Biochemical determinants for diagnosis and prediction of severity in 5q spinal muscular atrophy

Saffari A, Niesert M, Cannet C, Blaschek A, Hahn A, Johannsen J, Kockaya M, Kölbel H, Hoffmann GF, Claus P, et al. Identification of Biochemical Determinants for Diagnosis and Prediction of Severity in 5q Spinal Muscular Atrophy Using 1H-Nuclear Magnetic Resonance Metabolic Profiling in Patient-Derived Biofluids. International Journal of Molecular Sciences. 2024; 25(22):12123. https://doi.org/10.3390/ijms252212123

Abstract

This study explores the potential of 1H-NMR spectroscopy-based metabolic profiling in various biofluids as a diagnostic and predictive modality to assess disease severity in individuals with 5q spinal muscular atrophy. A total of 213 biosamples (urine, plasma, and CSF) from 153 treatment-naïve patients with SMA across five German centers were analyzed using 1H-NMR spectroscopy. Prediction models were developed using machine learning algorithms which enabled the patients with SMA to be grouped according to disease severity. A quantitative enrichment analysis was employed to identify metabolic pathways associated with disease progression. The results demonstrate high sensitivity (84–91%) and specificity (91–94%) in distinguishing treatment-naïve patients with SMA from controls across all biofluids. The urinary and plasma profiles differentiated between early-onset (type I) and later-onset (type II/III) SMA with over 80% accuracy. Key metabolic differences involved alterations in energy and amino acid metabolism. This study suggests that 1H-NMR spectroscopy based metabolic profiling may be a promising, non-invasive tool to identify patients with SMA and for severity stratification, potentially complementing current diagnostic and prognostic strategies in SMA management.

Transparency update 5

When CNN aired a scathing report in 2015, claiming the death rate at St. Mary’s Medical Center’s pediatric cardiac surgery center was three times higher than the national average, the hospital blasted the cable news giant, calling its reporting sensational and its numbers inaccurate.

Then, over the next several years, it quietly paid $102.4 million to settle nine lawsuits filed against it by the grieving parents of children who died or were permanently disabled after being treated at the now-shuttered kid’s surgery unit.

While the settlement amounts aren’t included in the files of the nine medical malpractice cases in Palm Beach County Circuit Court, they were obtained by lawyers who successfully defended CNN in a defamation lawsuit filed against it by Dr. Michael Black, director of the troubled unit.

CNN lawyers Martin Reeder and Charles Tobin used the massive payouts to bolster their claims that not only was the CNN report accurate, but that St. Mary’s agreed to write multimillion-dollar checks rather than fight the allegations of botched surgeries.

Dallas-based Tenet Healthcare, which owns the hospital on 45th Street in West Palm Beach, didn’t return emails for comment about why it settled the cases or why some of them weren’t recorded on the website of the Florida Office of Insurance Regulation as required by state law.

The largest settlement of $38.2 million was for the ongoing care of an Okeechobee County girl, who was left partially paralyzed at 6 weeks old when a clamp, left on twice as long as recommended, cut blood flow to her spine when she was undergoing heart surgery, court records show.

There was a $12 million settlement to the parents of a 16-day-old infant who languished for hours before dying after a 10-hour surgery to repair her heart. The same amount was paid to the parents of a now 9-year-old Palm Beach County girl who has required around-the-clock care for developmental disabilities and other infirmities she suffered since undergoing heart surgery when she was 18 days old.

The other settlements ranged from $3.5 million to $8.9 million.

Misgivings about the program intensified after a team of independent pediatric heart surgeons reviewed its operation and warned it didn’t have the expertise to perform surgery on infants under 6 months old or those with complex heart conditions.

Later, it was revealed that Black wasn’t a U.S. board-certified cardiovascular surgeon, a requirement under state law for hospitals operating such specialized and high-risk programs. Black's attorneys countered that he was certified by Canadian equivalents of the American board and state officials had signed off on it.

St. Mary’s closed the unit in August 2015, two months after CNN detailed the ignored warnings and the deaths of six of the unit’s 48 young patients from 2011 until 2013. It pointed out that the program’s 12.5% death rate was three times higher than the national average of 3.3% as reported by The Society of Thoracic Surgeons. Before the unit was folded, another three children died.

