Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the person has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. While a magnetic resonance imaging (MRI) is often normal in people with early stage ALS, it can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical spondylosis.

Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.

Viral infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV), Lyme disease, syphilis and tick-borne encephalitis can in some cases cause ALS-like symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain aspects of the disease and should be considered.

ALS must be differentiated from the "ALS mimic syndromes" which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants. Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, people with ALS symptoms should always obtain a specialist neurological opinion in order to rule out alternative diagnoses. Myasthenic syndrome, also known as Lambert–Eaton syndrome, can mimic ALS, and its initial presentation can be similar to that of myasthenia gravis (MG), a treatable autoimmune disease sometimes mistaken for ALS.

Benign fasciculation syndrome is another condition that mimics some of the early symptoms of ALS but is accompanied by normal EMG readings and no major disablement.

Most cases of ALS, however, are correctly diagnosed, with the error rate of diagnosis in large ALS clinics is less than 10%. One study examined 190 people who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these people (16%) had their diagnosis completely changed during the clinical observation development period. In the same study, three people had a false negative diagnosis of MG, which can mimic ALS and other neurological disorders, leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.

No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the person and a series of tests to rule out other diseases. Physicians obtain the person's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are worsening.

Like ALS, diagnosing PLS is a diagnosis of exclusion, as there is no one test that can confirm a diagnosis of PLS. The Pringle Criteria, proposed by Pringle et al, provides a guideline of nine points that, if confirmed, can suggest a diagnosis of PLS. Due to the fact that a person with ALS may initially present with only upper motor neuron symptoms, indicative of PLS, one key aspect of the Pringle Criteria is requiring a minimum of three years between symptom onset and symptom diagnosis. When these criteria are met, a diagnosis of PLS is highly likely. Other aspects of Pringle Criteria include normal EMG findings, thereby ruling out lower motor neuron involvement that is indicative of ALS, and absence of family history for Hereditary Spastic Paraplegia (HSP) and ALS. Imaging studies to rule out structural or demyelinating lesions may be done as well. Hoffman's sign and Babinski reflex may be present and indicative of upper motor neuron damage.

The importance of correctly recognizing progressive muscular atrophy as opposed to ALS is important for several reasons.

- 1) the prognosis is a little better. A recent study found the 5-year survival rate in PMA to be 33% (vs 20% in ALS) and the 10-year survival rate to be 12% (vs 6% in ALS).

- 2) Patients with PMA do not suffer from the cognitive change identified in certain groups of patients with MND.

- 3) Because PMA patients do not have UMN signs, they usually do not meet the "World Federation of Neurology El Escorial Research Criteria" for “Definite” or “Probable” ALS and so are ineligible to participate in the majority of clinical research trials such as drugs trials or brain scans.

- 4) Because of its rarity (even compared to ALS) and confusion about the condition, some insurance policies or local healthcare policies may not recognize PMA as being the life-changing illness that it is. In cases where being classified as being PMA rather than ALS is likely to restrict access to services, it may be preferable to be diagnosed as "slowly progressive ALS" or "lower motor neuron predominant" ALS.

An initial diagnosis of PMA could turn out to be slowly progressive ALS many years later, sometimes even decades after the initial diagnosis. The occurrence of upper motor neurone symptoms such as brisk reflexes, spasticity, or a Babinski sign would indicate a progression to ALS; the correct diagnosis is also occasionally made on autopsy.

PMA is a diagnosis of exclusion, there is no specific test which can conclusively establish whether a patient has the condition. Instead, a number of other possibilities have to be ruled out, such as multifocal motor neuropathy or spinal muscular atrophy. Tests used in the diagnostic process include MRI, clinical examination, and EMG. EMG tests in patients who do have PMA usually show denervation (neurone death) in most affected body parts, and in some unaffected parts too.

It typically takes longer to be diagnosed with PMA than ALS, an average of 20 months for PMA vs 15 months in ALS/MND.

Diagnosis of pseudobulbar palsy is based on observation of the symptoms of the condition. Tests examining jaw jerk and gag reflex can also be performed. It has been suggested that the majority of patients with pathological laughter and crying have pseudobulbar palsy due to bilateral corticobulbar lesions and often a bipyrimidal involvement of arms and legs. To further confirm the condition, MRI can be performed to define the areas of brain abnormality.

PBP is aggressive and relentless, and there were no treatments for the disease as of 2005. However, early detection of PBP is the optimal scenario in which doctors can map out a plan for management of the disease. This typically involves symptomatic treatments that are frequently used in many lower motor disorders.

Patients can often live with PLS for many years and very often outlive their neurological disease and succumb to some unrelated condition. There is currently no effective cure, and the progression of symptoms varies. Some people may retain the ability to walk without assistance, but others eventually require wheelchairs, canes, or other assistive devices.

