Multiple Neurologic Deficits and Cognitive Decline in a Young Woman.

We present the clinicopathologic conference of a 34-year-old lady with history of facial palsy 14 years ago who developed new deficits of mononeuritis multiplex, maculopapular rash, pancytopenia, splenomegaly, lung involvement and cognitive decline rapidly over three years. Investigations revealed pancytopenia, reversal of albumin globulin ratio, mediastinal adenopathy, ANA positivity, low C3 levels with the CSF being inflammatory and MRI showing extensive hemorrhagic lesions with mass effect. She had a rapidly progressive fatal course over three years with the disease being undiagnosed. This case was presented in the annual meeting of the Indian Academy of Neurology in September 2018. Copyright:

CASE PRESENTATION

We saw this 34-year-old Indian lady in late February 2017. She had been in her usual state of health till 20 years of age when she had an episode of facial weakness (? side) which resolved over 1 ½ months. She was then asymptomatic, got married and she went to the USA at the age of 25. For the next 7 years, she did not have any symptoms. 3 years before presentation (in March 2014), she had a transient episode of slurring of speech, which resolved in less than 24 hours. In September 2015, she developed bilateral lower limb swelling and erythema with a maculopapular rash which resolved in a few days. In November 2015, when she visited India, she had tingling and numbness of both lower limbs, bilateral painful swollen legs, maculopapular rash below knees (treated by a local practitioner with oral corticosteroids). Rash and swelling resolved in 2 days but paresthesias persisted. She was continued on oral steroids for the next few weeks before she left back to USA and steroids were stopped.

In March 2016, she developed high grade fever of 104°F, accompanied with right lower limb weakness and worsening of lower limb paresthesias. She was admitted and evaluated in a teaching hospital overseas. The following data were extracted from the documents from the treating hospital. Clinically she was alert, oriented and her speech, language and cranial nerves were normal. She had right foot drop with bilateral ankle hyporeflexia with normal upper limb and knee reflexes. At this point of time she was investigated extensively. MRI of the brain was done which showed multifocal lesions in both supratentorial and infratentorial compartments; predominantly in deep and subcortical white matter. These lesions were predominantly hyperintense on T2 and FLAIR images; some of the lesions contained foci of hypointensities on susceptibility-weighted images suggesting hemorrhages and some had a peripheral rim of diffusion restriction. Minimal perilesional edema was seen [Figure 1]. CSF examination revealed pleocytosis with raised protein. She had pancytopenia and anti-nuclear antibody was positive with a speckled pattern. The investigations done at this point of time are enumerated in Table 1.

Figure 1

Contrast enhanced MRI (May 12, 2016). Axial T2-WI (a-c) show hyperintense lesions in right middle cerebellar peduncle (arrow in a), bilateral cerebellar white matter (arrow-head in a), right periatrial and peri-insular white matter (b) and subcortical white matter of both frontal lobes (c). Diffusion-weighted images (d, e) show peripheral diffusion restriction in left posterior frontal lesion (arrow in e), SWI (f and g) show multiple hypointense foci within T2-hyperintense lesions suggesting hemorrhages. Contrast-enhanced T1-WI in axial (h and i) and coronal (j) plane foci patchy to no enhancement with the white matter lesions

