thebilirubin and transaminases were normal. The serumcholesterol was 168mg/dl, blood sugar 120mg/dl and serumcalcium 9.6 mg/dl.. Cerebrospinal fluid (CSF) examination

done on 13 January j.994Showed a protein of 250 mg/dl,sugar 90mg/dl and no:white blood cells (WBCs) or malignantcells. Cultures for fungi and acid-fast bacilli (AFB) werenegative. CSF examination repeated on 27.1.94 showed10 WBCs, protein 100 mg/dl and sugar 50 mg/dl. TheVDRL (venereal diseases research laboratory) test andexamination for AFB and the human immunodeficiencyvirus (HIV) were negative. Gram stain, fungal stain andcultures were also negative. Flowcytometry of the CSFshowed a few lymphocytes, RBCs and an occasionalmonocyte with a marked rise in gammaglobulin. The anti-neutrophil cytoplasmic antibody was absent in the bloodand tests for hepatitis B surface antigen (HBsAg), serumVDRL and HIV were also negative. Serum electrophoresiswas normal and there was no Bence Jones protein in theurine. The electrocardiogram was normal. The prothrombintime, prothrombin index and kaolin partial thromboplastintime were normal. No fibrin degradation products wereseen in the blood. The arterial blood gases revealed hypoxiaand mild respiratory alkalosis.

X-rays of the skull and chest were normal. Myelogramsdone on two separate occasions revealed a thickened caudaequina and changes suggestive of an intramedullary spinaltumour at the level ofthe conus. Computerized tomography(CT) of the head showed moderate hydrocephalus and afew low density opacities in the basal ganglia region withoutcontrast enhancement. Ultrasound ofthe orbits wasnormal.

The. admitting diagnosis was myeloradiculopathy withmultiple cranial nerve palsies. Because the cranial nerveswere involved at many different levels the possibility ofthe cause being infective arachnoiditis, demyelination orvasculitis was considered. However, the rapidly progressivecourse suggested a neoplastic infiltration of the cranialnerves and spinal cord. A search for a primary neoplasmwas unrewarding and during this time the patient's conditiondeteriorated. He developed' tenth cranial nerve palsy, upperlimb weakness, altered sensorium and retention of urine. Amyelo-CT done on 13 January 1994 suggested an intra-medullary lesion with a cut-off at D12. On 16January 1994the patient underwent a laminectomy at the D12-L3 level.At operation there was clumping of the nerve roots and aswollen cord. A biopsy was not taken. Postoperatively hewas started on antitubercular drugs together with steroids.In spite of this his neurological status worsened and herequired feeding through a nasogastric tube. On 6 February1994, 1 month after admission, he developed acute

CLiNICO-PATHOLOGICALCONFERENCE

breathlessness and chest examination revealed conductedsounds. He was treated for aspiration pneumonia withantibiotics and, because pulmonary thromboembolism wasalso a possibility, heparin was infused at a rate of 1000 IU .per hour. On 14 February 1994 he had increased breathless-ness and developed "hypotension. He was intubated,subsequently had a tracheostomy and was put on aventilator. On 26 February 1994, 7 weeks after admission,he died.

CLINICAL DIAGNOSIS

MyeloradiculopathyMultiple cranial nerve palsies-? Infective/vasculitic

? NeoplasticAspiration pneumonia/Pulmonary thromboembolismSepticaemia

DIFFERENTIAL DIAGNOSISDR ANIL Taussu: The outstanding features of this story arethe radicular symptoms which progressed to involve thespinal cord. Subsequently the disease involved the seventhcranial nerve on the left side and the sixth nerve on theright. The patient had a progressive illness with the CSFshowing increased proteins and a few lymphocytes. Themyelogram suggested a swollen conus and a thickened caudaequina. CT scan of the head showed a few small low densityareas in the basal ganglia and right parietal cortex and amild hydrocephalus.

