Milwaukee Protocol — from idea to implementation

Introduction

Rabies infection is caused by a neurotropic virus that originates from the Lyssavirus genus of the Rhabdoviridae family. It is characterized by a bullet-shaped morphology with a length of 80–180 nm. Its nucleocapsid is composed of single-stranded RNA. Currently, the rabies virus has two biotypes known as a street (wild-type) rabies virus that circulates in wild animal populations in their natural environment, and a fixed rabies virus that is used in anti-rabies vaccines. Additionally, natural biotypes of the rabies virus have been recognized [1].

The aim of this study was to evaluate the efficacy of experimental protocols used to treat patients with rabies by analyzing relevant literature.

Objectives:

1. To study the proposed treatment approaches.
2. To analyze the outcomes of the Milwaukee Protocol.

Materials and Methods

Rabies treatment options from scientific sources in the PubMed, Cochrane Library, Google Scholar, and eLibrary databases over the last three decades were reviewed.

Milwaukee Protocol

The concept that the human body can or should manage the virus without any intervention has long been in the air. Efforts to address the stage of clinical signs had been made before the inception of the Milwaukee Protocol. Michael Hattwick from the U.S. Center for Disease Control in Atlanta was the first to use the Milwaukee Protocol. However, there is still ongoing debate in the scientific community regarding whether or not the case in question was actually related to rabies.

On October 10, 1970, Atlanta City Hospital admitted 6-year-old Matthew Winkler due to a bat bite. Examination of the bat revealed it to be positive for rabies. However, despite receiving an anti-rabies vaccine, the boy developed clinical symptoms of the disease. Michael Huttwick speculated that the patient's symptoms were progressing too quickly. He suggested treating all symptoms as they occurred and proactively preventing them from occurring simultaneously. Three months later, the child was discharged from the hospital. The case was highly publicized, but was widely considered by medical experts to be fabricated [2][3].

The first documented recovery from rabies in a patient who had not received rabies prophylaxis was reported in Wisconsin (USA) in 2004. A 15-year-old girl named Jeanne Guice was bitten by a bat, but her parents did not pay attention, so she failed to obtain medical treatment immediately. Thirty-seven days later, she developed rabies symptoms that progressively worsened. Her attending physicians suggested and her parents agreed to try an experimental treatment. The girl was placed in a drug-induced coma and given an antiviral cocktail until her immune system developed an adequate response. The patient was brought out of the coma after 7 days. Thirty-one days later, she was declared virus-free [4][5].

Since then, several more attempts have been made to use the same treatment procedure: as of 2020, 35 individuals have been treated with this protocol.

The essence of this protocol is to place the patient in a drug-induced coma, administer antiviral drugs, and provide symptom management (anticonvulsants, ventilator, etc.). Currently, there is a sixth version of the Milwaukee Protocol (updated 2018), which gives general recommendations for its management, since the material base is too small to draw general conclusions [6][7].

Case Study

Survival after Rabies Treatment with Coma Induction. An article published on June 16, 2005 reports on the survival of a 15-year-old girl after she was bitten by a bat and developed clinical signs of rabies. The patient was not vaccinated and continued with her daily activities until one month later when she developed diplopia. Nausea and vomiting without fever, ataxia, and sixth cranial nerve palsy occurred the next day. On the fourth day, she developed blurred vision, weakness in her left leg, gait disturbance, fever (38.8 °C), slurred speech, and tremors in her left arm. The patient was admitted to the hospital with progressive symptoms and a history of a bat bite [8].

On hospital day 1, she presented with a fever (38.2 °C) and a depressed level of consciousness, i.e. the patient could only follow simple commands. Scanning speech, bilateral sixth nerve palsy, dysarthria, myoclonus, left hand tremor, and ataxia were also reported. Blood serum, cerebrospinal fluid (CSF), nuchal skin and saliva samples were tested for rabies. Magnetic resonance imaging (MRI) and brain angiography were normal. The patient was intubated for airway protection due to sialorrhea with poor coordination of the swallowing muscles. On hospital day 2, laboratory results showed that CSF and serum contained rabies virus-specific antibodies. Efforts to identify the rabies virus were unsuccessful.

She was offered hospice care and an experimental treatment protocol. Despite being fully informed of the potential risks of this treatment, the patient's parents gave their consent.