Table 1

Results of evaluation in June 2016

Parameter	Result
Hemoglobin	9.4 g/dL
TLC	2740/mm3
Platelets	126000/mm3
DLC 68/28/1/3	68% neutrophils; 28% lymphocytes; 1% eosinophils; 3% monocytes
Creatinine	0.78
Glucose	92 mg/dL
Albumin/Globulin	3.5/4.2 g/dL
Na/K	127/4.9 mEq/L
SGPT	8 U/L
ALP	68 U/L
CSF Examination
CSF cells	TLC WBC: RBC 8:1; all lymphocytes, count not mentioned.
Protein	87 mg/dL
Glucose	Normal [Value not mentioned, nor was corresponding blood sugar value]
Gram staining	No organisms seen
Bacterial c/s	No growth
Viral c/s	No growth
VDRL	Non- reactive
HSV PCR	Negative
ACE level	Normal
CSF lactate	Normal
Flow cytometry	No abnormal/lymphoid progenitor cells
Cryptococcal antigen	Negative
VZV PCR	Negative
CMV PCR negative	Negative
Paraneoplastic profile	Negative
Brucella IgG/IgM	Negative
Lyme antibody	Negative
Toxo IgG/IgM	Negative
Leptospira IgM	Negative
Schistosoma IgG	Negative
TB Smear	Negative
TB c/s @ 2 weeks	Negative
EBV PCR	Detected
Oligoclonal bands	Not detected
Serology and blood investigations
ANA	Positive; Speckled pattern
C3	13 U/mL (Low)
P-ANCA, c-ANCA	Negative
anti cardiolipin antibody, Lupus anticoagulant	Negative
HIV	Negative
HTLV 1, 2	Negative
JC virus DNA in serum	Negative
Measles IgG antibody	>3.5
NMO	Negative
Histoplasma, coccidioides, blastomyces, aspergillus serology	Negative
Quantiferon TB gold	Negative
Urine/serum IF electrophoresis negative	Negative
Urine protein	17 mg/dL
Brain imaging: MRI brain	Figure 1: Contrast MRI brain: multifocal lesions in both supratentorial and infratentorial compartments; predominantly in deep and subcortical white matter. These lesions are predominantly hyperintense on T2 and FLAIR images; some of the lesions contain foci of hypointensities on susceptibility-weighted images suggesting hemorrhages and some have peripheral rim of diffusion restriction. Minimal perilesional edema is seen.Figure 3: Follow-up MRI after 1 month (June 21, 2016): increase in size, edema and enhancement of lesions.Figure 4: MR brain scan after 8 months (February 21, 2017) showed significant increase in size and number of lesions, intralesional with significant perilesional edema. In additional multiple nodules of diffusion restriction were seen through the cerebral hemisphere.
CT of chest and abdomen: Splenomegaly, lung lesions, mediastinal adenopathy	Splenomegaly, lung lesions, mediastinal adenopathy
Biopsies done: Bone marrow, Mediastinal lymph node, Brain	Non contributory

She also underwent bone marrow, lung, brain and lymph node biopsies. However, no definite conclusion could be drawn. As patient and relatives wanted definite diagnosis, no empirical treatment was started.

Clinical progress

In the subsequent months, she worsened progressively. In October 2016, she fell down at home, had a fracture of the right femur, developed progressive cognitive decline and was confined to bed. She was placed in a nursing care facility. By December 2016, due to progressive cognitive decline she became dependent for activities of daily living and personal hygiene. By the end of January 2017, over one month, she became incontinent with irrelevant talking and reduced oral intake. She was shifted to India in an unconscious state. When she presented to this hospital, she was E1V1M2, had upper GI bleed in Ryle's tube aspirate and she succumbed in less than 24 hours of admission. After consent from caregivers, her autopsy was done.

DR JACOB GEORGE'S CLINICAL DISCUSSION

We have a case of a young lady who presented with relapsing remitting multiple neurologic deficits who went on to develop a progressive downhill course. For a better understanding of the illness’ clinical course, a timeline of the illness is shown in Figure 2.

Figure 2

Clinical course of the patient

Clinical localization and differential diagnosis

The episode of facial weakness she suffered at age of 20 years could be UMN or LMN. At the age of 31 years, she had an episode of dysarthria the localization of which again is uncertain. The right foot drop indicates a mononeurits of right peroneal nerve. The tingling and numbness of both lower limbs associated with painful swollen limbs is probably due to multiple peripheral nerve involvement. Dementia which occurred late in the course of the illness indicates cerebral involvement. The clinical differential diagnosis which may be considered are mentioned in Table 2.

