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|Year : 2015 | Volume
| Issue : 1 | Page : 30-34
Series of paraneoplastic vasculitic neuropathy: A rare, potentially treatable neuropathy
Meena A Kannan1, Sundaram Challa2, Rukmini M Kandadai1, Megha S Uppin2, Sheik A Jabeen1, Rupam Borgohain1
1 Department of Neurology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
|Date of Web Publication||4-Mar-2015|
Dr. Meena A Kannan
Department of Neurology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
Background: Paraneoplastic vasculitic neuropathy (PVN) is a rare paraneoplastic syndrome. It is characterized by non-systemic subacute vasculitic neuropathy. It is most commonly associated with small cell lung cancers (SCLC) and lymphomas. PVN presents as a painful symmetrical or asymmetrical sensorimotor axonal neuropathy. The neurological symptoms may predate the tumor and may be the initial manifestations, or they may develop after a tumor is diagnosed. Recognition of this entity is important because of its potential treatability.
Aim: To study the clinical features of PVN and briefly review the literature.
Materials and Methods: The data was collected retrospectively from the medical records of our hospital.
Results: Of the 14 cases of paraneoplastic neuropathies, 4 had a PVN. The age of onset was more than 50 years and there was no sex preponderance. Pain was seen in three patients. Two patients were previously treated for a thymoma. Two patients, following their presentation with PVN, were diagnosed with a colonic carcinoma and lung carcinoma, respectively.
Conclusions: The recognition of PVN is important as this syndrome may respond to immunosuppression and tumor removal.
Keywords: Morvan′s syndrome; paraneoplastic vasculitic neuropathy; thymoma
|How to cite this article:|
Kannan MA, Challa S, Kandadai RM, Uppin MS, Jabeen SA, Borgohain R. Series of paraneoplastic vasculitic neuropathy: A rare, potentially treatable neuropathy. Neurol India 2015;63:30-4
|How to cite this URL:|
Kannan MA, Challa S, Kandadai RM, Uppin MS, Jabeen SA, Borgohain R. Series of paraneoplastic vasculitic neuropathy: A rare, potentially treatable neuropathy. Neurol India [serial online] 2015 [cited 2019 Oct 14];63:30-4. Available from: http://www.neurologyindia.com/text.asp?2015/63/1/30/152629
| » Introduction|| |
Peripheral neuropathy occurs in up to 50% of patients with a carcinoma. The commonest causes are treatment toxicity, tumorous infiltration, metabolic disturbances, and terminal cachexia.  When none of the above mentioned reasons are detected, the cause of neuropathy is believed to be due to specific cancer-related immunological mechanisms. This immunological neuropathy, involving any part of the central or peripheral nervous system, is termed as paraneoplastic neuropathy.  Paraneoplastic neuropathy restricted to the peripheral nervous system occurs in Guillain Barre Syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), vasculitic neuropathy, chronic axonal neuropathy, and brachial plexopathy. Paraneoplastic vasculitic neuropathy (PVN) is a rare paraneoplastic neuropathic syndrome that is characterized by non-systemic subacute vasculitic neuropathy. , PVN is commonly associated with small cell lung cancers (SCLC) and lymphomas.  Diagnosing PVN is important as prompt recognition of the disease can maximize the institution of successful treatment and the likelihood of a favorable outcome. We share our experience in managing PVN and briefly review the literature.
| » Materials and Methods|| |
All those patients diagnosed as having a paraneoplastic syndrome (PNS) at our institute from May 2005 to May 2013 were analysed retrospectively. The diagnosis of PNS was established only after a malignancy had been confirmed on histopathological examination. The demographic data of all patients with their clinical details were obtained from the medical records, tumor registry, and the neuromuscular disorder registry. The laboratory investigations carried out at the time of the diagnosis included hematological [white blood cell (WBC) and red blood cell (RBC) counts, haemoglobin, platelet count, and erythrocyte sedimentation rate (ESR)] and, biochemical tests (total proteins, total bilirubin, liver and renal function tests), electrolytes, glucose, and creatinine kinase (CK). Testing of anti-neuronal antibodies/onconeural antibodies (anti-Hu, anti-Yo, anti-Ri, anti-amphiphysin, anti-CV2/CRMP 5, and anti-Ma) either in the serum or cerebrospinal fluid (CSF) was carried out according their relevance. Immunoelectrophoresis was also carried out for protein fractions when paraproteinemia was suspected. The computed tomography of the chest and abdomen, upper gastrointestinal endoscopy, and colonoscopy were performed to detect a malignancy. A whole body positron emission tomography (PET) scan was also carried out in one patient. Magnetic resonance imaging (MRI) of the brain and spine was carried out in cases with central nervous system (CNS) syndromes. Nerve conduction studies and electromyography were done in all cases with peripheral nervous system manifestations. Vasculitis was confirmed by a nerve biopsy.