Even after the unit was dismantled, St. Mary’s continued to keep Black on the payroll, CNN lawyers said in court documents. While Black no longer performed surgeries, he continued to collect his $800,000 annual salary until August 2018, they said.

And, the costs continue to mount.

Black’s defamation suit, initially filed against CNN and reporter Elizabeth Cohen, producer John Bonifield, digital editor Dana Ford and host Anderson Cooper, was thrown out in November. Black has appealed.

He is also asking the Florida Supreme Court to overturn a previous decision that barred him from seeking punitive damages against CNN.

All of his legal fees are being paid by Tenet, Reeder and Tobin said in court documents.

Last week, Black’s attorneys were back in Palm Beach County Circuit Court, trying to persuade Senior Judge Richard Oftedal not to force Black to pay $320,000 in court costs CNN incurred in an appeal.

While the amount pales compared to the money Tenet has already shelled out, Virginia lawyer Joseph Oliveri argued vigorously, calling the costs “wildly excessive” and premature. Oftedal should delay a decision until Black’s appeals run out, he wrote.

Oftedal showed no interest in waiting, but agreed to hold another hearing in April so attorneys can flesh out their arguments.

Like the 4th District Court of Appeal, which threw out Black’s request to seek punitive damages against CNN, Oftedal ruled Nov. 27 that there was nothing defamatory about CNN’s report.

Black unsuccessfully argued that the news outlet should have used mortality numbers adjusted for risk. Oftedal called the claim “disingenuous,” pointing out that St. Mary’s and Tenet repeatedly refused CNN’s requests for the adjusted numbers.

“We believe that we have provided you sufficient information about our program and trust that you can complete your story with the information we have already provided,” a hospital spokesperson wrote CNN reporters in April 2015, again rejecting their request for adjusted numbers and cutting off further communication.

Aside from St. Mary’s stone-walling, Oftedal said there is disagreement among medical experts about which numbers — the raw numbers or those that are risk-adjusted — are more meaningful. Further, CNN quoted then-hospital CEO Davide Carbone criticizing its use of raw numbers. “(It) could potentially lead to providing misleading information to consumers,” he said.

In any case, Oftedal ruled, Black had not been defamed.

“The overall picture painted by CNN for its viewers and readers depicted a program in crisis, besieged by parents and critics alike, all of whom expressed serious concerns regarding the competency and qualifications of Dr. Black and for a program that ignored repeated warnings and alarm bells calling for a cessation of these highly complex pediatric open heart surgeries,” he wrote.

His conclusion: “Because CNN’s reporting as a whole was substantially true, Dr. Black has not raised a triable issue of material falsity.”

https://www.wlrn.org/health/2024-03-29/st-marys-medical-center-pediatric-cardiac-settlements-top-100-million

Dealing with "defectives"

Courtesy of a colleague

Offen ML. Dealing with "defectives" Foster Kennedy and William Lennox on eugenics. Neurology. 2003 Sep 9;61(5):668-73. doi: 10.1212/wnl.61.5.668. PMID: 12963759.

No abstract. From the article:

Kennedy and Lennox on eugenics. The 1930s and 1940s were an especially turbulent period of history for the United States and the world, marked as it was by the Great Depression and World War II. First in 1936 and 1938, then on different occasions over subsequent years, Kennedy and Lennox each made known their own thinking about how “defective” individuals should be dealt with. Summarized here are some of these two neurologists’ most relevant and informative utterances on this subject, in which their arguments, supporting evidence, recommendations, and personal values are stated or implied.

Euthanasia. Lennox (WL) in an article (“Should They Live? Certain Economic Aspects of Medicine” ) published by the Phi Beta Kappa honor society’s journal American Scholar (AS) in 1938, and Kennedy (FK) first in an article (“Euthanasia: To Be or Not To Be” ) published by the popular weekly magazine Colliers in 1939 and then in a presentation (“The Problem of Social Control of the Congenital Defective: Education, Sterilization, Euthanasia”) made at a May 1941 American Psychiatric Association (APA) luncheon, both called for killing “defectives.”

