All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.

Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection. Those with a history of recent infection that also have a spontaneous and full resolution of their cryoglobulinemia need no further treatment. Individuals without a history of infection and not showing resolution of their cryoglobulinemia need to be further evaluated. Their cryoglobulins should be analyzed for their composition of immunoglobulin type(s) and complement component(s) and examined for the presence of the premalignant and malignant diseases associated with Type I disease as well as the infectious and autoimmune diseases associated with type II and type III disease. A study conducted in Italy on >140 asymptomatic individuals found five cases of hepatitis C-related and one case of hepatitis b-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be followed closely for any changes that may indicate development of cryoglobulinemic disease.

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made:

The protein electrophoresis test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a hematologist is required. The hematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey (X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function, check the urine for Bence Jones protein and perform a bone marrow biopsy. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis). Although patients with MGUS have sometimes been reported to suffer from Small Fiber Neuropathy in monoclonal gammopathy of undetermined significance:a debilitating condition which causes bizarre sensory problems to painful sensory problems. peripheral neuropathy, no treatment is indicated.

In terms of the differential diagnosis for polyneuropathy one must look at the following:

The diagnosis of polyneuropathies begins with a history and physical examination to ascertain the pattern of the disease process (such as-arms, legs, distal, proximal) if they fluctuate, and what deficits and pain are involved. If pain is a factor, determining where and how long the pain has been present is important, one also needs to know what disorders are present within the family and what diseases the person may have. Although diseases often are suggested by the physical examination and history alone, tests that may be employed include: electrodiagnostic testing, serum protein electrophoresis, nerve conduction studies, urinalysis, serum creatine kinase (CK) and antibody testing (nerve biopsy is sometimes done).

Other tests may be used, especially tests for specific disorders associated with polyneuropathies, quality measures have been developed to diagnose patients with distal symmetrical polyneuropathy (DSP).

In addition to tests corresponding to the above findings (such as EMG for neuropathy, CT scan, bone marrow biopsy to detect clonal plasma cells, plasma or serum protein electrophoresis to myeloma proteins, other tests can give abnormal results supporting the diagnosis of POEMS syndrome. These included raised blood levels of VEGF, thrombocytes, and/or erythrocyte parameters.

A diagnosis of Waldenström's macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples. Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of WM. A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate WM. Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.

Additional tests such as computed tomography (CT or CAT) scan may be used to evaluate the chest, abdomen, and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish between WM and multiple myeloma. Anemia is typically found in 80% of patients with WM. A low white blood cell count, and low platelet count in the blood may be observed. A low level of neutrophils (a specific type of white blood cell) may also be found in some individuals with WM.

Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström's macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström's macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström's macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström's macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Criteria for diagnosis of Waldenström's macroglobulinemia include:

1. IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia and Mantle cell lymphoma

2. Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.

Liver transplantation has proven to be effective for ATTR familial amyloidosis due to Val30Met mutation.

Alternatively, a European Medicines Agency approved drug Tafamidis or Vyndaqel now exists which stabilizes transthyretin tetramers comprising wild type and different mutant subunits against amyloidogenesis halting the progression of peripheral neuropathy and autonomic nervous system dysfunction.

Currently there are two ongoing clinical trials undergoing recruitment in the United States and worldwide to evaluate investigational medicines that could possibly treat TTR.

Patients diagnosed as having Castleman disease but also exhibiting many of the symptoms and signs of POEMS syndrome but lacking evidence of a peripheral neuropathy and/or clonal plasma cells should not be diagnosed as having POEMS syndrome. They are better classified as having Castleman disease variant of POEMS syndrome. These patients may exhibit high blood levels of the interleukin-6 cytokine and have an inferior overall survival compared to POEMS syndrome patients. Treatment of patients with this POEMS syndrome variant who have evidence of bone lesions and/or myeloma proteins are the same as those for POEMS syndrome patients. In the absence of these features, treatment with rituximab, a monoclonal antibody preparation directed against B cells bearing the CD20 antigen, or siltuximab, a monoclonal antibody preparation directed against interleukin-6, may be justified.

As in multiple sclerosis, another demyelinating condition, it is not possible to predict with certainty how CIDP will affect patients over time. The pattern of relapses and remissions varies greatly with each patient. A period of relapse can be very disturbing, but many patients make significant recoveries.

