The American College of Rheumatology has outlined 19 syndromes that are seen in NPSLE. These syndromes encompass disorders of the central and peripheral nervous systems:

- Aseptic meningitis

- Cerebrovascular disease

- Demyelinating syndrome

- Headache

- Movement disorder

- Myelopathy

- Seizure disorders

- Acute confusional state

- Anxiety disorder

- Cognitive dysfunction

- Mood disorder

- Psychosis

- Acute inflammatory demyelinating polyradiculoneuropathy

- Autonomic disorder

- Mononeuropathy (single/multiplex)

- Myasthenia gravis

- Cranial neuropathy

- Plexopathy

- Polyneuropathy

Each of the 19 syndromes are also stand-alone diagnoses, which can occur with or without lupus.

The majority of cases involve the central nervous system (CNS), which consists of the brain and spinal cord. The CNS syndromes can be subcategorized as either focal or diffuse. The focal syndromes are neurological, while the diffuse syndromes are psychiatric in nature. The most common CNS syndromes are headache and mood disorder.

Though neuropsychiatric lupus is sometimes referred to as "CNS lupus", it can also affect the peripheral nervous system (PNS). Between 10-15% of people with NPSLE have PNS involvement. Mononeuropathy and polyneuropathy are the most common PNS syndromes.

Neuropsychiatric systemic lupus erythematosus or NPSLE refers to the neurological and psychiatric manifestations of systemic lupus erythematosus. SLE is a disease in which the immune system attacks the body's own cells and tissues. It can affect various organs or systems of the body. It is estimated that over half of people with SLE have neuropsychiatric involvement.

Signs and symptoms of drug-induced lupus erythematosus include the following:

- Joint pain (arthralgia) and muscle pain (myalgia)

- Fatigue

- Serositis —inflammation of the tissues lining the heart and lungs.

- Anti-histone antibodies in 95% of cases

These signs and symptoms are not side effects of the drugs taken which occur during short term use. DIL occurs over long-term and chronic use of the medications listed below. While these symptoms are similar to those of systemic lupus erythematosus, they are generally not as severe unless they are ignored which leads to more harsh symptoms, and in some reported cases, death.

Lupus headache is an important item in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), a scoring system often used in lupus research. The SLEDAI describes lupus headache as a "severe, persistent headache; may be migrainous, but must be nonresponsive to narcotic analgesia". A score of 8 is given to this item (items are given a relative weight of 1, 2, 4 or 8).

The 1999 American College of Rheumatology case definitions of neuropsychiatric syndromes in SLE do not define lupus headache, but rather propose several headache disorders loosely based on the International Headache Society (IHS) classification.

In the IHS scheme, headache due to lupus would be classified as "Headache attributed to other non-infectious inflammatory disease" (7.3.3). This label requires evidence of a disease flare accompanying the headache, and resolution of the headache with immunosuppressant treatment. However, a meta-analysis found no correlation between headaches and disease activity.

Lupus headache is a proposed, specific headache disorder in patients suffering from systemic lupus erythematosus (SLE).

Research shows that headache is a symptom commonly described by SLE patients —57% in one meta-analysis, ranging in different studies from 33% to 78%; of which migraine 31.7% and tension-type headache 23.5%. The existence of a special lupus headache is contested, although few high-quality studies are available to form definitive conclusions.

Disease presentation varies widely from patient to patient, as UCTD is by definition nonspecific. Symptoms typically include constitutional complaints that are common to connective tissue diseases such as fatigue, a general sense of feeling unwell, and fever.

Other symptoms associated with UCTD include:

- dry eyes

- dry mouth

- hair loss

- joint inflammation

- joint pain

- oral ulcers

- positive ANA test

- raynaud's phenomenon

- sun sensitive rash

Lung involvement, such as nonspecific interstitial pneumonia, is a possible disease complication.

The symptoms of cerebritis may range from mild to severe.

The severity of the symptoms varies based on the degree of swelling and on how elevated is the intracranial pressure. Mild symptoms include headaches, depression, anxiety and in some cases, memory loss. In some cases inflammation of brain can be seen if the brain or the nervous system is attacked as a result of problems with the immune system. The serious problems caused because of inflammation include headaches, seizures, vision problems, dizziness, behavior changes and even stroke.

