Natalizumab (Tysabri, Biogen-Idec, Cambridge, MA) is a recombinant humanized monoclonal antibody produced in murine myeloma cells. It was initially approved by the U.S. Food and Drug Administration (FDA) in November 2004 for the treatment of patients with relapsing forms of multiple sclerosis (MS) who have not responded adequately, or can not tolerate, other treatments for MS. However, Tysabri was withdrawn from the market in February 2005, after 3 patients in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML). Two of the cases were fatal. The FDA allowed a clinical trial of natalizumab to resume in February 2006, following a re-examination of the patients who had participated in the previous clinical trials, confirming that there were no additional cases of PML. To decrease the possibility of patients developing PML in the future, the manufacturer, Biogen-IDEC, submitted to the FDA a Risk Management Plan, called the TOUCH Prescribing Program, to ensure safe use of the product (Baker, 2007). The FDA has determined that natalizumab can be made available under the TOUCH Prescribing Program with the following main features:
Natalizumab will only be administered to patients who are enrolled in the program.
Patients on natalizumab are to be evaluated at 3 and 6 months after the first infusion and every 6 months after that, and their status will be reported regularly to the product’s manufacturer.
Prior to initiating the therapy, health care professionals are to obtain the patient's magnetic resonance imaging (MRI) scan to help differentiate potential future MS symptoms from PML.
The drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the program.
An assessment of the use of natalizumab for MS by the American Academy of Neurology (AAN, 2008) reached several conclusions. The AAN found that natalizumab reduces measures of disease activity such as clinical relapse rate, gadolinium (Gd)-enhancement, and new and enlarging T2 lesions in patients with relapsing MS. The AAN also found that natalizumab improves measures of disease severity such as the Expanded Disability Status Scale (EDSS) progression rate and the T2-hyperintense and T1-hypointense lesion burden seen on MRI in patients with relapsing MS. The AAN reported that the relative efficacy of natalizumab compared to other available disease-modifying therapies is unknown. In addition, the AAN found that the value of natalizumab in the treatment of secondary progressive multiple sclerosis (SPMS) is unknown. The AAN stated that the SENTINEL trial provides evidence for the value of adding natalizumab to patients already receiving interferon-beta-1a (IFNbeta-1a,) 30 micrograms, intra-muscularly (IM) once-weekly. The AAN found that it provides no information either about the value of adding IFN-beta therapy to patients already receiving natalizumab in the treatment of relapsing-remitting multiple sclerosis (RRMS) or about the value of continuing IFN-beta therapy once natalizumab therapy is started. The AAN assessment found that there is an increased risk of developing PML in natalizumab-treated patients. The 2 cases seen in MS were treated with a combination of natalizumab and IFN-beta-1a, but the fact that PML occurred only with combination therapy may be a chance development. The AAN reported that there may also be an increased risk of other opportunistic infections. On the basis of clinical trial data, the PML risk has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this estimate could change in either direction with more patient-years of exposure. The AAN reported that, since the development of their guideline, 2 cases of PML have been reported in patients receiving natalizumab monotherapy, 1 of whom had never previously received any immunomodulatory or immunosuppressive treatment. The AAN noted that this observation indicates that natalizumab, by itself, is a risk factor for PML. However, the evidence has not been formally reviewed by the Therapeutics and Technology Assessment Subcommittee (TTA).
The AAN assessment of natalizumab for MS recommended: "Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML, it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. This recommendation is very similar to that of the FDA. "The AAN assessment also concluded: "Similarly, because combination therapy with IFN-beta and natalizumab may increase the risk of PML, it should not be used. There are also no data to support the use of natalizumab combined with other disease-modifying agents as compared to natalizumab alone. The use of natalizumab in combination with agents not inducing immune suppression should be reserved for properly controlled and monitored clinical trials."
Crohn's disease (CD), also known as enteritis or ileitis, is a chronic inflammatory bowel disease that affects men and women equally. The etiology of CD is unknown, but evidence suggests that a genetic predisposition combined with an abnormal interaction between the gastrointestinal (GI) tract and enteric microorganisms may play a role in the pathogenesis. About 20 % of patients with CD have a blood relative with some form of inflammatory bowel disease. While the ileum and the colon are most commonly affected, any area of the GI tract from the mouth to the anus may be involved. The ileum is affected in approximately 33 % of patients, the colon in 20 to 30 % of patients, and combined affliction of the ileum and the colon is observed in 40 to 50 % of patients. The severity of symptoms, frequency of complications, and likelihood of intestinal resection as a consequence of CD are usually greater in patients with ileo-colic involvement than in those with disease limited to the ileum or the colon alone (Huprich et al, 2005; NDDIC, 2006).