If diagnosed early, initiation of early treatment to prevent loss of nerve axons is recommended. However, many individuals are left with residual numbness, weakness, tremors, fatigue and other symptoms which can lead to long-term morbidity and diminished quality of life.

It is important to build a good relationship with doctors, both primary care and specialist. Because of the rarity of the illness, many doctors will not have encountered it before. Each case of CIDP is different, and relapses, if they occur, may bring new symptoms and problems. Because of the variability in severity and progression of the disease, doctors will not be able to give a definite prognosis. A period of experimentation with different treatment regimens is likely to be necessary in order to discover the most appropriate treatment regimen for a given patient.

A skin biopsy for the measurement of epidermal nerve fiber density is an increasingly common technique for the diagnosis of small fiber peripheral neuropathy. Physicians can biopsy the skin with a 3-mm circular punch tool and immediately fix the specimen in 2% paraformaldehyde lysine-periodate or Zamboni's fixative. Specimens are sent to a specialized laboratory for processing and analysis where the small nerve fibers are quantified by a neuropathologist to obtain a diagnostic result.

This skin punch biopsy measurement technique is called intraepidermal nerve fiber density (IENFD). The following table describes the IENFD values in males and females of a 3 mm biopsy 10-cm above the lateral malleolus (above ankle outer side of leg). Any value measured below the 0.05 Quantile IENFD values per age span, is considered a reliable positive diagnosis for Small Fiber Peripheral Neuropathy.

In the absence of symptoms, many clinicians will recommend simply monitoring the patient; Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance (i.e. IgM MGUS) and smoldering Waldenström's macroglobulinemia.

But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. Mohammad Reza Shah Pahlavi, the Shah of Iran, also suffered from Waldenström's macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis.

There are several types of immune-mediated neuropathies recognised. These include

- Chronic inflammatory demyelinating polyneuropathy (CIPD) with subtypes:

- Classical CIDP

- CIDP with diabetes

- CIDP/monoclonal gammopathy of undetermined significance

- Sensory CIDP

- Multifocal motor neuropathy

- Multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner syndrome)

- Multifocal acquired sensory and motor neuropathy

- Distal acquired demyelinating sensory neuropathy

- Guillain-Barre syndrome with subtypes:

- Acute inflammatory demyelinating polyradiculoneuropathy

- Acute motor axonal neuropathy

- Acute motor and sensory axonal neuropathy

- Acute pandysautonomia

- Miller Fisher syndrome

- IgM monoclonal gammopathies with subtypes:

- Waldenstrom's macroglobulinemia

- Mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome

- Myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS)

For this reason a diagnosis of chronic inflammatory demyelinating polyneuropathy needs further investigations.

The diagnosis is usually provisionally made through a clinical neurological examination. Patients usually present with a history of weakness, numbness, tingling, pain and difficulty in walking. They may additionally present with fainting spells while standing up or burning pain in extremities. Some patients may have sudden onset of back pain or neck pain radiating down the extremities, usually diagnosed as radicular pain. These symptoms are usually progressive and may be intermittent.

Autonomic system dysfunction can occur; in such a case, the patient would complain of orthostatic dizziness, problems breathing, eye, bowel, bladder and cardiac problems. The patient may also present with a single cranial nerve or peripheral nerve dysfunction.

On examination the patients may have weakness, and loss of deep tendon reflexes (rarely increased or normal). There may be atrophy (shrinkage) of muscles, fasciculations (twitching) and loss of sensation. Patients may have multi-focal motor neuropathy, as they have no sensory loss.

Most experts consider the necessary duration of symptoms to be greater than 8 weeks for the diagnosis of CIDP to be made.

Typical diagnostic tests include:

- Electrodiagnostics – electromyography (EMG) and nerve conduction study (NCS). In usual CIDP, the nerve conduction studies show demyelination. These findings include:

1. a reduction in nerve conduction velocities;

2. the presence of conduction block or abnormal temporal dispersion in at least one motor nerve;

3. prolonged distal latencies in at least two nerves;

4. absent F waves or prolonged minimum F wave latencies in at least two motor nerves. (In some case EMG/NCV can be normal).

- Serum test to exclude other autoimmune diseases.