Treatment included ketamine 2 mg/kg/hour and midazolam with 1% benzyl alcohol 1–3.5 mg/kg/hour for coma induction, red blood cell (RBC) transfusion to maintain hemoglobin levels greater than 10 g/dL, adequate fluid resuscitation, and mechanical ventilation to achieve arterial normoxia and mild hypercapnia. To assess adequate oxygen delivery, venous oxygen saturation was measured using near-infrared spectroscopy. The patient received prophylactic heparin 10 units/kg/hour, ribavirin 33 mg/kg, then 16 mg/kg every 6 hours, and amantadine 200 mg/day.

Because of signs of hemolysis and acidosis, the course of ribavirin was reduced to 9 doses of 8 mg/kg, and midazolam was reduced to 1.5 mg/kg/h with phenobarbital added.

On hospital days 5 to 7, the patient had transient signs of both decreased and increased ADH. Elevated levels of aminotransferase (52 IU/L), lipase (1193 U/mL), and amylase (288 U/mL) were also noted. Lipase and amylase reached their highest levels on days 15 to 18 (2532 U/mL and 539 U/mL, respectively), but the ultrasound-based imaging did not show any enlargement of the pancreas. Increased anti-rabies virus antibodies were found in the CSF and serum taken through a lumbar puncture on day 8. Ketamine was tapered off within 24 hours, and midazolam was replaced with diazepam.

On day 12, the patient developed a fever that was refractory to antipyretics and external cooling. A white blood cell (WBC) count was normal, and blood cultures were negative. Despite increased doses of ketamine, diazepam, and amantadine, the high fever persisted until the room was cooled down on day 15, and the fever subsided. The doses of ketamine and diazepam were reduced, and amantadine administration was continued for one week.

On day 12, the patient improved, with the recovery of deep tendon reflexes, eye blinking in response to eye drops, and eye movement on day 14. On day 16, the patient began to open her mouth and raise her eyebrows, and on day 19, she was able to move her toes and clench her hands in response to commands.

On day 31, the patient was released from isolation due to a continued response of neutralizing anti-rabies virus antibodies and negative saliva tests for rabies virus. After rehabilitation, the patient was discharged on day 76.

Human Rabies (Alberta, Canada, 2007). In August 2007, a 73-year-old man was bitten by a bat on his left shoulder while sleeping at home. He did not seek medical attention and had no history of previous rabies vaccination. The first clinical symptoms appeared on February 14, 2007, when he had an onset of left shoulder pain. The pain was radicular, progressive, and evolved to include left hand weakness. From February 15 to 17, the man sought care at a local emergency department and was administered analgesics [9].

On February 21 (day 7 of clinical illness), the patient was admitted to the local hospital with general weakness, dysphagia, and anorexia. Forty-eight hours after admission, the patient had left arm myoclonus and difficulty breathing. He developed high fever, hypoxia, hypersalivation, and a decreased level of consciousness. On February 23, he was admitted to the intensive care unit (ICU) with a presumptive diagnosis of aspiration pneumonia and sepsis, as the history of a previous bat bite was not obtained at that time.

A computed tomography (CT) scan was unremarkable. Analysis of CSF indicated no WBCs and elevated protein. A chest X-ray revealed a right lower lobe infiltrate, and treatment for presumed pneumonia with broad-spectrum antibiotics was initiated. Despite the treatment, the patient continued to deteriorate with cardiac dysrhythmias, significant hemodynamic lability, opisthotonus, and diffuse spasticity. Because of this evolution of the patient's symptoms, rabies was considered as a possible diagnosis on day 12 of clinical illness. When asked about bites or other exposures, the patient's family recalled that the patient had been bitten by a bat approximately 6 months before.

A saliva sample test on day 15 of clinical illness confirmed the rabies diagnosis. The presence of viral antigen and viral RNA was detected by the direct fluorescent antibody (DFA) test and reverse transcription polymerase chain reaction (RT-PCR), respectively.

Rabies immune globulin was administered (1,200 units i.m.) on March 1. After a discussion with the family, a decision was made to initiate the Milwaukee Protocol, a recently described experimental therapy [7].

This regimen involved induction of therapeutic coma, waiting for an adaptive immune response to evolve and clear the virus from the nervous system, and supportive antiviral and metabolic therapies.

On day 16 of clinical illness, the treatment was initiated, including parenteral ketamine infusion (2 mg/kg), midazolam infusion (0–20 mg/hour), ribavirin (560 μg every 8 hours), and amantadine (200 mg/day).

The protocol was modified to include L-arginine (35 g every 24 hours), enteral tetrahydrobiopterin (150 mg every 8 hours), and vitamin C (500 mg/day) to supplement possible deficiencies and to improve cerebral blood flow autoregulation.