In our experience, infection predominates as the causeof myeloradiculopathy with tuberculosis being the mostcommon. In Dr Wadia's series, tuberculosis was the causeof myeloradiculopathy in 20 out of 70 cases.' This patientwas diagnosed to have tubercular arachnoiditis on admissionand after laminectomy was given antitubercular therapy with4 bactericidal drugs in adequate doses for more than 6 weeks.However, there was no response to the treatment and nobasal exudates characteristic of tuberculosis were found onthe CT scan of the head. No exudates or tubercles wereseen peroperatively and in tuberculosis there is generally agreater cellular response in the CSF with a lower contentof glucose. There was no other site of tubercular involve-ment. All these points make tuberculous infection unlikely.However, as it is the commonest infectious aetiological agentcausing arachnoiditis, I will not exclude this possibilityfrom the list of differential diagnoses even though the AFBculture was negative.

Cryptococcal myeloradiculopathy can mimic tuberculosisbut is usually seen in immunocompromised states. In thispatient there was no evidence of cryptococcal infectionin the CSF on India Ink preparation and the culture wasnegative. I will therefore not consider this as a possibility.Syphilis need not be seriously considered as it is very rare.Further, the CSF was negative for VDRL twice and thecourse was too acute for syphilis.

HIV can involve nerve radicles and even the cord in itslate stages but is rarely seen at presentation. However,the HIV tests in the blood and CSF were negative on twooccasions. Amongst the non-infectious causes are prolapsedintervertebral disk, spondylosis, rheumatoid arthritis andchemical agents (penicillin, streptomycin) which may resultin localised arachnoiditis and involve a few radicles. Thispatient had extensive involvement with a progressive clinical

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course and this does not support any of these aetiologies.Spinal tumours such as ependymomas of the cauda and conusmay start with these features and progress to intracranialseedlings with involvement of the cranial nerves. However,the course of this illness was too acute for an ependymoma.

A primary CNS lymphoma presents with intracraniallesions in 90% of cases. 2 Diffuse meningeal and periventricularinvolvement occur in about 25%, uveal vitreous depositsare seen in 15% and a localised spinal variety may also beseen albeit rarely. Patients generally have a headache, signsof raised intracranial pressure and evidence of meningitis.Occasionally, cervical or lumbar radiculopathy occurs. Thisis not the usual presentation of primary CNS lymphoma butthen systemic lymphomas especially of the non-Hodgkin'svariety can present with leptomeningeal deposits in 4% to7%. of cases. Our patient had a few lymphocytes in the CSF,a few small hypodense non-enhancing lesions on CT and araised intracranial pressure. The possibility of a lymphomainvolving the CNS remains high, though systemic lymphomaspresent in this manner more often than the primary variety.

Meningeal carcinomatosis generally follows primarytumours of the lung, breast, ovary, pancreas and colon andmay rarely be the presenting feature. It is associated withlow levels of glucose and malignant cells in the CSF (whichwere absent in this case). Although I do not seriouslyconsider this diagnosis, I cannot exclude it completelybecause malignant cells in the CSF can be missed easily.Paraneoplastic involvement of the CNS is also unlikely asthere is usually a myaesthenic syndrome or sensory neuro-pathy. Necrotising myelopathy has been described in 24cases but cranial neuropathies are unusual. The result ofthe myelogram would be against this diagnosis. Sarcoidosiswithout pulmonary signs and uveitis is unlikely especiallywith such a rapid downhill course. Systemic vasculitides suchas polyarteritis nodosa with such clinical features have notbeen described especially in the absence of HBsAg positivityand a negative collagen profile. Systemic lupus erythematosusgenerally presents with infarcts, seizures, peripheralneuropathy and a positive antinuclear factor.