Table 2

Differential diagnosis for a patient with mononeuritis multiplex and dementia

No.	Differential diagnosis for a patient with mononeuritis multiplex and dementia.
1.	Vasculitic illnesses: SLE, Polyarteritis nodosa, Sjogren syndrome, Wegner’s granulomatosis
2.	Sarcoidosis
3.	Retroviral infection
4.	Neoplastic disorders: Lymphoma and leukemia
5.	Giant cell arteritis
6.	Cryogloblinemia and Waldenstrom’s macroglobulinemia
7.	Hypothyroidism

Review of investigations

The investigations done a year ago showed anemia, leukopenia and thrombocytopenia. There was also reversal of albumin globulin ratio (A/G ratio: 0.83). A low AG ratio could indicate overproduction of globulins as in autoimmune diseases, chronic inflammatory diseases, multiple myeloma, Waldenstrom's macroglobulinemia etc., or underproduction of albumins as in cirrhosis or loss of albumin from the circulation as in nephrotic syndrome. C3 levels were markedly low (13 U/ml). This indicates excessive consumption of complement as could occur in many autoimmune disorders such as SLE, APLA syndrome, Sjogren syndrome, mixed cryoglobulinemia, membranoproliferative glomerulonephritis etc. The speckled pattern of ANA positivity is the least specific pattern of and could occur in SLE, Sjogren syndrome, systemic sclerosis, polymyositis and MCTD.

CSF study had shown a lymphocytic pleocytosis with a mild elevation of protein and normal sugar values indicating an inflammatory or neoplastic disorder. CT scan of the chest showed splenomegaly, lung lesions and mediastinal adenopathy. Differential diagnosis for mediastinal lymphadenopathy include sarcoidosis, lymphoma, metastasis, tuberculosis, fungal infections and pneumoconiosis.

MRI of the brain showed extensive T2 hyperintense signals involving gray and white matter of bilateral frontal, temporal and parietal lobes, right insula, cerebellar white matter, midbrain, bilateral thalami, bilateral lentiform nuclei, right caudate nucleus and body and splenium of corpus callosum. There was significant mass effect with midline shift to left and uncal herniation on both sides. Gradient sequences showed very many hemorrhagic foci. There were no areas of diffusion restriction. Major arteries and venous sinuses were normal. Contrast images were not provided to me.

To summarise, this is a patient with a history of facial palsy 14 years ago, mononeuritis multiplex, dementia, Inflammatory CSF picture, a maculopapular rash, pancytopenia, splenomegaly, lung involvement, mediastinal adenopathy, ANA positivity, low C3 levels and MRI showing extensive hemorrhagic lesions with mass effect.

Differential diagnosis

Three differential diagnoses are considered here starting from the least likely possibility.

Diagnosis no. 3: Lymphoma

Lymphoma may involve peripheral nerves, cranial nerves, spinal roots, spinal cord, meninges and brain parenchyma.[1] Cranial nerve palsies occur in 80%. Bone marrow involvement may cause pancytopenia. Splenomegaly and mediastinal lymphadenopathy may occur. ANA positivity may occur in about 19% as well as a wide variety of autoimmune manifestations.[2] But the odd points for lymphoma include a long clinical course, and the MRI findings. Hemorrhages are unusual in lymphoma before treatment, though it may occur in HIV positive individuals. Lesions in lymphoma are diffusion restricting lesions, unlike in this case.[34]

Diagnosis no. 2: Central and peripheral nervous system vasculitis

The long duration of illness, mononeuritis multiplex, dementia, pancytopenia, ANA positivity as well as low C3 levels may occur with vasculitic conditions. Though cranial nerve palsies may occur, facial nerve involvement is not common. Gross splenomegaly and mediastinal lymphadenopathy are unusual for a vasculitic illness. The MRI showed a diffusely enlarged brain with mass effect, this too is unusual with vasculitis as long standing vasculitis tends to produce areas of atrophy as well as sequelae to infarcts.

Diagnosis no. 1: Systemic with neurosarcoidosis

The duration of illness (14 years) fits well with sarcoidosis. Facial palsy, mediastinal adenopathy and lung lesions are classic for sarcoidosis. Mononeuritis multiplex, polyradiculopathy as well as radiculoneuropathy may occur with sarcoidosis. Dementia may occur as sequelae to meningitis or intracranial mass lesions and an inflammatory CSF picture may result. Maculopapular rash is the commonest skin manifestation of sarcoidosis. Massive splenomegaly, hemolytic anemia and pancytopenia have been reported with sarcoidosis.[5] Sarcoidosis may produce immunologic findings similar to SLE.[6] The diffuse brain involvement with hemorrhages may be due to sarcoid vasculitis.

