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).

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.

Below are various methods/techniques used to diagnose demyelinating diseases.

- Exclusion of other conditions that have overlapping symptoms

- Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to visualize internal structures of the body in detail. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body. This method is reliable because MRIs assess changes in proton density. "Spots" can occur as a result of changes in brain water content.

- Evoked potential is an electrical potential recorded from the nervous system following the presentation of a stimulus as detected by electroencephalography (EEG), electromyography (EMG), or other electrophysiological recording method.

- Cerebrospinal fluid analysis (CSF) can be extremely beneficial in the diagnosis of central nervous system infections. A CSF culture examination may yield the microorganism that caused the infection.

- Quantitative proton magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that has been used to study metabolic changes in brain tumors, strokes, seizure disorders, Alzheimer's disease, depression and other diseases affecting the brain. It has also been used to study the metabolism of other organs such as muscles.

- Diagnostic criteria refers to a specific combination of signs, symptoms, and test results that the clinician uses in an attempt to determine the correct diagnosis.

- Fluid-attenuated inversion recovery (FLAIR) uses a pulse sequence to suppress cerebrospinal fluid and show lesions more clearly, and is used for example in multiple sclerosis evaluation.

The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria. In 2015 a new review was published by an international panel refining the previous clinical case definition but leaving the main criteria unmodified:

Absolute criteria:

1. Optic neuritis

2. Acute myelitis

Supportive criteria:

1. Brain MRI not meeting criteria for MS at disease onset

2. Spinal cord MRI with continuous T2-weighted signal abnormality extending over three or more vertebral segments, indicating a relatively large lesion in the spinal cord

3. NMO-IgG seropositive status (The NMO-IgG test checks the existence of antibodies against the aquaporin 4 antigen.)

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.

AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the oligoclonal bands respect MS can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after the attacks, while in MS they are nearly always present and persistent.

It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS

Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.

Myelitis has an extensive differential diagnosis. The type of onset (acute versus subacute/chronic) along with associated symptoms such as the presence of pain, constitutional symptoms that encompass fever, malaise, weight loss or a cutaneous rash may help identify the cause of myelitis. In order to establish a diagnosis of myelitis, one has to localize the spinal cord level, and exclude cerebral and neuromuscular diseases. Also a detailed medical history, a careful neurologic examination, and imaging studies using magnetic resonance imaging (MRI) are needed. In respect to the cause of the process, further work-up would help identify the cause and guide treatment. Full spine MRI is warranted, especially with acute onset myelitis, to evaluate for structural lesions that may require surgical intervention, or disseminated disease. Adding gadolinium further increases diagnostic sensitivity. A brain MRI may be needed to identify the extent of central nervous system (CNS) involvement. Lumbar puncture is important for the diagnosis of acute myelitis when a tumoral process, inflammatory or infectious cause are suspected, or the MRI is normal or non-specific. Complementary blood tests are also of value in establishing a firm diagnosis. Rarely, a biopsy of a mass lesion may become necessary when the cause is uncertain. However, in 15–30% of people with subacute or chronic myelitis, a clear cause is never uncovered.

Demyelinating diseases can be divided in those affecting the central nervous system and those presents in the peripheral nervous system, presenting different demyelination conditions. They can also be divided by other criteria in inflammatory and non-inflammatory, according to the presence or lack of inflammation, and finally, a division can also be made depending on the underlying reason for demyelination in myelinoclastic (myelin is attacked by an external substance) and leukodystrophic (myelin degenerates without attacks)

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.

Initial screening for CIP/CIM may be performed using an objective scoring system for muscle strength. The Medical Research Council (MRC) score is one such tool, and sometimes used to help identify CIP/CIM patients in research studies. The MRC score involves assessing strength in 3 muscle groups in the right and left sides of both the upper and lower extremities. Each muscle tested is given a score of 0-5, giving a total possible score of 60. An MRC score less than 48 is suggestive of CIP/CIM. However, the tool requires that patients be awake and cooperative, which is often not the case. Also, the screening tool is non-specific, because it does not identify the cause a person's muscle weakness.

Once weakness is detected, the evaluation of muscle strength should be repeated several times. If the weakness persists, then a muscle biopsy, a nerve conduction study (electrophysiological studies), or both should be performed.

For diagnosis of NPSLE, it must be determined whether neuropsychiatric symptoms are indeed caused by SLE, whether they constitute a separate comorbid condition, or whether they are an adverse effect of disease treatment. In addition, onset of neuropsychiatric symptoms may happen prior to the diagnosis of lupus. Due to the lack of uniform diagnostic standards, statistics about NPSLE vary widely.