- Lumbar puncture and serum test for anti-ganglioside antibodies. These antibodies are present in the branch of CIDP diseases comprised by anti-GM1, anti-GD1a, and anti-GQ1b.

- Sural nerve biopsy; biopsy is considered for those patients in whom the diagnosis is not completely clear, when other causes of neuropathy (e.g., hereditary, vasculitic) cannot be excluded, or when profound axonal involvement is observed on EMG.

- Ultrasound of the periferal nerves may show swelling of the affected nerves

- MRI can also be used in the diagnosic workup

In some cases electrophysiological studies fail to show any evidence of demyelination. Though conventional electrophysiological diagnostic criteria are not met, the patient may still respond to immunomodulatory treatments. In such cases, presence of clinical characteristics suggestive of CIDP are critical, justifying full investigations, including sural nerve biopsy.

Peripheral neuropathy may first be considered when an individual reports symptoms of numbness, tingling, and pain in feet. After ruling out a lesion in the central nervous system as a cause, diagnosis may be made on the basis of symptoms, laboratory and additional testing, clinical history, and a detailed examination.

During physical examination, specifically a neurological examination, those with generalized peripheral neuropathies most commonly have distal sensory or motor and sensory loss, although those with a pathology (problem) of the nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies, such as Guillain–Barré syndrome; or may show focal sensory disturbance or weakness, such as in mononeuropathies. Classically, ankle jerk reflex is absent in peripheral neuropathy.

A physical examination will involve testing the deep ankle reflex as well as examining the feet for any ulceration. For large fiber neuropathy, an exam will usually show an abnormally decreased sensation to vibration, which is tested with a 128-Hz tuning fork, and decreased sensation of light touch when touched by a nylon monofilament.

Diagnostic tests include electromyography (EMG) and nerve conduction studies (NCSs), which assess large myelinated nerve fibers. Testing for small-fiber peripheral neuropathies often relates to the autonomic nervous system function of small thinly- and unmyelinated fibers. These tests include a sweat test and a tilt table test. Diagnosis of small fiber involvement in peripheral neuropathy may also involve a skin biopsy in which a 3 mm-thick section of skin is removed from the calf by a punch biopsy, and is used to measure the skin intraepidermal nerve fiber density (IENFD), the density of nerves in the outer layer of the skin. Reduced density of the small nerves in the epidermis supports a diagnosis of small-fiber peripheral neuropathy.

Laboratory tests include blood tests for vitamin B-12 levels, a complete blood count, measurement of thyroid stimulating hormone levels, a comprehensive metabolic panel screening for diabetes and pre-diabetes, and a serum immunofixation test, which tests for antibodies in the blood.

The diagnosis of small fiber neuropathy often requires ancillary testing. Nerve conduction studies and electromyography are commonly used to evaluate large myelinated sensory and motor nerve fibers, but are ineffective in diagnosing small fiber neuropathies.

Quantitative sensory testing (QST) assesses small fiber function by measuring temperature and vibratory sensation. Abnormal QST results can be attributed to dysfunction in the central nervous system. Furthermore, QST is limited by a patient’s subjective experience of pain sensation. Quantitative sudomotor axon reflex testing (QSART) measures sweating response at local body sites to evaluate the small nerve fibers that innervate sweat glands.

Diabetic peripheral neuropathy is the most likely diagnosis for someone with diabetes who has pain in a leg or foot, although it may also be caused by vitamin B deficiency or osteoarthritis. A 2010 review in the Journal of the American Medical Association's "Rational Clinical Examination Series" evaluated the usefulness of the clinical examination in diagnosing diabetic peripheral neuropathy. While the physician typically assesses the appearance of the feet, presence of ulceration, and ankle reflexes, the most useful physical examination findings for large fiber neuropathy are an abnormally decreased vibration perception to a 128-Hz tuning fork (likelihood ratio (LR) range, 16–35) or pressure sensation with a 5.07 Semmes-Weinstein monofilament (LR range, 11–16). Normal results on vibration testing (LR range, 0.33–0.51) or monofilament (LR range, 0.09–0.54) make large fiber peripheral neuropathy from diabetes less likely. Combinations of signs do not perform better than these 2 individual findings. Nerve conduction tests may show reduced functioning of the peripheral nerves, but seldom correlate with the severity of diabetic peripheral neuropathy and are not appropriate as routine tests for the condition.

