POEMS syndrome

POEMS syndrome (also known as Crow–Fukase syndrome, Takatsuki disease, or PEP syndrome) is a rare medical syndrome. It is defined as the combination of a plasma-cell proliferative disorder (typically myeloma), polyneuropathy, and effects on many other organ systems. It begins in middle age – the average age at onset is 50 – and affects up to twice as many men as women. If untreated it is progressive and often fatal, with only 60% of sufferers remaining alive five years after onset. However, the symptoms can improve if the blood disorder is successfully treated.

The name 'POEMS syndrome', now the most prevalent, was coined in 1980 by Bardwick et al. The name is an acronym deriving from some of the main features: Polyneuropathy (peripheral nerve damage), Organomegaly (abnormal enlargement of organs), Endocrinopathy (damage to hormone-producing glands) or Edema, M-protein (an abnormal antibody) and Skin abnormalities (including hyperpigmentation and hypertrichosis). However, these features are neither an exhaustive list nor seen in all individuals with the condition.

Signs and symptoms
The following are the most common clinical features of POEMS syndrome, either symptoms or signs. The first two are present by definition; the remainder are frequent but not universal, and different individuals experience different combinations of them.

Defining features
The polyneuropathy is usually symmetrical and distal. There is a combination of demyelination and axonal damage, and sensory, motor and autonomic neurones are all affected. The typical symptoms are therefore of numbness, tingling and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with POEMS syndrome to seek medical attention.

Myeloma is the most common plasma-cell proliferative disorder associated with POEMS syndrome, present in more than half of all cases. Most myelomas associated with POEMS syndrome are osteosclerotic, in contrast to the osteolytic bone lesions in most other myelomas. Other blood disorders occur in a significant minority of cases, including Castleman's disease, plasmacytoma and MGUS.

Common features
Papilloedema is a common sign of POEMS syndrome, occurring in a significant proportion of cases. Less frequent ocular features include uveitis and preretinal haemorrhage.

Pulmonary disease: The lungs are often affected at more severe stages of the illness, although since by then physical exertion is usually limited by neuropathy, shortness of breath is unusual. Pulmonary hypertension is the most serious effect on the lungs, and there may also be restriction of chest expansion or impaired gas exchange.

Organomegaly: The liver may be enlarged, and less often the spleen or lymph nodes, though these organs usually function normally.

Oedema: Leakage of fluid into the tissues is a common and often severe problem. This may take several forms, including dependent peripheral oedema, pulmonary oedema, effusions such as pleural effusion or ascites, or generalised capillary leakage (anasarca).

Endocrinopathy: In women, amenorrhoea, and in men, gynaecomastia, erectile dysfunction and testicular atrophy, are common early symptoms due to dysfunction of the gonadal axis. Other hormonal problems occurring in at least a quarter of patients include type 2 diabetes, hypothyroidism and adrenal insufficiency.

Monoclonal paraprotein: In most cases a serum paraprotein can be detected, although this is not universal (75–80%). This may represent IgG or IgA, but the light chain type is almost always lambda. This is in contrast to most paraproteinaemic neuropathies, in which the paraprotein is usually an IgM antibody.

Skin changes: A very wide variety of skin problems have been reported in association with POEMS syndrome. The most common is non-specific hyperpigmentation. The fingernails may be clubbed or white, There may be thickening of the skin, excess hair or hair in unusual places (hypertrichosis), skin angiomas or haemangiomas, or there may be changes reminiscent of scleroderma.

Possible features
Some features have been observed in patients with POEMS syndrome but are not yet certain to form part of the syndrome itself. These include thrombophilia, arthralgia, cardiomyopathy (systolic dysfunction), fever, low vitamin B12 levels and diarrhea.

Laboratory findings
In addition to tests corresponding to the above findings (such as EMG for neuropathy or CT scan and bone marrow biopsy for myeloma), two other tests give abnormal results. These are: a raised level of VEGF in blood; and a raised CSF protein level, as in some other neuropathies. Even when myeloma is present, anaemia and thrombocytopaenia are rare; on the contrary, polycythaemia and thrombocytosis are often found.

Criteria
The most recent criteria for the diagnosis of POEMS syndrome require that all of the following be present:
 * polyneuropathy
 * a monoclonal plasma-cell proliferative disorder
 * one or more of the following major criteria:
 * sclerotic bone lesions
 * Castleman's disease
 * elevated VEGF levels
 * one or more of the following minor criteria:
 * organomegaly (enlarged spleen, liver or lymph nodes)
 * extravascular volume overload (oedema, pleural effusion or ascites)
 * endocrinopathy (adrenal, pituitary, gonadal, parathyroid); diabetes or hypothyroidism alone are insufficient
 * skin changes
 * papilloedema
 * thrombocytosis or polycythaemia

Pathogenesis
While the main features of the disease have been described, the exact mechanism of the disease has remained elusive. The paraprotein alone is insufficient to explain the multi-organ features, and various cytokines produced by plasmacytoma cells have therefore been linked with the features of POEMS syndrome, specifically interleukin 1β, interleukin 6 and TNFα. There also seems to be a role of vascular endothelial growth factor (VEGF), given the angiogenetic changes in many tissues.

Treatment
There are no randomised controlled trials of treatment in POEMS syndrome, owing to its rarity. Conventional treatments for demyelinating neuropathy, such as steroids, intravenous immunoglobulin and plasma exchange, are ineffective; treatment must be aimed at the haematological disorder.

Dispenzieri et al. list numerous treatments, the effect of many of which is almost anecdotal. Prednisolone and alkylating agents are the most commonly used. The Mayo Clinic group attempted hematopoietic stem cell transplantation in sixteen patients; one patient died during the treatment, and in several others respiratory problems were unmasked in the course of the procedure. The outcome of the treatment, though, was good.

Given that VEGF plays a central role in the symptoms of POEMS syndrome, some have tried bevacizumab (Avastin), a monoclonal antibody directed against VEGF. While some reports were positive, others have reported capillary leak syndrome suspected to be the result of overly rapid lowering of VEGF levels. It therefore remains doubtful as to whether this will become part of standard treatment for POEMS syndrome.

History
Crow, working in Bristol, first described the combination of osteosclerotic myeloma, polyneuropathy and various unusual features (such as pigmentation and clubbing) in two patients aged 54 and 67.