Tests which aid in diagnosis include MRI, electrophysiological studies, psychiatric evaluation, and autoantibody tests.

The serum creatine phosphokinase (CPK) can be mildly elevated. While the CPK is often a good marker for damage to muscle tissue, it is not a helpful marker in CIP/CIM, because CIP/CIM is a gradual process and does not usually involve significant muscle cell death (necrosis). Also, even if necrosis is present, it may be brief and is therefore easily missed. If a lumbar puncture (spinal tap) is performed, the protein level in the cerebral spinal fluid would be normal.

Transcutaneous electrical nerve stimulation therapy may be effective and safe in the treatment of diabetic peripheral neuropathy. A recent review of three trials involving 78 patients found some improvement in pain scores after 4 and 6, but not 12 weeks of treatment and an overall improvement in neuropathic symptoms at 12 weeks. Another review of four trials found significant improvement in pain and overall symptoms, with 38% of patients in one trial becoming asymptomatic. The treatment remains effective even after prolonged use, but symptoms return to baseline within a month of cessation of treatment.

AON is a rare disease and the natural history of the disease process is not well defined. Unlike typical optic neuritis, there is no association with multiple sclerosis, but the visual prognosis for AON is worse than typical optic neuritis. Thus AON patients have different treatment, and often receive chronic immunosuppression. No formal recommendation can be made regarding the best therapeutic approach. However, the available evidence to date supports treatment with corticosteroids and other immunosuppressive agents.

Early diagnosis and prompt treatment with systemic corticosteroids may restore some visual function but the patient may remain steroid dependent; vision often worsens when corticosteroids are tapered. As such, long-term steroid-sparing immunosuppressive agents may be required to limit the side-effects of steroids and minimize the risk of worsening vision.

Since each case is different, the following are possible treatments that patients might receive in the management of myelitis.

- Intravenous steroids

High-dose intravenous methyl-prednisolone for 3–5 days is considered as a standard of care for patients suspected to have acute myelitis, unless there are compelling reasons otherwise. The decision to offer continued steroids or add a new treatment is often based on the clinical course and MRI appearance at the end of 5 days of steroids.

- Plasma exchange (PLEX)

Patients with moderate to aggressive forms of disease who don’t show much improvement after being treated with intravenous and oral steroids will be treated with PLEX. Retrospective studies of patients with TM treated with IV steroids followed by PLEX showed a positive outcome. It also has been shown to be effective with other autoimmune or inflammatory central nervous system disorders. Particular benefit has been shown with patients who are in the acute or subacute stage of the myelitis showing active inflammation on MRI. However, because of the risks implied by the lumbar puncture procedure, this intervention is determined by the treating physician on a case-by-case basis.

- Immunosuppressants/Immunomodulatory agents

Myelitis with no definite cause seldom recurs, but for others, myelitis may be a manifestation of other diseases that are mentioned above. In these cases, ongoing treatment with medications that modulate or suppress the immune system may be necessary. Sometimes there is no specific treatment. Either way, aggressive rehabilitation and long-term symptom management are an integral part of the healthcare plan.

Management of neuropsychiatric lupus is similar to the management of neuropsychiatric disease in patients without lupus. Treatment depends on the underlying causes of a patient’s disease, and may include immunosuppressants, anticoagulants, and symptomatic therapy.

In October 2007 an astute medical interpreter noticed similar neurological symptoms being reported by Spanish-speaking patients seeking treatment from different physicians at the Austin Medical Center, in Austin, Minnesota. Not only did these patients share similar neurological symptoms, they also worked at the same pork processing plant. Dr. Daniel LaChance, a physician at both the Austin Medical Center and the Mayo Clinic in nearby Rochester, Minnesota, was notified. He launched a request to area physicians to refer other patients with similar symptoms to him. The Minnesota Department of Health (MDH) was notified and began an investigation into the "outbreak." The MDH identified workers from two other pork processing plants in Indiana and Nebraska who also had parallel neurological complaints. Several agencies including the Occupational Safety and Health Administration (OSHA) and the Center for Disease Control and Prevention (CDC) were brought in to assist. Simultaneously investigations were conducted to rule out contagious disease, to locate the source or carrier, and to identify what exactly was causing these workers to develop these symptoms.