WL: . . . the congenital idiots or monsters... What shall be done with these?... (Society) should eliminate . . . the idiots and monsters . . . The selection of the congenitally and hopelessly mindless for elimination would offer no more difficulties than their selection for lifelong incarceration. A court-appointed medical committee would be sufficient.(see Lennox reference below)

FK: What to do with the hopelessly unfit? . . . the place for euthanasia, I believe, is for the completely hopeless defective: nature’s mistake; something we hustle out of sight, which should never have been seen at all. These should be relieved of the burden of living . . . to allow them to continue such a living is sheer sentimentality, and cruel too; we deny them as much solace as we give our stricken horse. Here we may most kindly kill.(see Kennedy reference below)

The American Journal of Psychiatry (AJP) published Kennedy’s remarks in its July 1942 issue along with a lengthy, passionate rebuttal by the child psychiatrist Leo Kanner of Johns Hopkins. Kanner, who is credited with the classic description of infantile autism, challenged Kennedy’s view of the “feebleminded,” pleading in effect for a more sympathetic one. (see Kanner reference below) In the same issue, an editorial only a little shorter than Kennedy’s contribution summarized and assessed the two doctors’ respective arguments: (see Euthanasia citation below)

. . . the differences narrow down to a single point: for a specified group of defectives and under specified conditions Dr. Kennedy advocates euthanasia; Dr. Kanner opposes this procedure. Both writers are agreed as to the existence of the group in question and the hopelessness of their condition; one proposes a method of disposal which he believes would bring relief to all concerned, the other prefers to let the situation remain as it is... (Kennedy) offers strong arguments in support of his position. Dr. Kanner opposes this position but in his paper presents no arguments beyond the statement: “An idiotic child may have fond parents who want him alive.”

Euthanasia: “voluntary” versus “involuntary.” Although both wanted to legalize euthanasia for the “defectives” who could not give consent, Kennedy and Lennox differed on legalizing it for those seeking assistance in ending their own lives. Lennox was in favor, whereas Kennedy was outspoken in opposition on practical and philosophical grounds.

FK: . . . I have many instances in my own experience of seemingly fatally ill persons who for years after, lived useful lives... (B)esides, a civilization that deliberately shuts itself off from the bearing of pain and the presence of struggle and finally makes its bid for the softer life or death, is already slipping down the ways. To do this is a sign of degradation and defeat.3

Having been appointed the Euthanasia Society of America’s (ESA) founder as president only a month earlier, and with “a mercy death law” then under consideration by the New York state legislature, Kennedy appeared in the company of two others from the ESA on a program to “present the case for euthanasia—referred to in the official program as ‘the granting of peaceful death to incurable sufferers.’ ” As reported on February 14, 1939, this took place before “an overflow meeting of the Society of Medical Jurisprudence,” the NYT headlining the story, “Dr. Kennedy Gives Views: Euthanasia Needed Mainly For Defectives, Not For Easing Pain, He Declares.”

. . . the physician who was a “gentleman” was equipped to assist in a “necessary journey to death” . . . Then he turned to the “absurd and misplaced sentimental kindness” that seeks to preserve the life of a “person who is not a person.” ... “If the law sought to restrict euthanasia to those who could speak out for it, and thus overlooked those creatures who cannot speak,” Dr. Kennedy declared, “then, I say as Dickens did, ‘The law’s an ass.’ It’s time the law changed its mind.”

A few days later, Bernard Sachs, a past president of the ANA, responded to his “good friend” Kennedy in a letter to the NYT, summing up, “Irrespective of religious doctrines or sanctions, it is the solemn duty of the physician to prolong life, not to end it.” After another few days, the NYT printed a letter from the Cornell professor restating his support for euthanasia “for creatures born defective” and opposition to it “for those persons who, having been well, are ill,” and making clear these opinions were “entirely personal,” not “to be construed as the policy of the Euthanasia Society of America.” The next week, only a month after assuming the position, Kennedy resigned the ESA presidency.

Euthanasia: “active” versus “passive.” Like Malthus more than a century before, Lennox advocated a “non-interventional” approach to lifethreatening infectious illnesses for overpopulated countries to reduce their overall numbers. He also called for the same “non-interventional” approach, or what has been labeled “passive” euthanasia, for “defective” individuals overcrowding asylums and placing an economic burden on society. WL:

. . . until wealth could be increased or birthrates reduced, medicine in the Orient should abandon attempts to wholesale prevention of infection... There is not the same disproportion between population and material resources in America as in the Orient but if we are far-sighted we shall begin to do something about that portion of our population which is a heavy and permanent liability... Should the lives of incurables in institutions be prolonged by prophylactic injections against typhoid fever, scarlet fever and diphtheria? The death-rate in institutions from communicable diseases is decreasing and consequently the need for more institutions is increasing. To these facts medical superintendents point with pride and taxpayers with anxiety....