The patient's severe hemodynamic lability improved gradually on ventilator support. Anti-rabies immunoglobulin G (IgG) and immunoglobulin M (IgM) were detected in serum and then in CSF. Baseline serum and CSF tested negative for IgG and IgM against the rabies virus, and the development of an IgM response was thought to represent an immune response to the infection.

On day 46 of clinical illness, the patient was brought out of the coma; however, no neurologic recovery occurred despite low titers of virus-neutralizing antibodies (0.46–1.16 IU/mL) in CSF and normal cerebral perfusion. Antibody levels increased slowly and reached 0.9 IU/mL on day 69 of clinical illness. In addition, detectable rabies virus decreased significantly with a negative DFA on the skin biopsy and a small amount of viral RNA detected by PCR in saliva.

During the same period, the patient had cardiac arrhythmias, autonomic instability, syndrome of inappropriate antidiuretic hormone secretion (SIADH), ribavirin-induced hemolysis, and ventilator-associated pneumonia.

On day 68, a repeated MRI demonstrated abnormality of the cerebral cortex, white matter, basal ganglia, and thalamus. Clinical examination, including apnea testing, was consistent with brain death. Life support was withdrawn on April 26, and the patient died. DFA staining of the autopsied brain stem and cerebral cortex demonstrated an abundance of rabies viral inclusions. These results were confirmed by RT-PCR. Microscopic examination revealed extensive and virtually complete loss of cortical neurons, whereas the cerebellum and brainstem had preservation of neurons.

Human Rabies (Missouri, 2008). On November 19, a 55-year-old man experienced pruritus on his left ear that spread to his left face and arm. On November 21, he developed mild chest pain and sought emergency care. ECG and laboratory findings were negative for myocardial infarction. He was discharged and instructed to return if symptoms worsened. The next day, the patient returned with panic attacks and anxiety associated with swallowing water. He reported that he had been bitten by a bat on the left earlobe 4–6 weeks earlier. He was treated with rabies immune globulin (15.4 mL) and rabies human diploid cell vaccine (1 mL). Despite prophylaxis, the symptoms progressed and the patient was admitted to a tertiary-care facility on November 24. Lumbar puncture yielded CSF with glucose 78 mg/dL (normal = 50–80 ng/dL), protein 39 mg/dL (normal = 15–45 mg/dL), 6 RBCs/mm³ (normal = 0) and 1 WBC/mm³ (normal = 0–3 cells/mm³); differential showed lymphocytic predominance of 68%, 26% monocytes, and 6% neutrophils. Serum, CSF, nuchal skin biopsy, and saliva were collected and submitted on November 24, and a rabies diagnosis was confirmed two days later [10].

On November 25, the patient initiated rabies treatment using the Milwaukee Protocol, which included coma induction and administration of amantadine. On November 26, he became bradycardic and hypotensive and was administered atropine and dopamine. On November 28, dopamine was changed to norepinephrine. Because of increased intracranial pressure, the patient received diuretics. On November 29, he developed acute renal failure with lactic acidosis and was placed on dialysis. On November 30, signs of brain herniation were detected. The patient was removed from life support.

Brain histopathology confirmed eosinophilic cytoplasmic inclusion bodies in the hippocampus specimens, nucleus basalis, and Purkinje cells.

Recovery of a Patient from Clinical Rabies. While attending a church service in September, a girl was bitten by a bat on her left index finger. She did not seek medical attention, and an anti-rabies vaccine was not administered. Approximately 1 month after the bite, she complained of fatigue and numbness in her left hand, followed by diplopia 2 days later. On day 3 of illness, she developed nausea, vomiting, and partial sixth nerve palsy. MRI and MRA studies were normal, and the patient was sent home. On day 4, the patient's symptoms continued, and she was admitted to a local hospital. On admission, she was afebrile, alert, and able to follow commands. Lumbar puncture revealed a WBC count of 23 cells/μL (normal = 0 cells/μL) with 93% lymphocytes, an RBC count of 3 cells/μL (normal = 0 cells/μL), a protein concentration of 50 mg/dL (normal = 15–45 mg/dL) and a glucose concentration of 58 mg/dL (normal = 40–70 mg/dL). Over the next 36 hours, she had slurred speech, nystagmus, left arm tremor, increased lethargy, and a body temperature of 102 °F (38.9 °C) [11].