Crohn’s disease can occur in all age groups, but it is more often diagnosed in people aged 20 to 30 years. Moreover, individuals of Jewish heritage have an increased risk of developing CD, whereas African Americans are at decreased risk for developing CD. The most common symptoms of CD are abdominal pain and diarrhea. Other symptoms include abscesses, arthritis, cramping, fever, rectal bleeding, skin problems, and weight loss/malnutrition (NDDIC, 2006).
Conventional therapies for patients with CD include nutritional supplements, drugs, surgery, or a combination of these options. Currently, there is no cure for CD. The goals of treatment are to control inflammation, correct nutritional deficiencies, and relieve symptoms. Pharmacotherapy entails antibiotics (e.g., ampicillin, sulfonamide, and tetracycline), anti-diarrheal agents (e.g., codeine, diphenoxylate, and loperamide), anti-inflammatory drugs/disease modifying anti-rheumatic drugs (e.g., sulfasalazine and methotrexate), corticosteroids (e.g., budesonide and prednisone), immunosuppresssive agents (e.g., 6-mercaptopurine and azathioprine) as well as biologics such as tumor necrosis factor (TNF) inhibitors (e.g., infliximab and adalimumab) (NDDIC 2006; Lichtenstein et al, 2006).
Another biologic that has been used in the treatment of CD is natalizumab (Ghosh et al, 2003; Sanborn et al, 2005; Targan et al, 2007; Akobeng, 2008). In a double-blind, placebo-controlled trial, Ghosh and colleagues (2003) examined the effectiveness of natalizumab in 248 patients with moderate-to-severe CD. Subjects were randomly assigned to receive 1 of 4 treatments: (i) 2 infusions of placebo; (ii) 1 infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo; (iii) 2 infusions of 3 mg of natalizumab per kilogram; or (iv) 2 infusions of 6 mg of natalizumab per kilogram. Infusions were given 4 weeks apart. Outcomes included changes in scores for the CD Activity Index (CDAI; higher scores indicate more severe disease), the health-related quality of life, and C-reactive protein (CRP) levels. The group given 2 infusions of 6 mg of natalizumab per kilogram body weight did not have a significantly higher rate of clinical remission (defined by a score of less than 150 on the CDAI) than the placebo group at week 6 (the prospectively defined primary end point in the effectiveness analysis). However, both groups that received 2 infusions of natalizumab had higher remission rates than the placebo group at multiple time points. Natalizumab also produced a significant improvement in response rates (defined by a reduction of at least 70 points in the score on the CDAI). The highest remission rate was 44 % and the highest response rate was 71 % (at week 6 in the group given 2 infusions of 3 mg per kilogram). Overall, the 2 infusions of 6 mg of natalizumab per kilogram and of 3 mg per kilogram had similar effects. The quality of life improved in all natalizumab groups; CRP levels improved in groups receiving 2 infusions of natalizumab. The rates of adverse events were similar in all four groups. The authors concluded that treatment with natalizumab increased the rates of clinical remission and response, improved the quality of life and CRP levels, and was well-tolerated in patients with active CD.
Sandborn and associates (2005) performed 2 controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active CD. In the first study, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the CDAI score of at least 70 points, at week 10. In the second study, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every 4 weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150). The first study showed that the natalizumab and placebo groups had similar rates of response (56 % and 49 %, respectively; p = 0.05) and remission (37 % and 30 %, respectively; p = 0.12) at 10 weeks. Continuing natalizumab in the second study resulted in higher rates of sustained response (61 % versus 28 %, p < 0.001) and remission (44 % versus 26 %, p = 0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 % of each group in the first trial and in 10 % of the placebo group and 8 % of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from PML. The authors concluded that induction therapy with natalizumab for CD resulted in small, non-significant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every 4 weeks.