A motor neuron disease (MND) is any of several neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body. They include amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy (PBP) and pseudobulbar palsy. Spinal muscular atrophies (SMA) are sometimes included in the group by some neurologists but it is different disease with clear genetic cause. They are neurodegenerative in nature and cause increasing disability and eventually, death.

In the United States, the term is often used to denote ALS, the most common disorder in the group. In the United Kingdom, the term is also spelled "motor neurone disease" (MND) and is sometimes used for the entire group; but mostly it refers to ALS.

While MND refers to a specific subset of similar diseases, there are numerous other diseases of motor neurons that are referred to collectively as "motor neuron disorders", for instance disease belonging to spinal muscular atrophies. However, they are not classified as "motor neuron diseases" by the tenth International Statistical Classification of Diseases and Related Health Problems (ICD-10), which is the definition followed in this article.

Treatment depends upon the underlying disorder. Movement disorders have been known to be associated with a variety of autoimmune diseases.

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.

Step I : Decide the dominant type of movement disorder

Step II : Make differential diagnosis of the particular disorder

Step II: Confirm the diagnosis by lab tests

- Metabolic screening

- Microbiology

- Immunology

- CSF examination

- Genetics

- Imaging

- Neurophysiological tests

- Pharmacological tests

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.

Progressive Bulbar Palsy is slow in onset, with symptoms starting in most patients around 50–70 years of age. PBP has a life expectancy typically between 6 months and 3 years from onset of first symptoms. It is subtype of the Motor Neurone Diseases (MND) accounting for around 1 in 4 cases. Amyotrophic lateral sclerosis (ALS) is another sub-type. Pure PBP without any EMG or clinical evidence of abnormalities in the legs or arms is possible, albeit extremely rare. Moreover, about twenty-five percent of patients with PBP eventually develop the widespread symptoms common to ALS.

In regards to the diagnosis of spinal and bulbar muscular atrophy, the "AR Xq12" gene is the focus. Many mutations are reported and identified as missense/nonsense, that can be identified with 99.9% accuracy. Test for this gene in the majority of affected patients yields the diagnosis.

Since pseudobulbar palsy is a syndrome associated with other diseases, treating the underlying disease may eventually reduce the symptoms of pseudobulbar palsy.

Possible pharmacological interventions for pseudobulbar affect include the tricyclic antidepressants, serotonin reuptake inhibitors, and a novel approach utilizing dextromethorphan and quinidine sulfate. Nuedexta is an FDA approved medication for pseudobulbar affect. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, inhibits glutamatergic transmission in the regions of the brainstem and cerebellum, which are hypothesized to be involved in pseudobulbar symptoms, and acts as a sigma ligand, binding to the sigma-1 receptors that mediate the emotional motor expression.

Assessment of motor control may involve several health professionals depending on the affected individual's situation, and the severity of their condition. This may include physical therapists, physicians (including neurologists and psychiatrists ) and rehabilitation physicians, orthotists, occupational therapists, and speech-language pathologists. Assessment is needed of the affected individual's goals, their function, and any symptoms that may be related to the movement disorder, such as pain. A thorough assessment then uses a clinical reasoning approach to determine why difficulties are occurring. Elements of assessment will include analysis of posture, active movement, muscle strength, movement control and coordination, and endurance, as well as muscle tone and spasticity. Impaired muscles typically demonstrate a loss of selective movement, including a loss of eccentric control (decreased ability to actively lengthen); this decreased active lengthening of a muscle is a key factor that limits motor control. While multiple muscles in a limb are usually affected in the Upper Motor Neuron Syndrome, there is usually an imbalance of muscle activity (muscle tone), such that there is a stronger pull on one side of a joint, such as into elbow flexion. Decreasing the degree of this imbalance is a common focus of muscle strengthening programs. Impaired motor control also typically features a loss of stabilisation of an affected limb or the head from the trunk, so a thorough assessment requires this to be analysed as well, and exercise to improve proximal stability may be indicated.

Secondary effects are likely to impact on assessment of impaired muscles. If muscle tone is assessed with passive muscle lengthening, increased muscle stiffness may affect the feeling of resistance to passive stretch, in addition to neurological resistance to stretch. Other secondary changes such as loss of muscle fibres following acquired muscle weakness are likely to compound the weakness arising from the upper motor neuron lesion. In severely affected muscles, there may be marked secondary changes, such as muscle contracture, particularly if management has been delayed or absent.

Treatment of ALS2-related disorders includes physical therapy and occupational therapy to promote mobility and independence and use of computer technologies and devices to facilitate writing and voice communication.