Idiopathic granulomatous angiitis of the nervous systemhas a diffuse involvement and presents with headache,vomiting and focal deficits. Only rarely does it present witha myelopathy and the radicles can be involved in about 15%of cases. The mean age of onset is 49 years (range 3-78years). Males predominate and a raised protein level is seenin the CSF along with a few lymphocytes and a normalglucose. The CT scan is abnormal in 68% of cases and showsinfarcts, hydrocephalus and cerebral atrophy. Myelographyshows an enlarged conus and irregularity and clumping ofthe cauda equina. A magnetic resonance study is moresensitive in picking up these features. Our patient fits inmost closely with this description except that it is an unusualpresentation of a rare disease.

DR THUSSU'S DIAGNOSISMyeloradiculopathy (ascending) with cranial neuropathy,

hydrocephalus and infarcts due to-? Idiopathic granulomatous angiitis-? Lymphoma-? Carcinomatosis

HypertensionAspiration pneumonia/pulmonary thromboembolismSepticaemia

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CLINICAL DISCUSSIONDR B. S. SHARMA:I operated upon this patient only to

decompress his cord so I do not think an intramedullarytumour can be excluded. I did not find any evidence ofarachnoiditis.

DR V. K. KHOSLA:The diagnosis of a primary spinal cordtumour is very unlikely in this patient. It is also not possibleto exclude arachnoiditis as the CSF findings and myelogramsuggest the presence of adhesions. The most likely diagnosisis a primary demyelinating disease.

DR I. M. S. SAWHNEY:This patient seems to have hada radiculopathy and not a myelopathy. Multiple cranialnerve involvement suggests involvement of the brain stemespecially the left pons and midbrain. As far as the pathologyis concerned, there is no reasonable basis to suggest aninfective aetiology. I would consider two main diagnoses:vasculitis and neoplasia. Idiopathic granulomatous angiitisis rare. Also, for it to present like a myeloradiculopathy iseven rarer. Cranial nerve involvement is uncommon in thiscondition. I would consider a neoplastic pathology to bemost likely. Leukaemia can be ruled out but carcinomatosisis possible. Systemic lymphoma seems unlikely as by thetime it involves the CNS it is in stage II or III and the bonemarrow is usually involved. However, I would consider aprimary CNS lymphoma originating at the level of thebrainstem and spreading to involve the radicles. A multi-centric origin is possible. Primary demyelination is unlikelyin this patient as a CSF protein of more than 250 mg isunusual in this condition.

DR S. N. MATHURIA:The site of involvement seems to beentirely extra-axial. There are no brainstem signs to suggestparenchymal involvement. My first diagnosis would becarcinomatous meningitis.

DR J. S. CHOPRA:Although vasculitis remains the mostprobable diagnosis, the patient may have had an ependymomaoriginating in the lower spinal cord and then spreadingupwards.

DR B. K. SHARMA:Primary vasculitis of the brain alwaysbaffles me being restricted to the CNS alone. Only a brainbiopsy can establish the diagnosis before death. It is hardto accept that this patient may have had a carcinoma,systemic lymphoma or leukaemia. A primary CNS malignancyis a distinct possibility even though the surgeon was not ableto detect a tumour.

PATHOLOGICAL DISCUSSIONDR A. K. BANERJEE:Post-mortem examination showed bedsores in the lower back and a healed surgical wound in thelumbosacral region. The spinal canal revealed no extraduralabnormality. On opening the dura the cord appeared swollenfrom Dll to the cauda equina region (Fig. 1). The bloodvessels and the nerve roots were obliterated on both surfacesby an irregular, friable, greyish-white material. The spinalnerves in the cauda equina were glued together, thick andshowed nodular swellings. Serial cross sections of thecord revealed a thick material in the spinal subarachnoidspace completely encircling the cord and encasing the bloodvessels and the nerve roots (Fig. 2). This was most markedin the lower dorsal and lumbodorsal regions but was alsopresent almost throughout the cord. The cross sectionalarchitecture of the cord was altered at several levels butthere was no well defined intramedullary lesion. Examina-

THENATIONALMEDICALJOURNALOFINDIA VOL.8, NO.1, 1995

tion of the brain showed thickening of both the oculomotornerves (Fig. 3). The basal meninges also showed focalthickening which was most prominent in the interpeduncularfossa. On coronal slicing there was a moderate degree ofdiffuse ventricular dilatation. No parenchymal lesion wasseen in the brain.