In a randomized placebo-controlled trial, Targan et al (2007) evaluated the effectiveness of natalizumab induction therapy in patients with CD. Patients (n = 509) with moderate-to-severe active CD and active inflammation characterized by elevated CRP concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at weeks 0, 4, and 8. The primary end point was induction of response (greater than or equal to 70-point decrease from baseline in the CDAI score at week 8 sustained through week 12). Additional effectiveness end points included the proportion of patients with sustained remission (CDAI score less than 150 points) and response or remission over time. Response at week 8 sustained through week 12 occurred in 48 % of natalizumab-treated patients and 32 % of patients receiving placebo (p < 0.001). Sustained remission occurred in 26 % of natalizumab-treated patients and 16 % of patients receiving placebo (p = 0.002). Week 4 response rates were 51 % for natalizumab and 37 % for placebo (p = 0.001). Responses remained significantly higher at subsequent assessments (p < 0.001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at weeks 4, 8, and 12 (p < or = 0.009). The frequency and types of adverse events were similar between treatment groups. The authors concluded that natalizumab induced response and remission at week 8 that was sustained through week 12. Response and remission rates for natalizumab were superior to those for placebo at weeks 4, 8, and 12, demonstrating the early and sustained effectiveness of natalizumab as induction therapy in patients with elevated CRP and active CD. This is in agreement with a Cochrane review on the use of natalizumab for induction of remission in CD (MacDonald and McDonald, 2007), which concluded that pooled data suggest that natalizumab is effective for induction of clinical response and remission in some patients with moderate-to-severe active CD.
In a single-arm study, Hyams and colleagues (2007) evaluated the safety, tolerability, and effectiveness of natalizumab in adolescent patients with moderate-to-severe active CD (n = 38; aged 12 to 17 years; pediatric CDAI [PCDAI] greater than 30). Patients received 3 intravenous infusions of natalizumab (3 mg/kg) at 0, 4 and 8 weeks. The primary analysis was safety, assessed by adverse events, laboratory results, and vital signs. Pharmacokinetic and pharmacodynamic measurements and formation of anti-natalizumab antibodies also were analyzed. Effectiveness outcomes were assessed by changes in PCDAI, quality of life (IMPACT III), and levels of CRP and serum albumin. Thirty-one patients (82 %) received 3 natalizumab infusions. The most common adverse events were headache (26 %), pyrexia (21 %) and CD exacerbation (24 %). Clinical response (greater than or equal to 15-point decrease from baseline PCDAI) and remission (PCDAI less than or equal to 10) rates were greatest at week 10 (55 % and 29 %, respectively). Three patients (8 %) tested positive for anti-natalizumab antibodies. The peak level (61.0 and 66.3 microg/ml) and half-life (92.3 and 96.3 hours) of natalizumab were comparable after the first and third infusions. Mean [alpha]4 integrin receptor saturation was 93 % at 2 hours and less than 40 % at 4 weeks after the first and third infusions. Increase from baseline in circulating lymphocytes ranged from 106 % to 122 % at 2 weeks and 45 % to 65 % at 4 weeks after each infusion. The authors concluded that natalizumab (3 mg/kg) was well-tolerated in these adolescent patients with active CD, with a safety and effectiveness profile similar to that of adult natalizumab-treated CD patients. They noted that future studies should evaluate long-term safety and effectiveness.
On January 14, 2008, the FDA approved natalizumab for the treatment of moderate-to-severe CD in adults with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-alpha. Moreover, as in the use of this drug for relapsing forms of MS, CD patients using natalizumab must be enrolled in a special restricted distribution program called the Crohn's Disease - Tysabri Outreach Unified Commitment to Health (CD-TOUCH) Prescribing Program. Under CD-TOUCH, health care providers evaluate CD patients after 3 months of treatment to determine if they have improved on natalizumab. If not, patients should discontinue treatment. Individuals who are taking corticosteroids for CD should begin tapering steroid doses while on natalizumab. Treatment should be discontinued if steroids can not be fully tapered within 6 months.
In addition to PML, serious side effects of natalizumab include hypersensitivity reactions (e.g., anaphylaxis and liver injury). Other atypical infections have also been seen in patients receiving immunosuppressive agents while on natalizumab; serious herpes infections have also been observed. Common side effects of natalizumab include fatigue, headache, rash, infusion reactions, urinary tract infections, as well as joint and limb pain.
A small number of of patients receiving natalizumab developed detectable antibodies at least once during treatment. Calabresi et al (2007) ascertained the incidence and clinical effects of antibodies that develop during treatment with natalizumab. In 2 randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing MS, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies greater than or equal to 0.5 microg/ml) at a single time point or "persistently positive" if they had antibodies at 2 or more time points greater than or equal to 6 weeks apart. In the AFFIRM study, antibodies were detected in 57 of 625 (9 %) of natalizumab-treated patients: 20 (3 %) were transiently positive and 37 (6 %) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p less than or equal to 0.05), relapse rate (p = 0.009), and MRI (p less than or equal to 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after about 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant. The authors concluded that the incidence of persistent antibody positivity associated with natalizumab is 6 %. Reduced clinical efficacy is apparent in persistently positive patients. They noted that patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing.