The prognosis for those with spastic muscles depends on multiple factors, including the severity of the spasticity and the associated movement disorder, access to specialised and intensive management, and ability of the affected individual to maintain the management plan (particularly an exercise program). Most people with a significant UMN lesion will have ongoing impairment, but most of these will be able to make progress. The most important factor to indicate ability to progress is seeing improvement, but improvement in many spastic movement disorders may not be seen until the affected individual receives help from a specialised team or health professional.

A 2006 study followed 223 patients for a number of years. Of these, 15 died, with a median age of 65 years. The authors tentatively concluded that this is in line with a previously reported estimate of a shortened life expectancy of 10-15 years (12 in their data).

Doublecortin positive cells, Similar to stem cells, are extremely adaptable and, when extracted from a brain, cultured and then re-injected in a lesioned area of the same brain, they can help repair and rebuild it. The treatment using them would take some time to be available for general public use, as it has to clear regulations and trials.

The diagnosis for DMSA1 is usually masked by a diagnosis for a respiratory disorder. In infants, DMSAI is usually the cause of acute respiratory insufficiency in the first 6 months of life. The respiratory distress should be confirmed as diaphragmatic palsy by fluoroscopy or by electromyography. Although the patient may have a variety of other symptoms the diaphragmatic palsy confirmed by fluoroscopy or other means is the main criteria for diagnosis. This is usually confirmed with genetic testing looking for mutations in the "IGHMBP2" gene.

The patient can be misdiagnosed if the respiratory distress is mistaken for a severe respiratory infection or DMSA1 can be mistaken for SMA1 because their symptoms are so similar but the genes which are affected are different. This is why genetic testing is necessary to confirm the diagnosis of DMSA.

Treatment should be based on assessment by the relevant health professionals. For muscles with mild-to-moderate impairment, exercise should be the mainstay of management, and is likely to need to be prescribed by a physical therapist or other health professional skilled in neurological rehabilitation.

Muscles with severe impairment are likely to be more limited in their ability to exercise, and may require help to do this. They may require additional interventions, to manage the greater neurological impairment and also greater secondary complications. These interventions may include serial casting, flexibility exercise such as sustained positioning programs, and medical interventions.

Research has clearly shown that exercise is beneficial for impaired muscles, even though it was previously believed that strength exercise would "increase" muscle tone and impair muscle performance further. Also, in previous decades there has been a strong focus on other interventions for impaired muscles, particularly stretching and splinting, but the evidence does not support these as effective. One of the challenges for health professionals working with UMNS movement disorders is that the degree of muscle weakness makes developing an exercise programme difficult. For muscles that lack any volitional control, such as after complete spinal cord injury, exercise may be assisted, and may require equipment, such as using a standing frame to sustain a standing position. Often, muscles require specific stimulation to achieve small amounts of activity, which is most often achieved by weight-bearing (e.g. positioning and supporting a limb such that it supports body weight) or by stimulation to the muscle belly (such as electrical stimulation or vibration).

Medical interventions may include such medications as baclofen, diazepam, dantrolene, or clonazepam. Phenol injections or botulinum toxin injections into the muscle belly can be used to attempt to dampen the signals between nerve and muscle. The effectiveness of medications varies between individuals, and varies based on location of the upper motor neuron lesion (in the brain or the spinal cord). Medications are commonly used for movement disorders, but research has not shown functional benefit for some drugs. Some studies have shown that medications have been effective in decreasing spasticity, but that this has not been accompanied by functional benefits.

The symptoms of DLB overlap clinically with those of Alzheimer's disease and Parkinson's disease, but are associated more commonly with the latter. Because of this overlap, early DLB is often misdiagnosed. The overlap of neuropathological and presenting symptoms (cognitive, emotional, and motor) may make an accurate differential diagnosis difficult. In fact, DLB often is confused in its early stages with Alzheimer's disease and/or vascular dementia (multi-infarct dementia). However, while Alzheimer’s disease usually begins gradually, DLB frequently has a rapid or acute onset, with an especially rapid cognitive and physical decline in the first few months. Thus, DLB tends to progress more rapidly than Alzheimer’s disease. Despite the difficulty, a prompt diagnosis is important because of the risks of sensitivity to certain neuroleptic (antipsychotic) medications and because appropriate treatment of symptoms may improve life for both the person with DLB and the person's caregivers.

Dementia with Lewy bodies is distinguished from the dementia that sometimes occurs in Parkinson's disease by the time frame in which dementia symptoms appear relative to Parkinson symptoms. Parkinson's disease with dementia (PDD) would be the diagnosis when the onset of dementia is more than a year after the onset of Parkinsonian symptoms. DLB is diagnosed when cognitive symptoms begin at the same time or within a year of Parkinson symptoms.