Labels. Kennedy and Lennox referred to those they recommended for euthanasia variously as “idiots,” “imbeciles,” and “morons,” terms that, although offensive in modern usage, were accepted scientific labels at the time. In making their cases, Kennedy and Lennox did not limit themselves to the standard medical lexicon when speaking of “defectives” though. Kennedy, for example, labeled them “Nature’s mistakes.” Lennox reached further for images to characterize them. This former medical missionary, who went to medical school after he was turned down for theology school, saw them not as products of “Nature” but rather as the Creator’s mistakes (“the result of some slip of the hand of Him who made them, lumps of matter in human form but without human mind”). In Lennox’s view, they were, or may as well have been, inanimate, “clock case(s) without works,” which, of course, “can never tell time.” If animate, they might have “human form,” but they reminded Lennox more of the cattle he had tended as a ranch hand in his youth.

WL: As an inexperienced “hand” on a huge southwestern cattle range it used to be my job at round-up time to work on “the drag,” keeping the worn-out cows and little dogies from falling behind the herd, while the experienced cowboys rode at the head, skillfully “pointing” the wild-footed steers toward their destination. Physicians, as a class, work only on the drag— trying to keep the physically and mentally unfit in the procession...

Kennedy and Lennox saw Medicine as a player on the larger world stage, further subordinating the individual’s interests to what they perceived as the greater good. Lennox, for example, expounded on Medicine’s geopolitical possibilities, unselfconsciously suggesting not only that “birth-planning” might operate to avoid international conflict, especially between East and West, but also that “this principle of limiting certain races through limitation of offspring might be applied intranationally as well as internationally.” After opining in the fall of 1938 that “Germany in time might have solved her Jewish problems in this way,” he went on to hint that targeting of groups within the overall population might be desirable in the United States because a “solvent society must say how many and what sort are to be born”.

The views expressed by Drs. Kennedy and Lennox on eugenics were not novel nor truly exceptional among their peers and contemporaries generally. After Galton’s coinage of the term eugenics in 1883, many people of note involved themselves as active proponents of this developing “science,” if it can fairly be called such, and the movement it spawned. When Kennedy and Lennox took up the cause, though, both it and they were in their sixth decade. In the United States, enthusiasm for eugenics was by then cresting and would decline further as details of what transpired in Europe under the Nazis emerged.

Lennox WG. Should they live? Certain economic aspects of medicine. Am Scholar 1938;7:454–466, 509.

Kennedy F. The problem of social control of the congenital defective: education, sterilization, euthanasia. Am J Psychiatry 1942;99:13–16

Kanner L. Exoneration of the feebleminded. Am J Psychiatry 1942;99: 17–22.

Euthanasia. Am J Psychiatry 1942,99:141–143.

Tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations

Northrup, HopeAnnear, Nicholas M.P. et al.Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatric Neurology, Volume 123, 50 - 66.

Abstract

Background
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.

Methods
Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.

Results
Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.

Conclusions
Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

CHD2-related epilepsy with eyelid myoclonia

Padilla H, Pinto E Vairo F, Wirrell EC, Wong-Kisiel LC, Fine AL, Lanpher BC, Smith KM. CHD2-related epilepsy with eyelid myoclonia: Report of three cases. Epileptic Disord. 2024 Nov 6. doi: 10.1002/epd2.20305. Epub ahead of print. PMID: 39503459.