Severe lupus cerebritis symptoms include psychosis, dementia, peripheral neuropathy, cerebellar ataxia (failure of muscular coordination, usually on one side of the body), and chorea (jerky, involuntary movements). Stroke incidence is 3-20% in systemic lupus patients, and is highest in the first five years of the disease. Peripheral neuropathy (carpal tunnel syndrome, for example) occurs in more than 20% of systemic lupus patients and cranial nerve palsies occur in 10-15%.

Symptoms vary from person to person, and may come and go. Almost everyone with lupus has joint pain and swelling. Some develop arthritis. Frequently affected joints are the fingers, hands, wrists, and knees.

Other common symptoms include:

- chest pain during respiration

- joint pain

- oral ulcer

- fatigue

- fever with no other cause

- general discomfort, uneasiness, or ill feeling (malaise)

- hair loss

- sensitivity to sunlight

- skin rash – a "butterfly" rash in about half people with SLE

- swollen lymph nodes

Neuropsychiatric syndromes can result when SLE affects the central or peripheral nervous system. The American College of Rheumatology defines 19 neuropsychiatric syndromes in systemic lupus erythematosus. The diagnosis of neuropsychiatric syndromes concurrent with SLE (now termed as NPSLE), is one of the most difficult challenges in medicine, because it can involve so many different patterns of symptoms, some of which may be mistaken for signs of infectious disease or stroke.

A common neurological disorder people with SLE have is headache, although the existence of a specific lupus headache and the optimal approach to headache in SLE cases remains controversial.

Other common neuropsychiatric manifestations of SLE include cognitive dysfunction, mood disorder, cerebrovascular disease, seizures, polyneuropathy, anxiety disorder, psychosis, depression, and in some extreme cases, personality disorders. Steroid psychosis can also occur as a result of treating the disease. It can rarely present with intracranial hypertension syndrome, characterized by an elevated intracranial pressure, papilledema, and headache with occasional abducens nerve paresis, absence of a space-occupying lesion or ventricular enlargement, and normal cerebrospinal fluid chemical and hematological constituents.

More rare manifestations are acute confusional state, Guillain–Barré syndrome, aseptic meningitis, autonomic disorder, demyelinating syndrome, mononeuropathy (which might manifest as mononeuritis multiplex), movement disorder (more specifically, chorea), myasthenia gravis, myelopathy, cranial neuropathy and plexopathy.

Neurological disorders contribute to a significant percentage of morbidity and mortality in people with lupus. As a result, the neural side of lupus is being studied in hopes of reducing morbidity and mortality rates. One aspect of this disease is severe damage to the epithelial cells of the blood–brain barrier. In certain regions, depression affects up to 60% of women with SLE.

As many as 70% of people with lupus have some skin symptoms. The three main categories of lesions are chronic cutaneous (discoid) lupus, subacute cutaneous lupus, and acute cutaneous lupus. People with discoid lupus may exhibit thick, red scaly patches on the skin. Similarly, subacute cutaneous lupus manifests as red, scaly patches of skin but with distinct edges. Acute cutaneous lupus manifests as a rash. Some have the classic malar rash (or "butterfly rash") associated with the disease. This rash occurs in 30 to 60% of people with SLE.

Hair loss, mouth and nasal ulcers, and lesions on the skin are other possible manifestations.

MCTD combines features of scleroderma, myositis, systemic lupus erythematosus, and rheumatoid arthritis (with some sources adding polymyositis, dermatomyositis, and inclusion body myositis) and is thus considered an overlap syndrome.

MCTD commonly causes:

- joint pain/swelling,

- malaise,

- Raynaud phenomenon,

- muscle inflammation, and

- sclerodactyly (thickening of the skin of the pads of the fingers)

Drug-induced lupus erythematosus (DIL or DILE) is an autoimmune disorder (similar to systemic lupus erythematosus [SLE]) caused by chronic use of certain drugs. These drugs cause an autoimmune response (the body attacks its own cells) producing symptoms similar to those of SLE. There are 38 known medications to cause DIL but there are three that report the highest number of cases: hydralazine, procainamide, and isoniazid. While the criteria for diagnosing DIL has not been thoroughly established, symptoms of DIL typically present as muscle pain and joint pain. Generally, the symptoms recede after discontinuing use of the drugs.

