The term paraneoplastic was first used by Guichard and Vignon in 1949 to describe a patient presenting with multiple cranial nerve and radicular neuropathies [
A 69-year-old Caucasian female with no past medical history of note was admitted with a two-month history of progressive ataxia, impaired balance, and slurring of speech, associated with emotional liability. There was no family history, and she denied any systemic symptoms such as a headache. She was a nonsmoker, who lived with her partner, drinking alcohol only on occasion. On examination she displayed emotional liability and cerebellar signs including high pitched scanning speech, down beat vertical nystagmus, dysmetria, past pointing, dysdiadokinesis, truncal ataxia, and marked titubation of neck and trunk which impeded her gait. Visual acuity was 6/18 in the right eye and 6/9 in the left eye with intact visual fields and bilaterally pale discs. Examination of the upper and lower limbs revealed increased tone with brisk reflexes throughout and extensor plantars. There was no evidence of motor signs, bowel or bladder dysfunction. Systemic examination including breast examination was normal.
The patient had several blood tests, of which only B12 and ESR appeared to be abnormal at 142 ng/L (normal > 150 ng/L) and 80 mm, respectively. Other parameters, including immunoglobulins, protein electrophoresis, autoimmune and vasculitic screens, antineuronal antibodies, and tumour markers, were all negative. Her MRI revealed hyperintensities in the medial temporal lobes consistent with limbic encephalitis but was otherwise unremarkable, revealing no evidence of cerebellar or brainstem pathology or atrophy. She then went on to have a CSF examination; this revealed an IgG of 49, positive oligoclonal bands and weakly positive protein 14 : 3 : 3, with other parameters being within the normal range.
The patient was treated empirically for immune mediated subacute combined cerebellar degeneration, with high dose steroids with very little improvement. This prompted a 5-day course of plasma exchange, though the patient’s condition remained unstable, and she underwent a further 3 courses, all with minimal improvement. A more extensive search for a possible tumour was then conducted. Although transvaginal ultrasound was normal, mammography did reveal a noticeably enlarged lymph node in the right axilla and a poorly defined lesion at 11 o’clock to the nipple. FNA of the former determined it to be benign, and as for the latter, histology was consistent with a papillary change, with subsequent core biopsy being unremarkable.
Further radiological investigations were conducted, including a CT of her chest, abdomen, and pelvis, revealing a single intra-abdominal lymph node. She underwent a laparotomy and lymph node biopsy, which revealed in the discovery a grade 3A follicular lymphoma. She received immunotherapy, steroids followed by azathioprine but no specific chemotherapy for the lymphoma. Her neurological status remains essentially unchanged.
A 64-year-old Caucasian female presented with sudden onset of unilateral leg weakness, where she experienced great difficulty in hip flexion. She had previously been well but had recently complained of excessive fatigue and episodes of abdominal pain. Examination revealed a vasculitic rash covering extensor surfaces of her knees; proximal left leg weakness was also demonstrated. The patient was admitted with a provisional diagnosis of dermatomyositis, her blood results revealing a grossly elevated CK of 15,000 u/L (normal 25–170 u/L), and she was treated empirically with high dose steroids. Unfortunately, this failed to control her weakness, which gradually progressed over 8 weeks to involve both lower limbs. She additionally developed a bulbar palsy and weakness of neck flexion, prompting her transfer to ITU.
On admission to ITU, patient was moribund, with bulbar dysarthria, nasal speech, and a nonpruritic, vasculitic rash covering the extensor surfaces of her arms and knees. There was no evidence of Gottron’s sign or of a heliotropic rash. Examination of her limbs elicited significant weakness, more severe proximally.
An EMG revealed a myodestructive pattern, with reduced amplitudes on NCS. A muscle biopsy was also performed, revealing atrophic sclerotic muscle, which was histologically consistent with dermatomyositis. Throughout her admission, the patient had several investigations, including routine bloods, glucose, TFTs, B12 and folate, autoantibodies, iron studies, and tumor markers; the only abnormality appeared to be an elevated Ca-125 (see Figure
Ca-125 levels.
Whilst in ITU, the patient additionally developed complex partial seizures originating from the left occipitotemporal region, though she had a normal CT head and only evidence of small vessel disease on MRI. A maintenance regimen of propofol and phenytoin seemed to control her seizures. She then developed what appeared to be an acute abdomen, for which a laparotomy was arranged; despite exploration revealing inflammatory changes involving her right adnexa, no malignancy was identified, and she was transferred back to ITU and eventually to a ward.
The patient’s weakness was refractory to immunoglobulins and methotrexate, though it showed a dramatic response to rituximab, and plans were made for her discharge, during which time she developed a DVT with a concurrent PE, despite pharmacological and mechanical measures. Therefore a PET scan was arranged upon her discharge. Before this could be done, the patient presented with disseminated ovarian carcinoma, which was ultimately fatal.
Suspecting and investigating paraneoplastic syndromes (PNSs) are crucial as up to 80% of patients present with PNS before there is any other indication of malignancy [
Some of the known paraneoplastic syndromes with their associated antibodies and malignancies.
Syndrome | Antibodies | Associated malignancies |
---|---|---|
Cerebellar degeneration | Anti-Hu, Anti-Yo, Anti Ri, Anti CV2, and Anti-GAD, Anti-Tr, Anti-Zic4, Anti-mGluR1, and Anti-VGCC | SCLC, gynaecological, breast, thymoma, and others |
Limbic encephalitis | NMDA, VGKC related antibodies, Anti-Hu, Anti-Ma, and Anti-GAD | Gynaecological, germ cell tumours of testis, and SCLC |
Opsoclonus myoclonus | Anti- Ri, neuroleukin, gliadin, and Zic2 | Gynaecological, breast, and SCLC |
Brainstem encephalitis | Anti-Hu, Anti-Ri, and Anti-Ma | |
Stiff person Syndrome | Antiamphiphysin, Anti-GAD | SCLC, breast, |
Myelitis | Anti-Hu, Antiamphiphysin | |
Peripheral neuropathy | Anti-CV2 | SCLC, thymoma, and others |
LEMS | Anti-VGCC | SCLC |
The cerebellum is commonly involved in paraneoplastic syndromes. The extent of the involvement, clinical course, and the prognosis depends on the associated antibody and the underlying tumour [
Dermatomyositis is an autoimmune myopathy which typically features characteristic skin changes in association with subacute proximal muscle weakness, elevated muscle enzymes, and histological changes consistent with inflammation or necrosis [
Recommended diagnostic guidelines exist to ascertain the likelihood of a neurological presentation representing one of the paraneoplastic syndromes (see Figure
Diagnostic guidelines for paraneoplastic syndromes (adapted from source) [
Other laboratory tests of significance include tumour markers, which appeared to be the only investigative abnormality in one of the cases. The National Academy of Clinical Biochemistry does not favour requests for panels of tumour markers, recommending their use based on individualized clinical evaluations to yield the risk of malignancy [
Other authors have noted that a significant time interval may be present between the first presentation of, and discovery of, the underlying tumour, even after extensive investigations [
Corticosteroids, intravenous immunoglobulins, plasma exchange, and various other immunomodulatory therapies have been tried and can be effective in some paraneoplastic conditions such as NMDAR encephalitis [
Patients presenting with features of a PNS should be investigated extensively for an underlying malignancy. After routine investigations, we recommend for patients to have tumour markers, paraneoplastic screen, imaging of the body including PET, and invasive procedures (i.e., biopsies and excision of “cysts”) if indicated. Ideally, the underlying malignancy should be managed prior to or in conjunction with the PNS.