Protean manifestations make sarcoidosis a great mimicker. Best diagnostic clues for sarcoidosis are solitary or multifocal mass lesions with mediastinal adenopathy. Sarcoidosis may involve any part of the CNS such as pachymeninges, leptomeninges, pituitary, hypothalamus, it may produce parenchymal masses, vasculitis of the cerebral vessels, may thicken and infiltrate the choroid plexus, may involve the spinal cord, may produce hydrocephalus, may infiltrate the orbital adnexa and optic nerves.[7]

Though sarcoidosis may seem possible, there are many odd points for sarcoidosis as well. It is mostly a benign disease with good response to steroids. At the same time, though it may be associated with vasculitis, it is unlikely to produce such extensive hemorrhagic brain lesions.

DR AJAY GARG'S RADIOLOGIC DISCUSSION

Contrast MRI scan of brain (May 12, 2016) showed multifocal lesions in both supratentorial and infratentorial compartments; predominantly in deep and subcortical white matter [Figure 1]. These lesions were predominantly hyperintense on T2 and FLAIR images. Some of the lesions contain foci of hypointensities on susceptibility-weighted images suggesting hemorrhages and some had peripheral rim of diffusion restriction. Minimal perilesional edema was seen.

Follow-up MRI after 1 month (June 21, 2016) showed increase in size, edema and enhancement of lesions [Figure 3]. MR brain scan after 8 months (February 21, 2017) showed significant increase in size and number of lesions with significant perilesional edema [Figure 4]. In addition to that, multiple nodules of diffusion restriction were seen through the cerebral hemisphere. I would consider vasculitis and neurosarcoidosis as the most possible differentials.

Figure 3

Contrast enhanced MRI (June 21, 2016). Axial T2-WI (a-c) show hyperintense lesions in bilateral middle cerebellar peduncles and cerebellar white matter (a), right periatrial and peri-insular white matter (b) and subcortical white matter of both frontal and parietal lobes (c). SWI (d) show multiple hypointense foci within T2-hyperintense lesions suggesting hemorrhages. Contrast-enhanced T1-WI in axial (e-g) and coronal (h) plane show foci of patchy to no enhancement with the white matter lesions

Figure 4

MR brain scan (February 21, 2017). Axial T2-WI (a-c) show hyperintense lesions in bilateral cerebellar and temporal lobe white matter (a), bilateral periatrial, right frontal and peri-insular white matter, both thalami and posterior limb of internal capsules (b) and subcortical white matter of both frontal and parietal lobes (c). SWI (d) show multiple hypointense foci within T2-hyperintense lesions suggesting hemorrhages. Axial DWI maps (e and f) and ADC maps (g and h) show multiple nodules of diffusion restriction, bright on DWI maps (arrowheads in e and f) and dark on ADC maps (arrowheads in g and h)

DR MC SHARMA'S PATHOLOGICAL DISCUSSION

Neuropathology: Dr Jacob George discussed the case very nicely but missed one positive finding of PCR positivity for EBV in CSF. We received consent for complete autopsy as well as later on biopsies from brain, lung and bone marrow done in the overseas hospital.

The weight of various organs examined on autopsy is as in Table 3. Gross examination of brain revealed haemorrhagic areas at the previous biopsy site and multiple greyish areas in the white mater which at places were extending into grey mater [Figure 5]. Multiple sections examined [Figure 6] showed polymorphic infiltrate around blood vessels, predominantly in white matter but also extending into grey matter at places, comprising of lymphocytes, plasma cells and macrophages. Amidst this infiltrate, few large atypical cells with prominent nucleoli were also identified. Some of these cells were binucleated and resembled Reed-Sternberg cells of Hodgkin Lymphoma. This infiltrate was seen infiltrating blood vessel walls which was better appreciated on reticulin stain. There was involvement of meninges, choroid plexuses and cerebellar hemispheres. Subpial gliosis was also significant. In addition to that, few areas of necrosis along with sheets of foamy macrophages and areas of old haemorrhage were also noted. This inflammatory infiltrate was admixture of B cells (CD20), T cells (CD3), plasma cells (CD138) and macrophages (CD68 immunopositive). Plasma cells were polyclonal (immunopositive for kappa and lambda). Large atypical lymphoid cells were EBER (Epstein Barr virus encoded small RNA) positive [Figure 7].