In an editorial that accompanied the study by Calabresi et al, Freedman and Pachner (2007) stated that "routine NAb testing for anti-natalizumab antibodies is unwarranted, but clinicians need to reconsider the effect of a treatment when patients continue to have an increased level of disease activity. Whether this is due to the development of NAb against the treatment or some other biologic reason, it still might be in the best interest of the patient to consider a change in therapy that will produce a better clinical response".
Indeed the FDA-approved labeling for natalizumab (Tysabri) states that testing for antibodies should be performed if they are suspected. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first 6 months) may be transient and disappear with continued dosing. Repeat testing at 3 months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent.
Neumann and colleagues (2009) stated that natalizumab is approved by the DFA for the treatment of patients with MS and Crohn's disease. These investigators focused on its role in the context of hematopoietic stem cell transplantation and stem cell diseases. The use of natalizumab alone or in combination with either cytotoxic drugs or other antibodies might be a new modality for stem cell mobilization and a therapeutic option for patients with hematologic malignancies.
Wolf et al (2010) presented the clinical and para-clinical effects of natalizumab (300 mg)in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) who did not respond to standard therapies. Main outcome measures included clinical disability, MRI, and saturation of the alpha(4) integrin on T lymphocytes. T cells expressing the alpha(4) integrin were found in the inflamed peripheral nerve. Natalizumab bound with high affinity to the alpha(4) integrin on T lymphocytes in the patient. However, the patient's clinical condition deteriorated and as seen on MRI without any measurable effect after treatment with natalizumab. The authors concluded that although experimental evidence suggests that natalizumab could theoretically be effective in immune-mediated disorders of the peripheral nervous system, this patient with CIDP did not benefit from this therapeutic approach. They stated that natalizumab can not be recommended in CIDP at present and should only be explored in controlled clinical trials.
In a retrospective case-series study, Kleiter and colleagues (2012) described their first experiences with natalizumab, given to patients with suspected RRMS who were later diagnosed with aquaporin 4-positive neuromyelitis optica (NMO). Main outcome measures were relapses and accumulation of disability. These investigators identified 5 patients (1 male and 4 females; median age of 45 years) who were initially diagnosed with MS and treated with natalizumab before diagnosis of NMO was established. Natalizumab was given as escalation therapy after failure of 1st- or 2nd-line immunomodulatory therapies for MS. During natalizumab therapy (median duration of 8 infusions; range of 2 to 11 infusions), all 5 patients displayed persisting disease activity; a total of 9 relapses occurred (median duration to relapse, 120 days; range of 45 to 230 days) after the start of treatment. Four patients had an accumulation of disability and 1 patient died 2 months following cessation of natalizumab treatment. The authors concluded that these findings suggested that natalizumab fails to control disease activity in patients with NMO.
Barnett and associates (2012) noted that auto-antibody mediated astrocyte injury is implicated as a primary event in NMO by biomarker, post-mortem and experimental studies that differentiate the condition from MS. These researchers described the clinical, radiological and neuropathological features of a severe cerebral attack in a natalizumab-treated patient with relapsing myelitis and serum aquaporin-4 antibodies. These findings supported autopsy evidence that abrupt astrocyte destruction precedes demyelination in NMO, and emphasize the importance of serological testing in patients with limited disease. The authors stated that adherence to current NMO diagnostic criteria may delay treatment, or lead to inappropriate therapy with beta-interferon or natalizumab.
In a review on "Monoclonal antibodies in the treatment of neuroimmunological diseases", Rommer et al (2012) stated that over the past 25 years, monoclonal antibodies (MAbs) have become important elements in the therapeutic concepts for numerous clinical specialities, including oncology, gastroenterology, hemostaseology and endocrinology. One of the most dynamic fields of their use is the treatment of autoimmune diseases. Although the number of existing MAbs interfering with the immune system has increased remarkably and many studies have yielded encouraging results in the treatment of neuroimmunological diseases, their clinical use is still limited compared with standard treatments. The only MAb that has been approved for a neuroimmunological disease by now is natalizumab for the treatment of RRMS. The authors provided an overview on MAbs that are currently in use or under investigation for treating neuroimmunological diseases like MS, NMO, CIDP, inclusion body myositis, dermatomyositis, polymyositis, opsoclonus-myoclonus syndrome, multi-focal motor neuropathy, anti-myelin-glycoprotein neuropathy, stiff person syndrome, and myasthenia gravis.
The FDA-approved labeling for natalizumab (Tysabri) states that 300 mg of natalizumab (Tysabri) should be infused intravenously over approximately 1 hour, every 4 weeks. In CD patients, natalizumab should be discontinued in patients that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in patients that can not discontinue chronic concomitant steroids within 6 months of starting therapy.
