Blood tests, cerebrospinal fluid examination by lumbar puncture (also known as spinal tap), brain imaging studies, electroencephalography (EEG), and similar diagnostic studies may be used to differentiate the various causes of encephalopathy.

Diagnosis is frequently clinical. That is, no set of tests give the diagnosis, but the entire presentation of the illness with nonspecific test results informs the experienced clinician of the diagnosis.

Treatment varies according to the type and severity of the encephalopathy. Anticonvulsants may be prescribed to reduce or halt any seizures. Changes to diet and nutritional supplements may help some patients. In severe cases, dialysis or organ replacement surgery may be needed.

Sympathomimetic drugs can increase motivation, cognition, motor performance and alertness in patients with encephalopathy caused by brain injury, chronic infections, strokes, brain tumors.

CT and MRI are most commonly used to observe the brain for cerebral atrophy. A CT scan takes cross sectional images of the brain using X-rays, while an MRI uses a magnetic field. With both measures, multiple images can be compared to see if there is a loss in brain volume over time.

Cerebral atrophy can be hard to distinguish from hydrocephalus because both cerebral atrophy and hydrocephalus involve an increase in cerebrospinal fluid (CSF) volume. In cerebral atrophy, this increase in CSF volume comes as a result of the decrease in cortical volume. In hydrocephalus, the increase in volume happens due to the CSF itself.

Currently, CTE can only be definitively diagnosed by direct tissue examination after death, including full and immunohistochemical brain analyses.

The lack of "in vivo" techniques to show distinct biomarkers for CTE is the reason CTE cannot currently be diagnosed while a person is alive. The only known diagnosis for CTE occurs by studying the brain tissue after death. Concussions are non-structural injuries and do not result in brain bleeding, which is why most concussions cannot be seen on routine neuroimaging tests such as CT or MRI. Acute concussion symptoms (those that occur shortly after an injury) should not be confused with CTE. Differentiating between prolonged post-concussion syndrome (PCS, where symptoms begin shortly after a concussion and last for weeks, months, and sometimes even years) and CTE symptoms can be difficult. Research studies are currently examining whether neuroimaging can detect subtle changes in axonal integrity and structural lesions that can occur in CTE. Recently, more progress in in-vivo diagnostic techniques for CTE has been made, using DTI, fMRI, MRI, and MRS imaging; however, more research needs to be done before any such techniques can be validated.

PET tracers that bind specifically to tau protein are desired to aid diagnosis of CTE in living individuals. One candidate is the tracer [F]FDDNP, which is retained in the brain in individuals with a number of dementing disorders such as Alzheimer's disease, Down syndrome, progressive supranuclear palsy, familial frontotemporal dementia, and Creutzfeldt–Jakob disease. In a small study of 5 retired NFL players with cognitive and mood symptoms, the PET scans revealed accumulation of the tracer in their brains. However, [F]FDDNP binds to beta-amyloid and other proteins as well. Moreover, the sites in the brain where the tracer was retained were not consistent with the known neuropathology of CTE. A more promising candidate is the tracer [F]-T807, which binds only to tau. It is being tested in several clinical trials.

A putative biomarker for CTE is the presence in serum of autoantibodies against the brain. The autoantibodies were detected in football players who experienced a large number of head hits but no concussions, suggesting that even sub-concussive episodes may be damaging to the brain. The autoantibodies may enter the brain by means of a disrupted blood-brain barrier, and attack neuronal cells which are normally protected from an immune onslaught. Given the large numbers of neurons present in the brain (86 billion), and considering the poor penetration of antibodies across a normal blood-brain barrier, there is an extended period of time between the initial events (head hits) and the development of any signs or symptoms. Nevertheless, autoimmune changes in blood of players may consist the earliest measurable event predicting CTE.

Robert A. Stern, one of the scientists at the Boston University CTE Center, said in 2015 that "he expected a test to be developed within a decade that will be able to diagnose C.T.E. in living people".

Mild and moderate cerebral hypoxia generally has no impact beyond the episode of hypoxia; on the other hand, the outcome of severe cerebral hypoxia will depend on the success of damage control, amount of brain tissue deprived of oxygen, and the speed with which oxygen was restored.

If cerebral hypoxia was localized to a specific part of the brain, brain damage will be localized to that region. A general consequence may be epilepsy. The long-term effects will depend on the purpose of that portion of the brain. Damage to the Broca's area and the Wernicke's area of the brain (left side) typically causes problems with speech and language. Damage to the right side of the brain may interfere with the ability to express emotions or interpret what one sees. Damage on either side can cause paralysis of the opposite side of the body.