Abstract

The aim of this study is to report three cases of epilepsy with eyelid myoclonia (EEM) with CHD2 pathogenic variants. A database of 134 patients with EEM evaluated at Mayo Clinic sites was searched to identify patients with CHD2 variants. The medical records of those identified were reviewed to describe their presentation, treatment, and clinical course. Three patients (2 males, 1 female) with EEM were found to harbor de novo CHD2 pathogenic variants (c.2636C>T p.(Ala879Val), c.3734delA p. (Lys1245Asnfs*4), and c.3896delTinsCG p. (Val1299Alafs*5)). All three patients had comorbid autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit disorder (ADHD). Eyelid myoclonia was a prominent seizure type that persisted in the three patients despite trials of multiple antiseizure medications. Generalized tonic-clonic seizures occurred in two of the patients but were controlled with antiseizure medications. Genetic testing should be considered in patients presenting with EEM, especially when ADHD, ID, ASD, and drug-resistant seizures are present. Further understanding of the relationship between CHD2 variants and epileptogenesis may provide important insights into the pathogenesis of EEM.

Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DK, Knupp KG, Nordli DR Jr, Riva A, Stern JM, Striano P, Thiele EA, Zawar I. A comprehensive narrative review of epilepsy with eyelid myoclonia. Epilepsy Res. 2023 Jul;193:107147. doi: 10.1016/j.eplepsyres.2023.107147. Epub 2023 Apr 26. PMID: 37121024.

Abstract

Epilepsy with eyelid myoclonia (EEM) is a generalized epilepsy syndrome with childhood-onset and 2:1 female predominance that consists of: 1. eyelid myoclonia with or without absence seizures, 2. eye closure induced seizures or EEG paroxysms, 3. clinical or EEG photosensitivity. While eyelid myoclonia is the disease hallmark, other seizure types, including absence seizures and generalized tonic-clonic seizures, may be present. It is thought to have a genetic etiology, and around one-third of patients may have a positive family history of epilepsy. Recently, specific genetic mutations have been recognized in a minority patients, including in SYNGAP1, NEXMIF, RORB, and CHD2 genes. There are no randomized controlled trials in EEM, and the management literature is largely restricted to small retrospective studies. Broad-spectrum antiseizure medications such as valproate, levetiracetam, lamotrigine, and benzodiazepines are typically used. Seizures typically persist into adulthood, and drug-resistant epilepsy is reported in over 50%.

CLDN5 mutations

Deshwar AR, Cytrynbaum C, Murthy H, Zon J, Chitayat D, Volpatti J, Newbury-Ecob R, Ellard S,

Inspired by sibling patients

Allen HL, Yu EP, Noche R, Walker S, Scherer SW, Mahida S, Elitt CM, Nicolas G, Goldenberg A, Saugier-Veber P, Lecoquierre F, Dabaj I, Meddaugh H, Marble M, Keppler-Noreuil KM, Drayson L, Barañano KW, Chassevent A, Agre K, Létard P, Bilan F, Le Guyader G, Laquerrière A, Ramsey K, Henderson L, Brady L, Tarnopolsky M, Bainbridge M, Friedman J, Capri Y, Athayde L, Kok F, Gurgel-Giannetti J, Ramos LLP, Blaser S, Dowling JJ, Weksberg R. Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications. Brain. 2023 Jun 1;146(6):2285-2297. doi: 10.1093/brain/awac461. PMID: 36477332.

Abstract

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.

Acute toxic leukoencephalopathy

Jake Haendel had “everything going for him.” He was newly married and working as a head executive chef in Boston when he received a devastating and life-changing diagnosis.

In May 2017, Haendel noticed that his voice started to become higher pitched than normal. Initially brushing it off, it wasn’t until he started having balance issues that he decided to visit the emergency room on Memorial Day weekend.

Doctors believed he was having stroke-like symptoms, so he was admitted and given IV fluids. Haendel, now 36, had been to the hospital many times before and expected to be monitored for a few hours and then simply sent home with antibiotics. And he was right.

“They were actually about to discharge me when my wife came in and said, ‘You cannot discharge him. This is not my husband.’ She played an old voicemail for them. My voice and the voice I had been using were completely different,” he tells PEOPLE. “So the doctors and nurses and emergency room staff were like, ‘Whoa,’ and ordered an emergency MRI.”

One day later, Haendel was diagnosed with acute toxic leukoencephalopathy (ATL), a rare and often fatal brain disease caused by exposure to toxic substances. He was given six months to live.

“I woke up and there was a whole team of people in the room,” he recalls. “A doctor was sitting on the

Haendel immediately thought about his late mother, who died of breast cancer when he was 19. He remembered watching her struggle to fight the disease for 10 years before her death, a time where he struggled mentally and turned to drugs to cope.