Bittner et al (2013) presented the first case of Rasmussen encephalitis (RE) treated with natalizumab. This therapy was initiated under the rationale that peripheral lymphocytes invading the central nervous system contribute to disease activity and seizure generation. Leukocyte-endothelial interaction has been proposed as a potential target for the treatment of epilepsy in pre-clinical studies. Interestingly, treatment with natalizumab in a patient with MS and refractory epilepsy improved both MS condition and seizure frequency previously. In this patient, these investigators observed a reduction of seizure frequency early after treatment initiation with natalizumab. The effect lasted for more than 1 year. It should be kept in mind that interpretation of these data is limited by an additional co-administration of varying anti-epileptic medications. The authors concluded that treatment strategies for RE that target specific immune cell subtypes (such as B cells with rituximab and CD4+ T cells with natalizumab) remain to be clarified in future clinical studies.
Bright et al (2014) prospectively reviewed the literature to determine the effectiveness of therapies for CIDP. Articles published from January 1990 to December 2012 were searched for studies to treat adults with CIDP; peer-reviewed full-text articles published in English were included. A total of 9 placebo-controlled double-blinded randomized trials were reviewed to treat subjects with CIDP exhibiting various degrees of effectiveness. The most effect treatments were; 3 randomized controlled trials (RCTs) using intravenous immunoglobulin (IVIG), a study comparing pulsed dexamethasone and short-term prednisolone and rituximab all showed promising results and were well-tolerated. The authors concluded that IVIG and corticosteroids remain first line treatments for CIDP. Therapies using monoclonal antibodies, such as rituximab and natalizumab offer the most promise for treatment of CIDP; however they also need further research, as does the use of stem cell therapy for treating CIDP. Moreover, they stated that large RCTs and better patient selection are needed to address responsiveness of CIDP patients to conventional treatments to elucidate mechanisms of action and future directions for therapeutic improvement.
An UpToDate review on “Natalizumab for treatment of Crohn disease in adults” (Korzenik, 2014) states that “Natalizumab is intended for use as monotherapy. It should not be used in patients who may have impaired immunity, are taking immunosuppressants, or are taking TNF inhibitors. We suggest stopping glucocorticoids within a few months of initiation of natalizumab. A two-month washout is reasonable for azathioprine/6 mercaptopurine, methotrexate, anti-TNF agents, and mycophenolate. Leukocyte and neutrophil counts should be within or close to the normal range prior to starting therapy”.
Furthermore, the product labeling warns against concurrent use of Tysabri and TNF inhibitors because of the potential for increase in risk of progressive multifocal leukoencephalopathy. The product labeling also states that, in clinical studies of natalizumab for CD, concurrent use of TNF inhibitors was not permitted, and it states that subgroup analysis showed that persons who failed to respond to a prior course of TNF inhibitors had a lower response rate than other CD patients.
Table: Expanded Disability Status Scale (EDSS)
The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist.
||No disability, minimal signs in one FS
||No disability, minimal signs in more than one FS
||Minimal disability in one FS
||Mild disability in one FS or minimal disability in two FS
||Moderate disability in one FS, or mild disability in three or four FS. No impairment to walking
||Moderate disability in one FS and more than minimal disability in several others. No impairment to walking
||Significant disability but self-sufficient and up and about some 12 hours a day. Able to walk without aid or rest for 500m
||Significant disability but up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance. Able to walk without aid or rest for 300m
||Disability severe enough to impair full daily activities and ability to work a full day without special provisions. Able to walk without aid or rest for 200m
||Disability severe enough to preclude full daily activities. Able to walk without aid or rest for 100m
||Requires a walking aid - cane, crutch, etc - to walk about 100m with or without resting
||Requires two walking aids - pair of canes, crutches, etc - to walk about 20m without resting
||Unable to walk beyond approximately 5m even with aid. Essentially restricted to wheelchair; though wheels self in standard wheelchair and transfers alone. Up and about in wheelchair some 12 hours a day
||Unable to take more than a few steps. Restricted to wheelchair and may need aid in transfering. Can wheel self but can not carry on in standard wheelchair for a full day and may require a motorised wheelchair
||Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed itself much of the day. Retains many self-care functions. Generally has effective use of arms
||Essentially restricted to bed much of day. Has some effective use of arms retains some self care functions
||Confined to bed. Can still communicate and eat
||Confined to bed and totally dependent. Unable to communicate effectively or eat/swallow
||Death due to MS