The effects of certain kinds of severe generalized hypoxias may take time to develop. For example, the long-term effects of serious carbon monoxide poisoning usually may take several weeks to appear. Recent research suggests this may be due to an autoimmune response caused by carbon monoxide-induced changes in the myelin sheath surrounding neurons.

If hypoxia results in coma, the length of unconsciousness is often indicative of long-term damage. In some cases coma can give the brain an opportunity to heal and regenerate, but, in general, the longer a coma, the greater the likelihood that the person will remain in a vegetative state until death. Even if the patient wakes up, brain damage is likely to be significant enough to prevent a return to normal functioning.

Long-term comas can have a significant impact on a patient's families. Families of coma victims often have idealized images of the outcome based on Hollywood movie depictions of coma. Adjusting to the realities of ventilators, feeding tubes, bedsores, and muscle wasting may be difficult. Treatment decision often involve complex ethical choices and can strain family dynamics.

The diagnosis may be made on the clinical features alone, along with tests to rule out other possible causes. An EEG will usually show the electrical features of epilepsy and slowing of brain activity in the affected hemisphere, and MRI brain scans will show gradual shrinkage of the affected hemisphere with signs of inflammation or scarring.

Brain biopsy can provide very strong confirmation of the diagnosis, but this is not always necessary.

Leukoaraiosis (LA) refers to the imaging finding of white matter changes that are common in Binswanger disease. However, LA can be found in many different diseases and even in normal patients, especially in people older than 65 years of age.

There is controversy whether LA and mental deterioration actually have a cause and effect relationship. Recent research is showing that different types of LA can affect the brain differently, and that proton MR spectroscopy would be able to distinguish the different types more effectively and better diagnosis and treat the issue. Because of this information, white matter changes indicated by an MRI or CT cannot alone diagnose Binswanger disease, but can aid to a bigger picture in the diagnosis process. There are many diseases similar to Binswanger's disease including CADASIL syndrome and Alzheimer's disease, which makes this specific type of white matter damage hard to diagnose. Binswanger disease is best when diagnosed of a team by experts including a neurologist and psychiatrist to rule out other psychological or neurological problems. Because doctors must successfully detect enough white matter alterations to accompany dementia as well as an appropriate level of dementia, two separate technological systems are needed in the diagnosing process.

Much of the major research today is done on finding better and more efficient ways to diagnose this disease. Many researchers have divided the MRIs of the brain into different sections or quadrants. A score is given to each section depending on how severe the white matter atrophy or leukoaraiosis is. Research has shown that the higher these scores, the more of a decrease in processing speed, executive functions, and motor learning tasks.

Other researchers have begun using computers to calculate the percentage of white matter atrophy by counting the hyper-intense pixels of the MRI. These and similar reports show a correlation between the amount of white matter alterations and the decline of psychomotor functions, reduced performance on attention and executive control. One recent type of technology is called susceptibility weighted imaging (SWI) which is a magnetic resonance technique which has an unusually high degree of sensitivity and can better detect white matter alternations.

Blood tests usually come back normal in affected individuals, so they do not serve as a reliable means of diagnosis. Blood tests can show low serum ferritin levels. However, this is unreliable as method of diagnosis, as some patients show typical serum ferritin levels even at the latest stages of neuroferritinopathy. Cerebral spinal fluid tests also are typically normal.

Ferritin found in the skin, liver, kidney, and muscle tissues may help in diagnosing neuroferritinopathy. More cytochrome c oxidase-negative fibers are also often found in the muscle biopsies of affected individuals.

Genetic testing can confirm a neuroferritinopathy diagnosis. A diagnosis can be made by analyzing the protein sequences of affected individuals and comparing them to known neuroferritinopathy sequences.

Binswanger's disease can usually be diagnosed with a CT scan, MRI, and a proton MR spectrography in addition to clinical examination. Indications include infarctions, lesions, or loss of intensity of central white matter and enlargement of ventricles, and leukoaraiosis. Recently a Mini Mental Test (MMT) has been created to accurately and quickly assess cognitive impairment due to vascular dementia across different cultures.

Several specific diagnostic criteria can be used to diagnose vascular dementia, including the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, the International Classification of Diseases, Tenth Edition (ICD-10) criteria, the National Institute of Neurological Disorders and Stroke criteria, Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria, the Alzheimer's Disease Diagnostic and Treatment Center criteria, and the Hachinski Ischemic Score (after Vladimir Hachinski).