Distinguishing laboratory characteristics are a positive, speckled anti-nuclear antibody and an anti-U1-RNP antibody.

Lupus erythematosus is a name given to a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs. The most common and severe form is systemic lupus erythematosus.

An overlap syndrome is an autoimmune disease of connective tissue in which a person presents with symptoms of two or more diseases.

Examples of overlap syndromes include mixed connective tissue disease and scleromyositis. Diagnosis depends on which diseases the patient shows symptoms and has positive antibodies for in their lab serology.

In overlap syndrome, features of the following diseases are found (most common listed):

- Systemic lupus erythematosus (SLE),

- Systemic sclerosis,

- Polymyositis,

- Dermatomyositis,

- Rheumatoid arthritis (RA)

- Sjögren's syndrome

- Eosinophilic granulomatosis with polyangiitis (EGPA)

- Autoimmune thyroiditis

- Antiphospholipid antibody syndrome

The treatment of overlap syndrome is mainly based on the use of corticosteroids and immunosuppressants. Biologic drugs, i.e. anti-TNFα or anti-CD20 monoclonal antibodies, have been recently introduced as alternative treatments in refractory cases. There are some concerns with the use of anti-TNF agents in patients with systemic autoimmune diseases due to the risk of triggering disease exacerbations.

Cerebritis is an infection of the brain that normally leads to the formation of an abscess within the brain itself. It is the inflammation of the cerebrum, a structure within the brain, which performs a number of important functions, including most of the things which people associate with being human, such as memory and speech. It is also defined as a purulent nonencapsulated parenchymal infection of brain which is characterized by nonspecific features on CT (ill-defined low density area with peripheral enhancement) and cannot reliably be distinguished from neoplasms.

Cerebritis usually occurs as a result of an underlying condition, which causes the inflammation of the brain tissue. It is commonly found in patients with lupus. Lupus cerebritis may occur in adults and children. The duration of the central nervous system involvement may vary from a few minutes, as in classic migraine or a transient ischemic attack, to years, as in dementia. Resulting neurological deficits may be transient or permanent, occasionally resulting in death.

Undifferentiated connective tissue disease (UCTD) is a disease in which the body mistakenly attacks its own tissues. It is diagnosed when there is evidence of an existing autoimmune condition which does not meet the criteria for any specific autoimmune disease, such as systemic lupus erythematosus or scleroderma. Latent lupus and incomplete lupus are alternative terms that have been used to describe this condition.

The term is sometimes used interchangeably with mixed connective tissue disease, an overlap syndrome. However, MCTD is thought by some researchers to be a clinically distinct entity and is strongly associated with the presence of high titers of ribonucleoprotein (RNP) antibodies.

It is estimated that up to 25 percent of people with systemic autoimmune disease could be considered to have UCTD.

Differential diagnoses can be:

- Todd's paresis

- Stroke

- Systemic lupus erythematosus

- Metabolic disorders

- Inherited disorders such as mitochondrial myopathy

Diagnostic criteria require motor symptoms and at least one visual, sensory, or speech symptom, resembling basilar migraine. They may also be associated with cerebellar signs.

The signs and symptoms of Kikuchi disease are fever, enlargement of the lymph nodes (lymphadenopathy), skin rashes, and headache. Rarely, enlargement of the liver and spleen and nervous system involvement resembling meningitis are seen. Often a bout of extreme fatigue can occur - often taking hold during latter parts of the day and the affected person can be more prone to fatigue from exercise.

Collagen disease is a term previously used to describe systemic autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue.

The term "collagen disease" was coined by Dr. Alvin F. Coburn in 1932, on his quest to discover streptococcal infection as the cause for rheumatic fever.

AON was first described in 1982. It presents with visual loss and signs of optic nerve dysfunction, such as loss of color vision, afferent pupil defect, and sometimes abnormalities of the optic disc. The clinical features of AON can be variable and present in several unilateral or bilateral forms:

- Acute anterior or retrobulbar optic neuritis sometimes associated with pain.