Removal from exposure was the first line of treatment. Due to progressive sensory loss and weakness, immunotherapy was often required. These treatments included intravenous methylprednisolone, oral prednisone, azathioprine, and/or immunoglobulin. All 24 patients improved, including 7 who received no treatment and 17 who required immunotherapy.

Traditional autonomic testing is used to aid in the diagnosis of AAG. These tests can include a Tilt Table Test (TTT), thermoregulatory sweat test (TST), quantitative sudomotor autonomic reflex testing (QSART) and various blood panels. Additionally, a blood test showing high levels of the antibody ganglionic nicotenic acetylcholine receptor (gAChr) occur in about 50% of patients with AAG (seropositive AAG). The seronegative patients (those without detectable gAChR levels) are theorized to have one or more different antibodies responsible for the autonomic dysfunction. However, both seropositive and seronegative patients have been seen to respond to the same treatments. A paraneoplastic panel may also be ordered to rule out paraneoplastic syndrome.

CNS demyelinating autoimmune diseases are autoimmune diseases which primarily affect the central nervous system.

Examples include:

- Diffuse cerebral sclerosis of Schilder

- Acute disseminated encephalomyelitis

- Acute hemorrhagic leukoencephalitis

- Multiple sclerosis (though the cause is unknown, it is sure that immune system is involved)

- Transverse myelitis

- Neuromyelitis optica

Anti-GQ1b antibodies are found in two-thirds of patients with this condition. This antibody is also found in almost all cases of Miller Fisher syndrome. The EEG is often abnormal, but shows only slow wave activity, which also occurs in many other conditions, and so is of limited value in diagnosis. Similarly, raised CSF protein levels and pleocytosis are frequent but non-specific. It was originally thought that raised CSF protein without pleocytosis ('albuminocytological dissociation') was a characteristic feature, as it is in Guillain–Barré syndrome, but this has not been supported in more recent work. In only 30% of cases is a MRI brain scan abnormal. Nerve conduction studies may show an axonal polyneuropathy.

MRI is the most sensitive imaging technique that can be used for diagnosing NBD. As for the parenchymal NBD, medical doctors mainly monitor the upper brainstem lesion. In fact, it is possible that lesions extends to thalamus and basal ganglia. Another advantage of using MRI is the ability to perform Diffusion-weighted imaging, or diffusion MRI. This technique is the most sensitive tool to image an acute infarct. In the case of NBD, Diffusion MRI can determine whether the lesion were due to cerebral infarction. In other words, it can distinguish NBD from non-NBD neural disease. When only spinal cord is affected by NBD, brain looks perfectly normal when scanned by MRI. Therefore, it is necessary to scan the spinal cord as well when diagnosing possible NBD involvement. As for the non-parenchymal NBD, venous sinus thrombosis can be detected.

Most patients reported in the literature have been given treatments suitable for autoimmune neurological diseases, such as corticosteroids, plasmapheresis and/or intravenous immunoglobulin, and most have made a good recovery. The condition is too rare for controlled trials to have been undertaken.

Over 40 laboratory tests were initially conducted to rule out various pathogens and environmental toxins. These tests were used to try to identify potential viruses carried by humans, pigs, or both, including rotoviruses, adenoviruses, hepatitis A, and hepatitis E. They also tried to identify bacteria such as salmonella and escherichia coli (e. coli), and parasites such as Giardia and cryptosporidium that could be causing the symptoms. All were ruled out.

Neurodegenerative diseases were considered specifically because of the similarity of symptoms and animal involvement thus included investigation of prion associated diseases such as bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD), and variant Creutzfeldt–Jakob disease (vCJD). These all have highly transmissible pathogenic agents that induce brain damage. Since no pathogenic agent had been found, these diseases were ruled out as being related.

Next two very similar neuropathies were ruled out. Guillain–Barré syndrome (GBS) induces an acute autoimmune response which affects the Schwann cells in the peripheral nervous system. GBS is usually triggered by an infection that causes weakness and tingling that may lead to muscle loss. This condition may be life-threatening if muscle atrophy ascends to affect the pulmonary or cardiac systems. So far, no infectious agents have been found that relate to the current disease, progressive infammatory neuropathy. They looked at chronic inflammatory demyelinating polyneuropathy (CIDP) which is characterized by progressive weakness and sensory impairment in the arms and legs. Damage occurs to the myelin sheath in the peripheral nervous system. As doctors at the Mayo Clinic were beginning to note, the problem they were seeing in progressive inflammatory neuropathy was occurring in the spinal nerve roots.

Also inside standard MS different clinical courses can be separated.