The recommended investigations for cognitive impairment include: blood tests (for anemia, vitamin deficiency, thyrotoxicosis, infection, etc.), chest X-Ray, ECG, and neuroimaging, preferably a scan with a functional or metabolic sensitivity beyond a simple CT or MRI. When available as a diagnostic tool, single photon emission computed tomography (SPECT) and positron emission tomography (PET) neuroimaging may be used to confirm a diagnosis of multi-infarct dementia in conjunction with evaluations involving mental status examination. In a person already having dementia, SPECT appears to be superior in differentiating multi-infarct dementia from Alzheimer's disease, compared to the usual mental testing and medical history analysis. Advances have led to the proposal of new diagnostic criteria.

The screening blood tests typically include full blood count, liver function tests, thyroid function tests, lipid profile, erythrocyte sedimentation rate, C reactive protein, syphilis serology, calcium serum level, fasting glucose, urea, electrolytes, vitamin B-12, and folate. In selected patients, HIV serology and certain autoantibody testing may be done.

Mixed dementia is diagnosed when people have evidence of Alzheimer's disease and cerebrovascular disease, either clinically or based on neuro-imaging evidence of ischemic lesions.

Gross examination of the brain may reveal noticeable lesions and damage to blood vessels. Accumulation of various substances such as lipid deposits and clotted blood appear on microscopic views. The white matter is most affected, with noticeable atrophy (tissue loss), in addition to calcification of the arteries. Microinfarcts may also be present in the gray matter (cerebral cortex), sometimes in large numbers.

Although atheroma of the major cerebral arteries is typical in vascular dementia, smaller vessels and arterioles are mainly affected.

For newborn infants starved of oxygen during birth there is now evidence that hypothermia therapy for neonatal encephalopathy applied within 6 hours of cerebral hypoxia effectively improves survival and neurological outcome. In adults, however, the evidence is less convincing and the first goal of treatment is to restore oxygen to the brain. The method of restoration depends on the cause of the hypoxia. For mild-to-moderate cases of hypoxia, removal of the cause of hypoxia may be sufficient. Inhaled oxygen may also be provided. In severe cases treatment may also involve life support and damage control measures.

A deep coma will interfere with body's breathing reflexes even after the initial cause of hypoxia has been dealt with; mechanical ventilation may be required. Additionally, severe cerebral hypoxia causes an elevated heart rate, and in extreme cases the heart may tire and stop pumping. CPR, defibrilation, epinephrine, and atropine may all be tried in an effort to get the heart to resume pumping. Severe cerebral hypoxia can also cause seizures, which put the patient at risk of self-injury, and various anti-convulsant drugs may need to be administered before treatment.

There has long been a debate over whether newborn infants with cerebral hypoxia should be resuscitated with 100% oxygen or normal air. It has been demonstrated that high concentrations of oxygen lead to generation of oxygen free radicals, which have a role in reperfusion injury after asphyxia. Research by Ola Didrik Saugstad and others led to new international guidelines on newborn resuscitation in 2010, recommending the use of normal air instead of 100% oxygen.

Brain damage can occur both during and after oxygen deprivation. During oxygen deprivation, cells die due to an increasing acidity in the brain tissue (acidosis). Additionally, during the period of oxygen deprivation, materials that can easily create free radicals build up. When oxygen enters the tissue these materials interact with oxygen to create high levels of oxidants. Oxidants interfere with the normal brain chemistry and cause further damage (this is known as "reperfusion injury").

Techniques for preventing damage to brain cells are an area of ongoing research. Hypothermia therapy for neonatal encephalopathy is the only evidence-supported therapy, but antioxidant drugs, control of blood glucose levels, and hemodilution (thinning of the blood) coupled with drug-induced hypertension are some treatment techniques currently under investigation. Hyperbaric oxygen therapy is being evaluated with the reduction in total and myocardial creatine phosphokinase levels showing a possible reduction in the overall systemic inflammatory process.

In severe cases it is extremely important to act quickly. Brain cells are very sensitive to reduced oxygen levels. Once deprived of oxygen they will begin to die off within five minutes.

CT scan or MRI can confirm dementia via observation of ventricular dilation and cortical substance degeneration.

Pick's disease can be confirmed via CT scan or MRI with atrophy of frontal and temporal lobe roots.

Alzheimer's is a disease confirmed by atrophy of the parietal and temporal lobe ganglia along with changes in the cortical ganglia found in a CT scan or MRI.

The confirmatory diagnosis is made via brain biopsy, however, other tests can be used to help such as MRI, EEG, CT, as well as the physical exam and history

Routine blood tests are also usually performed to rule out treatable causes. These tests include vitamin B, folic acid, thyroid-stimulating hormone (TSH), C-reactive protein, full blood count, electrolytes, calcium, renal function, and liver enzymes. Abnormalities may suggest vitamin deficiency, infection, or other problems that commonly cause confusion or disorientation in the elderly.