Doctors told Haendel that in his case, the ATL was attributed to that past substance abuse. “I literally said out loud, ‘I am f—ed.’ My first thought was how disappointed my mom would be in me,” he says. “There were very powerful emotions all at once.”

“I told my wife, ‘I watched my mom die. You shouldn't have to watch me die,’” he adds.

After revealing his diagnosis, doctors pulled out a whiteboard and broke down exactly how Haendel’s disease was expected to progress. The first month he wouldn’t be able to walk, even with the help of assistive devices. Month two, he would be confined to a wheelchair until he’s unable to tolerate it due to chronic pain. By month three, he would be bedridden and lose the ability to eat, swallow and talk. In the fourth and final stage of the disease, he would slip into a coma and eventually die.

“And no one had ever survived stage four,” Haendel says.

Unfortunately, Haendel’s doctors were “right on the money with that timeframe,” and his health took a turn for the worst. “I underestimated the amount of pain I would be in,” he admits, comparing his body to a car that’s gone haywire.

By November, Haendel’s speech was fully gone. He was admitted to the neuro ICU at Massachusetts General Hospital as he continued to deteriorate. Around this time, he slipped into what doctors believed was a coma, which was consistent with the natural progression of the disease.

December 1, 2017 was the first time he heard someone refer to him as brain dead.

“One of the doctors told my wife, ‘We're really sorry Mrs. Haendel, but your husband will not make it to Christmas.’ In my head, I was bummed because I had no illusion that I was going to die. But I'm in so much pain that it was also a relief that this constant struggle was going to be over,” he explains.

“But then I heard them say I was brain dead and it's time to start considering withdrawing life support. I was contemplating, am I brain dead? How can I think, how do I have memories?” he continues. “So even though I was having those thoughts that this is going to be over soon, I was like, ‘Oh, don't do that, I'm still in here.’”

Haendel appeared to be in a vegetative state. However, unknown to his doctors, his disease triggered locked-in syndrome, a rare and serious neurological disorder where damage to the brain stem leads to complete paralysis over all voluntary muscles except for the ones that control the eyes, according to the National Organization for Rare Disorders (NORD). While he can still feel touch, pain, an itch and other sensations, and he is entirely aware of his environment and surroundings, Haendel is “locked” inside his body, as the name of the syndrome implies.

“It was the worst you can imagine,” he explains. “It was like being a prisoner in solitary confinement, but worse. You're totally paralyzed, you can't move, talk or signal. I was just talking to myself in my head. It was more of survival to keep my brain going and kind of talk myself out of a full panic attack.”

“Everything in my body was failing and the one thing that seemed to be fully intact was my brain, which is always strange to me considering I had a brain illness and the damage was really catastrophic,” he adds.

Haendel remained in this state for 10 months, which he recalls being a brutal time. He was transferred to hospice care; however, he was eventually admitted back to the hospital because insurance only covered six months of care.

“I wasn't dying, but I wasn't getting better, which was a frightening thought,” he shares. “I kept overhearing them say I wouldn't make it out of this state. And I was like, ‘Oh my god. I could be stuck like this forever,’ which was actually more terrifying than dying.”

In June 2018, Haendel was transferred from hospice care back to Mass Gen’s neuro ICU. While there, he experienced the first glimpse of hope that he’d come out of locked-in syndrome.

“Around 4th of July, I heard the familiar voice of Dr. Levinson, who was in charge of my complex care. He was like, ‘You guys see that? He's moving something.’ And the other doctors were like, ‘No, that's involuntary.’”

“It was the first time medical staff had talked to me directly in a while. He just said, ‘Hey, I don't know if you can hear me, but if you can, do that again.’ I kind of had this rush go through me and I was like, ‘Wow, this is my one and only shot. I don't even know what I moved, but just do something,’” he recalls. “I tensed up my entire body and I didn't think it was working, but then I heard, ‘Wow, he is actually doing it.’”

Haendel’s doctors immediately brought in a specialist in nonverbal augmented speech therapy, who started working with him regularly to relearn how to blink. Over the next two weeks, he was able to blink. Medical staff then created a system where he was able to communicate yes and no by blinking and sticking out his tongue, which eventually progressed to him using a letter board to create sentences. “The first thing I spelled out was, ‘I can hear you,’” he says.

