A 49-year-old Caucasian man developed a cough in early 2004. A chest X-ray revealed bilateral hilar lymphadenopathy, confirmed by thoracic computed tomography (CT) scan. He had no other symptoms. A diagnosis of sarcoidosis was considered, but his symptoms were thought insufficient to warrant treatment.
In July 2004, he developed numbness and pain behind the right knee which gradually spread to the lower back, right buttock and posterior thigh. Upon examination he had reduced sensation over the lateral border of the right foot, an absent right ankle tendon reflex and a positive Lasegue's sign at 70 . He also had a dusky discolouration of the skin of the right foot.
He was admitted to our hospital in September 2004 because of progressive worsening of the symptoms. Lumbrosacral spinal magnetic resonance imaging (MRI) showed an increased heterogeneous signal within the S1 nerve root and of the nerve root ganglion on T2 images, thought to be due to oedema, with right piriformis wasting. His cerebrospinal fluid (CSF) contained no white cells, 0.52 g/l protein and 0.36 g/l glucose. Nerve conduction studies and an electromyogram (EMG) revealed abnormalities in the S1 segment, consistent with an S1 radiculopathy. Serum angiotensin converting enzyme (sACE) was persistently normal but an isotope-labelled gallium scan showed increased bilateral lung hilar and lachrymal gland uptake. He developed skin nodules on his right thigh which, when biopsied, were confirmed as erythema nodosum. The diagnosis of sarcoidosis was considered overwhelmingly likely, and in the absence of compression, the involvement of the S1 root was thought most likely due to neurosarcoidosis. He started treatment with prednisone 30 mg/day but his pain persisted; intravenous steroids and then local steroid nerve root injection was tried with temporary benefit. In April 2005, he started methotrexate (up to 12.5 mg per week) because of persistent pain and the need to lower his steroid dose because of his elevated glucose levels.
In November 2005, he developed left peri-orbital and hemicranial headache, followed by diplopia on left gaze. He was found to have a partial left sixth nerve palsy and was re-admitted. MRI showed thickening and gadolinium enhancement in the left cavernous sinus with no parenchymal change. Repeat gallium scanning showed normal lung hilar and lachrymal gland uptake. Serum rheumatoid factor, plasma viscosity, C-reactive protein, urea and electrolytes, liver function, clotting, auto-immune profile, protein electrophoresis, acetylcholine receptor antibodies, anti-neuronal antibodies, anti-thyroid antibodies, creatine kinase and ACE were all normal. He was treated with a three-day course of intravenous methylprednisone and experienced significant improvement.
The following month, he developed headache and further diplopia and he was found to have a painful pupil-sparing left third nerve palsy. His CSF was again entirely normal, including negative oligoclonal band assay. Brain and orbit MRI scanning were normal. EMG and nerve conduction studies suggested improvement of S1 radiculopathy. He also complained of left facial pain with tearing of the left eye. There was a patchy decrease in sensation on the left side of the face and scalp. Corneal reflex was diminished. Blink reflex and facial nerve conduction studies showed an afferent defect on the left suggesting a left trigeminal ophthalmic division neuropathy. His prednisone was increased to 60 mg/day, and cyclophosphamide was started instead of methotrexate. However, after reducing his steroids to 40 mg/day, severe facial pain recurred.
In March 2006, he developed numbness and tingling on the left side of his face, and was found to have a left maxillary ophthalmic division Vth neuropathy. A month later he developed a lower motor neuron left seventh nerve palsy and numbness in the right shoulder and in the left thorax. His CSF was again normal and/or negative including cytological study, acid-fast bacilli staining, and fungal and Mycobacterium tuberculosis cultures and sACE was also still normal. His blood count showed mild lymphopenia and macrocytosis. Lactate dehydrogenase was normal. Borrelia, syphilis, cytomegalovirus, HIV and human T-lymphotropic virus Type 1 serology were negative. An ophthalmological examination was normal with no signs of granulomata.
At this stage, new neurological symptoms developed while the patient was on treatment with steroids and cyclophosphamide. Because no diagnosis emerged other than sarcoidosis, alternative immunosuppressive therapy was administered. Intravenous immunoglobulins, however, had no impact. Infliximab was added in June 2006. Despite this, the patient's right shoulder became weak, his headache persisted and he also developed unsteadiness of gait and significant weight loss. He now had bilateral seventh nerve palsies with weakness of the left palate, right serratus anterior, right triceps, left triceps and left finger abductors. All the upper limb deep tendon jerks were absent. A left vocal cord palsy was noted. EMG and nerve conduction studies showed abnormalities compatible with a pre-ganglionic lesion at C5 and C6 level (right), but no generalised neuropathy. Repeat brain MRI scanning showed enhancement of the fifth, sixth, seventh and eighth cranial nerves (Figure 1). Spine MRI scanning was normal. MRI scanning of the upper brachial plexus was normal. A CT scan of the pelvis and abdomen were normal. A whole body fluorodeoxyglucose-positron emission tomography (FDG-PET) scan was normal. Urine thallium screening and lead level were negative. Upper gastrointestinal endoscopy was normal.
The patient then developed three subcutaneous nodules, one in the left outer inferior breast quadrant, without lymphadenopathy. Biopsy of the nodules showed lymphomatous change, and the final diagnosis was diffuse large B-cell lymphoma involving cranial and peripheral nerves (neurolymphomatosis). Bone marrow was normal.
He was transferred to the Oncology department and treated with chemotherapy including methotrexate. After chemotherapy he received total body irradiation and a bone marrow stem cell transplant. There was no significant improvement in his neurological condition.