Along with occupational and environmental evaluation, a neurological exam, ECHO, EEG, CT-San, and X-ray of the brain may be conducted to determine disorder. Neuroimaging that detects cerebral atrophy or cardiovascular subcortical alterations can help point to psychoorganic syndrome. Strong CNS lesions are detected in POS patients. However, this is found to be difficult as many psychiatric disorders, like dementia, have common diagnosis.

Diagnosing POS is an ongoing and developing in the medical and psychiatric industry. Exact diagnosis is difficult due to many symptoms mirroring other psychological disorders in the older aged patients.

A CT scan or magnetic resonance imaging (MRI scan) is commonly performed, although these tests do not pick up diffuse metabolic changes associated with dementia in a person that shows no gross neurological problems (such as paralysis or weakness) on neurological exam. CT or MRI may suggest normal pressure hydrocephalus, a potentially reversible cause of dementia, and can yield information relevant to other types of dementia, such as infarction (stroke) that would point at a vascular type of dementia.

The functional neuroimaging modalities of SPECT and PET are more useful in assessing long-standing cognitive dysfunction, since they have shown similar ability to diagnose dementia as a clinical exam and cognitive testing. The ability of SPECT to differentiate the vascular cause (i.e., multi-infarct dementia) from Alzheimer's disease dementias, appears superior to differentiation by clinical exam.

Recent research has established the value of PET imaging using carbon-11 Pittsburgh Compound B as a radiotracer (PIB-PET) in predictive diagnosis of various kinds of dementia, in particular Alzheimer's disease. Studies from Australia have found PIB-PET 86% accurate in predicting which patients with mild cognitive impairment will develop Alzheimer's disease within two years. In another study, carried out using 66 patients seen at the University of Michigan, PET studies using either PIB or another radiotracer, carbon-11 dihydrotetrabenazine (DTBZ), led to more accurate diagnosis for more than one-fourth of patients with mild cognitive impairment or mild dementia.

Microscopic features of PKAN include:

- Iron granules

- Spheroid bodies

- Lewy bodies within neurons

It is usually associated with amyloid beta.

However, there are other types:

- the "Icelandic type" is associated with Cystatin C

- the "British type" is associated with ITM2B

Research is currently being conducted to determine if there is a link between cerebral amyloid angiopathy and ingestion of excessive quantities of aluminum.

The prognosis for gliomatosis cerebri is generally poor. Surgery is not practical considering the extent of the disease, standard chemotherapy (nitrosourea) has been unsuccessful, and while brain irradiation can stabilize or improve neurologic function in some patients, its impact on survival has yet to be proven.

In 2014, Weill Cornell Brain and Spine Center launched an international registry for Gliomatosis Cerebri, where tissue samples can be stored for genomic study.

Susceptibility weighted imaging has been proposed as a tool for identifying CAA-related microhemorrhages.

Biopsies also play a role in diagnosing the condition.

A neurological examination would show evidence of muscle rigidity; weakness; and abnormal postures, movements, and tremors. If other family members are also affected, this may help determine the diagnosis. Genetic tests can confirm an abnormal gene causing the disease. However, this test is not yet widely available. Other movement disorders and diseases must be ruled out. Individuals exhibiting any of the above listed symptoms are often tested using MRI (Magnetic Resonance Imaging) for a number of neuro-related disorders. As PKAN is a disease prominently evident in the brain, MRIs are very useful in making a sound diagnosis. An MRI usually shows iron deposits in the basal ganglia. Development of diagnostic criteria continues in the hope of further separating PKAN from other forms of neurodegenerative diseases featuring NBIA.

During the acute stage, treatment is aimed at reducing the inflammation. As in other inflammatory diseases, steroids may be used first of all, either as a short course of high-dose treatment, or in a lower dose for long-term treatment. Intravenous immunoglobulin is also effective both in the short term and in the long term, particularly in adults where it has been proposed as first-line treatment. Other similar treatments include plasmapheresis and tacrolimus, though there is less evidence for these. None of these treatments can prevent permanent disability from developing.

During the residual stage of the illness when there is no longer active inflammation, treatment is aimed at improving the remaining symptoms. Standard anti-epileptic drugs are usually ineffective in controlling seizures, and it may be necessary to surgically remove or disconnect the affected cerebral hemisphere, in an operation called hemispherectomy. This usually results in further weakness, hemianopsia and cognitive problems, but the other side of the brain may be able to take over some of the function, particularly in young children. The operation may not be advisable if the left hemisphere is affected, since this hemisphere contains most of the parts of the brain that control language. However, hemispherectomy is often very effective in reducing seizures.