Table 3

Organs examined at autopsy

Organ examined	Weight
Brain	1500 g
Right lung	375 g
Left lung	425 g
Liver	1985 g
Spleen	750 g
Right kidney	300 g
Left kidney	325 g

Figure 5

Cut surface of brain showing hemorrhagic areas (short arrow in the gray matter and greyish white areas at the junction of white and gray matter (long arrow)

Figure 6

Photomicrographs showing polymorphic infiltrate in the meninges (a), around blood vessels with angioinvasion (b). Some of the cells are binucleated and resembles Reed-Sternberg cells of Hodgkin lymphoma (c) and are immunopositive for CD20 (d)

Figure 7

Microphotomicrograph of spleen showing EBER (nuclear positivity) by chromogenic in situ hybridization)

Sections from lungs showed polymorphic infiltrate in the interstitium, at places it was bronchocentric. In addition to that, some of the bronchioles show aspiration material with surrounding neutrophilic abscesses. Spinal nerve roots, liver, spleen, kidneys, adrenals and endometrium revealed similar infiltrates as was seen in the brain. Brain biopsy and lung biopsy slides were subsequently reviewed which showed similar features and bone marrow was unremarkable.

Based on above features of polymorphic infiltrate of predominantly T cells admixed with few atypical B cells which were positive for EBER, the possibility of lymphomatoid granulomatosis (a type of NHL, B immunophenotype) was considered. This was further supported by PCR positivity for EBV in the CSF. Central nervous symptoms, organomegaly and nerve infiltration explains all her symptoms.

Lymphomatoid granulomatosis (LG): According to WHO classification[8] of haemato-lymphoid malignancies 2018, LG is a rare lymphoproliferative disorder involving extranodal sites and is characterised by EBV positive atypical B cells of variable number, predominance of T cells, admixed with other cells. This infiltrate is angiocentric/angioinvasive/angiodestructive. Histological spectrum is related to proportion of larger atypical B cells. It is believed that there is dysregulation between T and B cells functions. T cell immunosuppression lead to EBV infection of B cells, hence the proliferation.

Prevalence of LG is not precisely known but it is more common in men between 5th to 6th decades and is rare in children.

The common manifestations are of LG are:

Pulmonary-typical and seen in 90%

Cutaneous: 25–50%

Renal: 30–40%

Hepatic: 29%

Central nervous system involvement: CNS; 26%

Cranial nerve palsies and peripheral polyneuropathy: 7% of case.

Treatment modality depends upon grading. According to number of EBER positive cells three grade are assigned. Grade 1: Large atypical cells are rare and EBER positive cells are <5 per high power field; Grade 2: Occasional large cell but EBER count is 5-20 per HPF; Grade 3: Large number of large cells like diffuse large cell lymphoma and EBER positive cells >50 per HPF. Grade 1 and2 may not require any treatment or mild immunosuppression or immunomodulation may be sufficient. Even spontaneous remissions can occur in lower grades. Grade 3 LG is treated like high grade lymphomas and prognosis is dismal.

Isolated brain involvement is rare and difficult to diagnose. Clinical, radiological and morphological mimics are many. High index of suspicion is required for diagnosis. I appreciate the succinct presentation of Dr Jacob George who came very close to the diagnosis.

Final diagnosis

Dr Jacob George's clinical Diagnosis: Neurosarcoidosis

Dr Ajay Garg's radiologic diagnosis: Vasculitis/Neurosarcoidosis

Dr MC Sharma's pathologic diagnosis: Lymphomatoid granulomatosis (grade I/II) involving Brain, lungs, liver, kidneys, uterus, adrenals, spleen and peripheral nerves

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.