Patients with diabetes and proximal (hip, thigh) pain and weakness are often suspected of having diabetic amyotrophy. More definitive diagnosis is commonly made with electrodiagnostic studies including nerve conduction studies (NCS) and electromyogram (EMG). Diabetic amyotrophy is often a diagnosis of exclusion in diabetic patients with a lumbosacral plexopathy for whom no other cause of lumbosacral plexopathy can be determined.

Paraproteinemias may be categorized according to the type of monoclonal protein found in blood:

- Light chains only (or Bence Jones protein). This may be associated with multiple myeloma or AL amyloidosis.

- Heavy chains only (also known as "heavy chain disease");

- Whole immunoglobulins. In this case, the paraprotein goes under the name of "M-protein" ("M" for monoclonal). If immunoglobulins tend to precipitate within blood vessels with cold, that phenomenon takes the name of cryoglobulinaemia.

The three types of paraproteins may occur alone or in combination in a given individual. Note that while most heavy chains or whole immunoglobulins remain within blood vessels, light chains frequently escape and are excreted by the kidneys into urine, where they take the name of Bence Jones protein.

It is also possible for paraproteins (usually whole immunoglobulins) to form polymers by aggregating with each other; this takes the name of macroglobulinemia and may lead to further complications. For example, certain macroglobulins tend to precipitate within blood vessel with cold, a phenomenon known as cryoglobulinemia. Others may make blood too viscous to flow smoothly (usually with IgM pentamer macroglobulins), a phenomenon known as Waldenström macroglobulinemia.

Detection of this type of neuropathy has concentrated mostly on detecting presence of antibodies because the antibodies are the main cause for the disease. Anti-MAG antibodies can be readily detected in a patient’s sera using various types of assays, but mainly an ELISA has been shown to be most effective. There are also various biological indicators, such as elevated cerebral spinal fluid proteins and elevated IgM monoclonal levels. These can also be tested either by drawing serum from a patient or by drawing spinal fluid from a spinal tap and testing using an assay or blot.

The aggregation of one precursor protein leads to peripheral neuropathy and/or autonomic nervous system dysfunction. These proteins include: transthyretin (ATTR, the most commonly implicated protein), apolipoprotein A1, and gelsolin.

Due to the rareness of the other types of familial neuropathies, transthyretin amyloidogenesis-associated polyneuropathy should probably be considered first.

"FAP-I" and "FAP-II" are associated with transthyretin. (Senile systemic amyloidosis [abbreviated "SSA"] is also associated with transthyretin aggregation.)

"FAP-III" is also known as "Iowa-type", and involves apolipoprotein A1.

"FAP-IV" is also known as "Finnish-type", and involves gelsolin.

Fibrinogen, apolipoprotein A1, and lysozyme are associated with a closely related condition, familial visceral amyloidosis.

Diabetic neuropathy encompasses a series of different neuropathic syndromes which can be schematized in the following way:

- Focal and multifocal neuropathies:

- Mononeuropathy

- Amyotrophy, radiculopathy

- Multiple lesions "mononeuritis multiplex"

- Entrapment (e.g. median, ulnar, peroneal)

- Symmetrical neuropathies:

- Acute sensory

- Autonomic

- Distal symmetrical polyneuropathy (DSPN), the diabetic type of which is also known as diabetic peripheral neuropathy (DPN) (most common presentation)

In terms of diagnosis of HNPP measuring nerve conduction velocity may give an indication of the presence of the disease.Other methods via which to ascertain the diagnosis of hereditary neuropathy with liability to pressure palsy are:

- Family history

- Genetic test

- Physical exam(lack of ankle reflex)

The life span in patients with Schnitzler syndrome has not been shown to differ much from the general population. Careful follow-up is advised, however. A significant proportion of patients develops a lymphoproliferative disorder as a complication, most commonly Waldenström's macroglobulinemia. This may lead to symptoms of hyperviscosity syndrome. AA amyloidosis has also been reported in people with Schnitzler syndrome.

Among the methods of diagnosing tropical spastic paraparesis are MRI (magnetic resonance imaging) and lumbar puncture (which may show lymphocytosis).