Microscopic examination showed diffuse infiltration ofthe leptomeninges by small and large lymphoid cells(Fig. 4). Intramedullary extension of the infiltrate occurredat various levels of the cord (Fig. 5). The infiltration waslimited to the perivascular spaces in most of the foci butextension into the cord parenchyma (Fig. 6) occurred atsome levels in the lumbar segments. The tumour cellsshowed a predilection for perivascular arrangement alongwith increased reticulin fibres. This concentric meshwork offibres enclosing the tumour cells is a characteristic featureof a primary CNS lymphoma. Small foci of recent infarctswere also noted in some segments of the cord. The nerveroots were diffusely infiltrated by the tumour cells whichextended into the nerves along their endoneurial sheaths(Fig. 7). Similar infiltrates were seen in the basal leptomeninges

-, lot""': .• ~-----------------

FIG 1. Specimen of lower end of spinal cord showingobliteration of surface landmarks and thickening andnodularity of spinal nerves

FIG 2. Cross section of L3 segment of spinal cord showingenlarged subarachnoid space and diffuse leptomeningealinfiltration by tumour. Spinal nerves and blood vessels areglued together. There is also a recent infarct in theposterior and lateral columns (H & E, x3)

CLINICO-PATHOLOGICAL CONFERENCE

FIG 3. Interpeduncular fossa of the brain showing thickoculomotor nerves (arrows)

FIG 4. Morphology of the tumour consisting of large andsmall lymphoid cells (H & E, x480)

FIG 5. Leptomeningeal tumour extending into spinal cordalong the perivascular spaces (H & E, x50)

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FIG 6. Anterior horn of L3 segment of spinal cord showingtumour infiltration (H & E, x 120)

FIG 7. Tumour infiltration of spinal nerve (H & E, x50)

FIG 8. Section of mid brain showing thick oculomotor nervesand leptomeningeal tumour tissue (H & E, x3)

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of the brain extending into the parenchyma along theperivascular spaces. This was particularly prominent in theoculomotor nerves (Fig. 8), mid brain and hypothalamicareas.

Examination of the extracranial organs showed broncho-pneumonia, mild coronary atherosclerosis and left ventricularhypertrophy. The liver, spleen, lymph nodes and bonemarrow were unremarkable. Thus the autopsy findings arethose of a primary non-Hodgkin's lymphoma of the CNS ofthe diffuse leptomeningeal type.

Primary CNS lymphomas are most commonly seen as masslesions, mainly located supratentorially. Multicentric formsare well known but the diffuse leptomeningeal type is rare.Diffuse meningeal and periventricular lesions may accountfor upto a quarter of primary CNS lymphomas in immuno-competent patients? This type of leptomeningeal involvementis however not uncommon in secondary involvement ofthe CNS by extracranial non-Hodgkin's lymphoma. Theassociation of primary CNS lymphoma with immuno-deficient states has been recognized for over two decadesand in recent years a large number of cases related to AIDShave been reported. AIDS-related primary CNS lymphomaoccurs at a younger age than non-AIDS related lymphomaand carries a worse prognosis."

The most valuable investigation is a good cytologicalexamination of the CSF. I am aware of cases in which theprecise diagnosis was made using only this method. Unfor-tunately in the present case it was non-contributory.

AUTOPSY DIAGNOSISPrimary non-Hodgkin's lymphoma of the central nervous

system, diffuse leptomeningeal involvementBronchopneumonia

CONCLUDING DISCUSSIONDR B. K. SHARMA:We have seen a very lucidly illustrated

case of primary CNS lymphoma. A thorough CSF examina-tion could have given us the diagnosis.