One day, Haendel recalls overhearing a conversation about moving him to a rehabilitation facility.

“I heard crosstalk of how I wouldn't be accepted because I can't participate in the mandatory three hours of physical, occupational and speech therapy. I could only participate in speech. I started freaking out. I heard my heart machine going off.”

“They were like, ‘Calm down, calm down. Do you want to use the letter board?’ And I just spelled out ‘I can do three hours.’ I heard them say, ‘Oh my God, he's actually tracking our conversations.’ And that was really the moment they realized how intact I was. And that was when I first felt like, okay, they actually know I'm in here.”

Days later Haendel was transferred to Spaulding Rehabilitation Hospital in Boston. “It was very motivating for me and at that point I was like, I am going to do everything in my power to get out of this.”

The next few years were a “very grueling, slow process,” as Haendel went through intense therapy retraining his brain to communicate with his body at Western Massachusetts Hospital.

“I thought I'd been through the worst. Not that it was any worse than being locked in, but it was a new type of pain that I hadn't experienced,” he explains on his recovery. “It was quite bad, but I kept telling myself if you want to get out of the hospital, if you want to have a life again, this is what it takes.”

By 2019, Haendel started coming out of his paralysis and making baby sounds. The following year, he started talking in sentences and was able to get out of bed and into a wheelchair for the first time.

In December 2020, he officially returned home and has since been doing outpatient therapy, which he will continue as his recovery remains ongoing.

“Now, I'm walking with a walker at home. I can also transfer in and out of cars. I navigate my community on a scooter, but in therapy I'm using a cane. I can also feed myself and hydrate myself,” he says. “In 2021, I was still not able to take care of myself whatsoever. And in the last year I've been able to take care of myself.”

Haendel, who is now divorced, says it’s unbelievable that he’s come so far in his recovery. He’s been sharing his journey on social media to help others understand the importance of determination when things get tough. The 36-year-old also co-founded an accessibility-focused app, Ahoi, which helps users find places that meet their specific needs like accessible parking, entry ramps, elevators, automatic doors, etc.

“I have such a different perspective on what's important in life. And going through what I went through has definitely made me stronger,” he tells PEOPLE. “It feels amazing and a big part of why I'm telling my story and have this company is to help people and help the world.”

“I want people to not give up in recovery when they hear they have terminal disease,” Haendel says. “That's a lot of what I want to do with my life now is just help and motivate people.”

https://people.com/man-declared-brain-dead-talks-locked-in-syndrome-recovery-exclusive-8740104

Macchi ZA, Carlisle TC, Filley CM. Prognosis in substance abuse-related acute toxic leukoencephalopathy: A scoping review. J Neurol Sci. 2022 Nov 15;442:120420. doi: 10.1016/j.jns.2022.120420. Epub 2022 Sep 13. PMID: 36156344; PMCID: PMC11008924.

Abstract

Objectives:

Abuse of opiates, cocaine, and lipophilic inhalants (e.g., toluene) can damage brain myelin and cause acute toxic leukoencephalopathy (TL), but little is known about recovery or prognosis in this condition. In light of the ongoing opiate epidemic in the United States, it is important to understand the natural history of patients who have acute neurological complications from illicit drug exposure. Our aim was to conduct a scoping review of the literature regarding prognosis in described cases of substance abuse-related TL.

Methods:

A strategic search of PubMed, Ovid, Cumulative Index to Nursing, and Allied Health Literature (CINAHL) databases yielded adult cases of acute TL from opiates, cocaine, or inhalants. Cases and case series were eligible for inclusion if they described acute leukoencephalopathy with a clear temporal association with opiate, cocaine, or inhalant abuse. Inclusion was contingent on availability of clinical descriptions until death or ≥4 weeks follow-up with neuroimaging consistent with TL.

Results:

Among 52 cases from 14 articles, 21 (40.4%) individuals died with mean time to death of 28.2 days; with mean follow-up of 12.8 months, 10 (19.2%) survived with no recovery, 17 (32.7%) had partial recovery, and 4 (7.7%) individuals had full recovery.

Conclusion:

Substance abuse-related acute TL often has a poor prognosis, but partial or even full recovery is possible in a subgroup of individuals over months to years.