- Anterior or retrobulbar ischemic optic neuropathy not associated with pain.

- Chronic progressive vision loss that mimics a compressive lesion.

The main features that differentiate AON from the more common typical demyelinating optic neuritis is the poor recovery of vision and the chronic or recurrent or bilateral course of AON. Furthermore, the workup for multiple sclerosis including MRI, will be negative. Thus, it may be necessary to diagnose AON after a period of observation, noting the problem is not behaving as expected for demyelinative disease.

These are also referred to as systemic autoimmune diseases. The autoimmune CTDs may have both genetic and environmental causes. Genetic factors may create a predisposition towards developing these autoimmune diseases. They are characterized as a group by the presence of spontaneous overactivity of the immune system that results in the production of extra antibodies into the circulation. The classic collagen vascular diseases have a "classic" presentation with typical findings that doctors can recognize during an examination. Each also has "classic" blood test abnormalities and abnormal antibody patterns. However, each of these diseases can evolve slowly or rapidly from very subtle abnormalities before demonstrating the classic features that help in the diagnosis. The classic collagen vascular diseases include:

- Systemic lupus erythematosus (SLE) – An inflammation of the connective tissues, SLE can afflict every organ system. It is up to nine times more common in women than men and strikes black women three times as often as white women. The condition is aggravated by sunlight.

- Rheumatoid arthritis – Rheumatoid arthritis is a systemic disorder in which immune cells attack and inflame the membrane around joints. It also can affect the heart, lungs, and eyes. Of the estimated 2.1 million Americans with rheumatoid arthritis, approximately 1.5 million (71 percent) are women.

- Scleroderma – an activation of immune cells that produces scar tissue in the skin, internal organs, and small blood vessels. It affects women three times more often than men overall, but increases to a rate 15 times greater for women during childbearing years, and appears to be more common among black women.

- Sjögren's syndrome – also called Sjögren's disease, is a chronic, slowly progressing inability to secrete saliva and tears. It can occur alone or with rheumatoid arthritis, scleroderma, or systemic lupus erythematosus. Nine out of 10 cases occur in women, most often at or around mid-life.

- Mixed connective tissue disease – Mixed connective-tissue disease (MCTD) is a disorder in which features of various connective-tissue diseases (CTDs) such as systemic lupus erythematosus (SLE); systemic sclerosis (SSc); dermatomyositis (DM); polymyositis (PM); anti-synthetase syndrome; and, occasionally, Sjögren syndrome can coexist and overlap. The course of the disease is chronic and usually milder than other CTDs. In most cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or Scleroderma.

- Undifferentiated connective tissue disease (UCTD) is a disease in which the body mistakenly attacks its own tissues. It is diagnosed when there is evidence of an existing autoimmune condition which does not meet the criteria for any specific autoimmune disease, such as systemic lupus erythematosus or scleroderma. Latent lupus and incomplete lupus are alternative terms that have been used to describe this condition.

- Psoriatic arthritis is also a collagen vascular disease.

Polyradiculoneuropathy describes a condition in which polyneuropathy and polyradiculopathy occur together. An example is Guillain–Barré syndrome.

Treatment with a single course of intravenous immunoglobulin (IVIG) infusions has been demonstrated to be a potentially effective treatment (reported to have caused prolonged remission in a case associated with systemic lupus (Systemic lupus erythematosus) ).

Autoimmune optic neuropathy (AON), sometimes called autoimmune optic neuritis, may be a forme fruste of systemic lupus erythematosus (SLE) associated optic neuropathy. AON is more than the presence of any optic neuritis in a patient with an autoimmune process, as it describes a relatively specific clinical syndrome. AON is characterized by chronically progressive or recurrent vision loss associated with serological evidence of autoimmunity. Specifically, this term has been suggested for cases of optic neuritis with serological evidence of vasculitis by positive ANA, despite the lack of meeting criteria for SLE. The clinical manifestations include progressive vision loss that tends to be steroid-responsive and steroid dependent.

Patients with defined SLE that go on to develop optic neuritis should be better identified as lupus optic neuritis.