DR I. M. S. SAWHNEY:The story of this patient was typicalof a neoplastic meningeal syndrome. A male in the fourthto fifth decade of life with no fever but multiple radicularand cranial nerve involvement is most likely to have thiscondition. The majority of such patients die within 3 to5 months. The clue to the diagnosis, as already mentioned,comes from the CSF examination. In this case there wereless than 50 cells per high power field and this suggestedthe following possibilities: sarcoidosis, benign lymphocyticmeningitis and neoplastic meningitis. Primary CNSlymphomas are often missed on cr scan as there may beno mass lesion but just a diffuse infiltration.

DR P. N. CHHUTfANI:I would like to know why, whenthe spinal cord was exposed, a fine needle aspiration cytology(FNAC) was not done and also what is the therapy andprognosis of such lymphomas.

DR B. S. SHARMA:The FNAC was tried twice but nomaterial was obtained. On gross examination, the cordprolapsed at the time of the incision and as there was nothing

THENATIONALMEDICALJOURNALOFINDIA VOL.8, NO.1, 1995

abnormal, no biopsy was taken. We decided to simplydecompress, wait for an MRI and if necessary repeat thesurgery.

DR S. SEHGAL:We had examined the CSF particularlywith a view to rule out lymphoma. However, no malignantcells were seen. The number of cells in the CSF depend onthe degree of shedding from the tumour.

DR J. S. CHOPRA:Several cases of primary CNS lymphomahave been discussed in these CPCs. Most predominantlyinvolved the brain. We have never seen a case that haspresented in this manner. I wonder had the diagnosis beenmade could the patient have been saved?

DR S. VERMA:In primary CNS lymphoma, the responseto chemotherapy is generally obtained but it is not lasting.The treatment is given intrathecally and is followed bycranial irradiation. Long survivals are known but overallthe prognosis is dismal.

DR A. RAJWANSHI:The CSF has to be examined withinone hour of withdrawal if one wants to detect malignantcells. Temperature and transportation are critical factorsinfluencing the preservation of cells.

DR A. K. BANERJEE:We have seen over 20 cases of primaryCNS lymphoma but not with this kind of presentation.However, it is not uncommon as a secondary manifestationof systemic lymphoma. The overall median survival forAIDS-related cases is between 2 and 3 months. Non-AIDSrelated cases have a median survival of between 12 and15 months.' The treatment for mass lesions consists ofsurgical excision followed by chemotherapy and radio-therapy. In this case there was no possibility of excision.There was no involvement of the medulla oblongataalthough the cervical spinal cord was involved by thelymphomatous process. Pulmonary embolism was notdetected and the immediate cause of death was broncho-pneumonia.

REFERENCES1 Wadia NH, Dastur DK. Spinal meningitis with radiculo-myelopathy. 1:Clinical

and radiological features. J Neurol Sci 1969;8:239-60.2 Hochberg FR, Miller MD. Primary central nervous system lymphoma.

J Neurosurg 1988;68:835-53.3 Remick SC, Diamond C, Migliozzi JA, Solis 0, Wagner H Jr, Haase RF,

et al. Primary central nervous system lymphoma in patients with and withoutthe acquired immune deficiency syndrome. Medicine (Baltimore) 1990;69:345-60.

Compiled by DR A. K. BANERJEE

ParticipantsA. K. BANERJEE:Department of HistopathologyP. N. CHHUlTANI:Department of MedicineJ. S. CHOPRA:Department of NeurologyV. K. KHOSLA:Department of NeurosurgeryS. N. MArnuRIA: Department of NeurologyA. RAJwANsm: Department of CytologyI. M. S. SAWHNEY:Department of NeurologyS. SEHGAL:Department of ImmunopathologyB. K. SHARMA:Department of Internal MedicineB. S. SHARMA:Department of NeurosurgeryANILTHussu: Department of NeurologyS. VERMA:Department of Internal Medicine