| » Results|| |
A total of 14 patients were identified with paraneoplastic neuropathies. Four (28.5%) of these patients had a PVN. The age at presentation was greater than (>) 50 years in three of the patients and both men and women were affected equally. All patterns of neuropathy were seen and pain was seen in 3 patients. PVN anteceded the tumor in two patients and occured following the tumor appearance in other two patients [Figure 1] and [Figure 2]. Two patients with a PVN had a thymoma. Two patients had other associated paraneoplastic neurological syndromes. The details of the cases are given in [Table 1] and the following case identifies one pattern of neuropathy.
|Figure 1: H and E × 40 stain. A case of myasthenia gravis (a) Microscopic section of a thymoma with lobular arrangement showing epithelial cells and lymphocytes; (b) sural nerve biopsy transverse section; (c) a focus of endoneural inflammation; and, (d) H and E × 100. Epineurial vessel showing a dense perivascular infiltrate of lymphocytes with vascular destruction consistent with a diagnosis of vasculitis|
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|Figure 2 (a and b): H and E × 40 and 100, respectively. Nerve biopsy of a patient with colonic carcinoma and mononeuritis multiplex. The nerve biopsy shows a dense epineurial perivascular lymphocytic infiltrate with marked neovascularization|
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|Table 1: Clinical characteristics and outcome of four cases with paraneoplastic neuropathy|
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A 57-year-old male patient presented with continuous painful twitching in both calves and paresthesiae in the feet in the month of May 2009. He gave a history of anxiety, insomnia, and increased sweating. His past history revealed that in the year 2004, he was diagnosed with myasthenia gravis. In the year 2008, he was found to have a thymoma type B (WHO) and underwent a thymectomy. Following surgery, he received 25 fractions of radiotherapy.
On physical examination, myokymia was detected in both lower limbs. There was associated hyperhydrosis. The other findings were normal. His vital parameters were within normal limits. His neurological examination revealed normal cognitive function, cranial nerve and motor function. He had decreased pain and vibration perception in both feet, and normal temperature and joint position sensation. The nerve conduction studies showed a low amplitude compound motor action potential (CMAP) in the peroneal and posterior tibial nerves. The amplitude of CMAP in the median and ulnar nerves was normal. The conduction velocity, distal latency, and F wave latency in all the nerves were normal. The amplitude of sensory nerve action potential (SNAP) of sural and superficial peroneal nerves was reduced. The needle examination of quadriceps, tibialis anterior, and gastrosoleus muscles showed spontaneous discharges in the form of quadruplets and doublets (myokymic discharges).
Based on the above findings, a diagnosis of Morvan's syndrome (MS) was made. The patient was advised 5 cycles of plasmapharesis (in each cycle, 50 ml/kg body weight was exchanged). He was also given pyridostimine, 60 mg twice daily; prednisolone, 20 mg/day; and azathioprine 100 mg/day. He showed a significant improvement with the above treatment.
He was admitted again in the month of September 2009 with breathlessness, twitching movements of calves, and pain in both legs. On examination, he was found to have hyperhidrosis. His body temperature was 98.6 F; pulse rate, 76/min; blood pressure, 140/80 mmHg; respiratory rate, 40/min; and, single breath count, 12. His chest and cardiovascular system examination were normal. Neurological examination revealed mild confusion, mild proximal weakness in all the extremities (4/5 MRC grading), and sinusoidal twitching movements over the thighs and calves. The blood chemistry and hematology values were within normal range. The blood culture was sterile and an arterial blood gas analysis revealed a respiratory failure.
The patient was given mechanical ventilation (SIMV mode) and plasma exchange. He also required treatment of nosocomial pneumonia and hyponatremia. Despite showing clinical improvement, he could not be weaned from the ventilator. There was no improvement with pyridostigmine administration. On phrenic nerve stimulation, no CMAP was elicited. He underwent a tracheotomy, twice had a cardiac arrest and finally succumbed to his illness after a prolonged stay in the hospital.
The autopsy and nerve and muscle biopsy did not reveal any residual tumor. There was presence of lobar pneumonia. His sural nerve biopsy showed a dense perivascular lymphomononuclear infiltrate with transmural infiltration and vessel wall destruction. The K-Pal stain for myelin showed a multifocal, symmetrical fiber loss. The Masson trichrome stain showed increase in collagen [Figure 3]. The muscle biopsy showed type 2 atrophy. The cause of death was attributed to respiratory failure secondary to myasthenia gravis.
|Figure 3: Nerve biopsy of patient with lung carcinoma. (a) The transverse section of the nerve biopsy showing fascicles with perivascular inflammation around epineurial vessel (H and E × 40); (b) the perivascular infiltrate causing vessel wall destruction and luminal narrowing (H and E × 100); (c) the epineurium showing mild fibrosis. Masson's trichrome stain × 100; and (d) mild non-uniform loss of myelinated fibers (Kpal × 40)|
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| » Discussion|| |
VN may occur as an initial manifestation of the underlying cancer and may delay its diagnosis. PVN presents as a painful symmetrical or asymmetrical, sensorimotor axonal neuropathy or as a mononeuritis multiplex. The course is generally subacute or chronic and progressive. It usually affects older men. Its course is often severe, but may also be mild, especially when it occurs late in the course of the illness.