On day 6 of illness, the history of the bat bite approximately one month earlier was reported. The patient was transferred to a tertiary care facility. On admission, she had a body temperature of 100.9 °F (38.3 °C), impaired muscle coordination, difficulty speaking, double vision, myoclonus, and tremors in her left arm. She was somewhat obtunded but answered questions adequately and followed commands. She had hypersalivation and was intubated. Rabies-specific antibodies were detected in the patient's serum and CSF. Identification of the virus variant responsible for the infection was not possible.

Clinical management of the patient consisted of supportive care, neuroprotective measures, including a drug-induced coma, ventilator support, and antiviral therapy (ribavirin).

The patient was kept comatose for 7 days. During that period, results from lumbar puncture indicated an increase in anti-rabies IgG from 1:32 to 1:2048. On day 33 of illness, she was extubated. Three days later, she was transferred to a rehabilitation unit. As of December 17, the patient remained hospitalized with steady improvement. The prognosis for her full recovery is unknown.

Human Rabies (Indiana and California, 2006). Indiana. On September 30, 2006, a 10-year-old girl presented with pain in her left arm and skin eruption on her trunk and extremities. On October 3, she began vomiting, had increased arm pain, and developed arm numbness. During her visit to the health care provider on October 4, examinations were normal. Three to five days later, the patient's speech became difficult to understand, and she had a decreased appetite, sore throat and neck pain, and a body temperature of 101 °F. She became irritable and agitated.

On October 8, neurologic involvement became more evident, and the girl was transferred to a tertiary care facility. Clinical manifestations included slurred speech, difficulty swallowing, intermittent moments of alertness, and lethargy. Because of difficulty breathing and low oxygen saturation, the patient was intubated and placed on a mechanical ventilator. A lumbar puncture was performed indicating a WBC count of 26 cells/mm³ (normal = 0–7 cells/mm³), an RBC count of 1 cell/mm³ (normal = 0 cells/mm³), a protein level of 28 mg/dL (normal = 1545 mg/dL), and a glucose level of 89 mg/dL (normal = 4070 mg/dL). Vancomycin, cefotaxime, and acyclovir were administered for the presumptive diagnosis of meningoencephalitis. On hospital day 2, the patient experienced episodes of lethargy, somnolence, generalized skin flushing (associated with vancomycin administration), and hypersalivation [12].

Detailed interviews indicated that the girl might have been scratched or bitten by an animal (unknown) in June 2006. In spite of her intubation, the patient was able to indicate that she had been bitten by a bat. On the same day, serum, saliva, CSF, and a skin biopsy from the nape of the neck (nuchal sample) were submitted to the laboratory for rabies virologic testing. The serum rabies-specific antibody test was positive. RT-PCR performed on saliva and skin samples was also positive for rabies virus amplicons, and DFA staining of the skin biopsy was positive for rabies virus antigens. The patient had not received a rabies vaccine.

After rabies was confirmed, the Wisconsin Rabies Treatment Protocol was initiated, including phenobarbital, midazolam, ketamine, amantadine, ribavirin (i.v. under the investigational drug trial protocol), coenzyme Q10, L-arginine, tetrahydrobiopterin, and vitamin C were also administered in an attempt to replenish neurotransmitter substrates.

During hospitalization, the patient experienced multiple complications, including increased intracranial pressure, episodes of diabetes insipidus, SIADH, reversible pancreatitis secondary to ribavirin, intracranial venous sinus thrombosis, and cerebral and cerebellar herniation. In spite of a reduction in sedation drugs, the patient never regained consciousness. Because of a deteriorating clinical condition and poor prognosis, life support was withdrawn. The girl died on November 2, 2006, on hospital day 26. Rabies virus antigen was detected in brain tissue collected postmortem.

California. On November 15, 2006, an 11-year-old boy had a sore throat, fatigue, and fever. On the evening of November 16, he was taken to the hospital emergency department with chest tightness, dysphagia, and insomnia. He was tachycardic (128 beats/min) and hypertensive (148/99 mmHg) but not febrile; his respiratory rate and oxygen saturation level were normal. Over the next several hours in the emergency department, the boy experienced irregular lip and mouth movements, hallucinations, and agitation. Rabies-associated signs such as aerophobia, hydrophobia, profuse salivation, and copious oral secretions were noted, and he was transported to a tertiary care pediatric hospital.