Apart from lung cancer and lymphoma, the other tumors frequently associated with paraneoplastic syndromes include breast carcinoma, ovarian carcinoma, Hodgkin's lymphoma, germ cell tumor, and a thymoma. In PVN, neurological symptoms may predate the tumor. They may be responsible for both the initial manifestation or the manifestations developing after a tumor is diagnosed. In elderly patients, the presence of a chronic and persistent neuropathy especially warrants a search for malignancy. Thus, it should be viewed as a paraneoplastic disorder and may also involve the muscles. The frequent laboratory findings are an elevated ESR and high CSF protein concentrations. Electrophysiology findings usually show axonal degeneration involving both motor and sensory components equally. Sural nerve biopsy demonstrates focal mononuclear cell infiltration of epineural vessel walls and active nerve fiber degeneration. Rarely, there may additionally be arteriolar fibrinoid necrosis with luminal obliteration. The inflammatory response mediated by CD8 T cells should be corroborated by biopsy findings. Presence of myelin ovoid bodies and axonal changes indicate an axonal degeneration.
In patients having a PVN, extra-neurological manifestations are generally absent. A careful follow-up of patients with sensory motor neuropathy of undetermined cause would lead to a diagnosis of cancer as an etiology. However, the association does not necessarily indicate that it is paraneoplastic in nature. Some patients with peripheral nerve vasculitis and a coexisting small cell lung cancer (SCLC) may have clinical and pathological features of subacute sensory neuronopathy (SSN) and paraneoplastic encephalomyelitis (PEM).  The diagnosis of a paraneoplastic neuropathy remains a challenge when anti-neuronal antibodies are negative. Furthermore, no specific antibodies have been identified in any of the paraneoplastic vasculitidis. The antibodies usually reported in association with these neuropathies are anti-Hu or anti-CV2 antibodies. Patients with SCLC may have anti-Hu antibodies, with or without overt CNS involvement. 
PVN may be differentiated into two groups.  In the first group, vasculitis is a component of subacute sensory neuropathy. This may either be confirmed on autopsy as determined in our second patient; or may be considered as being highly probable on clinical and electrophysiological data. These patients often have an underlying SCLC. In the second group of patients, peripheral neuropathy is the only clinical manifestation (as seen in our third and fourth patients). Various cancers associated with this group of patients include a lymphoma, Hodgkin's disease, uterine and stomach cancer, and non-small cell lung cancer.
There are studies reporting that 10-15% of patients with vasculitis of the nerve and muscle have an underlying neoplasm, the incidence of which appears to be higher than in the general population. , However, there are no controlled clinical and epidemiological studies.  Our study documented PVN in 28% of cases of paraneoplastic neuropathies. In a study, 13 patients had paraneoplastic vasculitis of the nerve.  The associated tumors mentioned in the study were SCLC in four patients, lymphoma in three patients, and cancers of the kidney, bile duct, stomach, and prostate in other patients. There are other reports of this unique association of Morvan's syndrome with a thymoma, as seen in our case.  Colorectal cancer may rarely present with a neurological paraneoplastic disorder. , A 10 year retrospective study of 115,081 patients suffering from cancer reported that only 58 of them (0.05%) suffered from a paraneoplastic neurological syndrome. Out of them, five patients had a colon cancer.  Another case report described an unusual association of P-ANCA-positive vasculitis in a patient suffering from colon cancer in whom the vasculitis resulted in impressive neurological symptoms. 
The recognition of PVN is important as these syndromes may respond to primary tumor removal and immunosuppression using corticosteroids along with cyclophosphamide.  The response to treatment may either be complete or partial. In our cases also, the patients improved partially after treatment with corticosteroids and cyclophosphamide. Corticosteroids alone do not seem to have much effect.
| » Conclusion|| |
A malignancy may initially present as a vasculitic neuropathy. Vasculitic neuropathy without systemic vasculitis is more often reported in association with solid tumors. A search for malignancy is warranted when patients, especially older individuals, develop symptoms of symmetric or asymmetric painful, sensorimotor neuropathy often accompanied by proximal muscle weakness, and when chronic or persistent vasculitis develops that is poorly responsive to standard medication.
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[Figure 1], [Figure 2], [Figure 3]
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