The patient was admitted to the pediatric ICU. He had profuse salivation and required tracheal intubation, and he experienced altered mental status. In the emergency department and subsequently in the pediatric ICU, the patient developed hemodynamic instability associated with sedatives, and he required cardiac resuscitation. An electrocardiogram showed sinus tachycardia with diffuse ST-T wave changes, and an echocardiogram indicated high systemic vascular resistance and secondary cardiomyopathy. Lumbar puncture showed a WBC count of 8 cells/mm³, an RBC count of 0 cells/mm³, a protein level of 25 mg/dL, and a glucose level of 128 mg/dL. Based on the patient's history, clinical signs, and symptoms, he received ketamine and midazolam infusions on hospital day 1 for control of dysautonomia, as described in the Wisconsin Rabies Treatment Protocol [13]. Rabies virus antigens were detected in corneal impressions by DFA on November 18. Intravenous ribavirin and enteral amantadine, tetrahydrobiopterin, and coenzyme Q10 were administered. The patient's family reported that the patient had been bitten by a dog approximately 2 years previously, when he was living in the Philippines. He did not receive any anti-rabies vaccine at that time.

Rabies virus RNA was detected by RT-PCR in the patient's saliva samples obtained on day 3 of the hospital stay. Rabies virus antigen was detected by DFA in a nuchal biopsy that was obtained on hospital day 4. Serology for detection of rabies virus antibodies was performed daily using an indirect immunofluorescent assay and was negative until hospital day 12, when an IgG titer of 1:128 was detected. The following day, the serum IgG titer increased to 1:256 and the IgM titer was 1:10. Rabies virus IgG was first detected in the CSF on hospital day 14 with a titer of 1:8. A repeat nuchal biopsy was performed on hospital day 20 to assess viral elimination.

While hospitalized, the patient experienced multiple complications, including autonomic lability, SIADH, renal failure, superficial thrombophlebitis of the left lower extremity, cerebral artery spasm, subclinical seizures, moderate pancreatic enzyme elevation attributed to ribavirin, and progressive heart block requiring transvenous cardiac pacing. Cerebral perfusion was monitored daily by transcranial Doppler. Because of seizures, additional anticonvulsant therapy was initiated on hospital day 18. A continuous electroencephalogram (EEG) indicated bursts of electrical brain activity followed by little brain activity, and by hospital day 21, almost no brain activity remained. Transcranial Doppler sonography results remained within normal limits.

On hospital day 24, the patient developed diabetes insipidus, and the EEG indicated almost no electrical brain activity. A cranial CT scan on the same day showed a loss of differentiation of the grey-white boundary of the brain and diffuse cerebral edema. Transcranial Doppler sonography indicated a high resistive index with no diastolic blood flow. Midazolam infusion was discontinued. On December 13 (hospital day 27), life support was withdrawn, and the patient died. Rabies virus antigen was detected in brain tissue collected postmortem.

Failure of the Milwaukee Protocol in a Child with Rabies. In November 2006, an 11-year-old boy from the Philippines presented to a community emergency department with symptoms suggestive of rabies. Two years earlier, the patient had been bitten by a dog in the Philippines and did not receive rabies vaccine or other post-exposure prophylaxis. Clinical presentation included sore throat, fever, and fatigue, followed by progressive dyspnea, dysphagia, and insomnia. In the emergency department, he developed irregular mouth movements, visual hallucinations, agitation, aerophobia, and hypersalivation. On hospitalization, his mental status alternated between extreme agitation and obtundation. Significant heart rate and blood pressure variability were compatible with severe dysautonomia. The patient was intubated. Following sodium thiopental for sedation, he became severely bradycardic, requiring brief cardiopulmonary resuscitation (CPR). Neuromuscular blockade was administered due to pharyngeal and diaphragmatic spasms [13].

On admission to the ICU, simultaneous severe variable hypertension and heart rate suggested a neurally mediated catecholamine storm. An echocardiogram revealed severe secondary left ventricular dysfunction. With a fosphenytoin load, the patient developed a second transient bradycardic event, which again responded to CPR. Inotropic support was required for 4 days. Coma was induced with ketamine and midazolam infusions, as recommended in the Milwaukee Protocol (version 1.1), for suspected rabies.

On hospital day 1, DFA detected rabies virus antigen in corneal impressions; serum and CSF serologies were negative. From a saliva sample on hospital day 3, molecular testing performed at the Centers for Disease Control and Prevention (CDC) detected rabies virus RNA genetically consistent with Philippine dog rabies. Anti-rabies IgG was first detected by indirect immunofluorescence in serum and CSF on days 11 and 13, respectively. The initial nuchal biopsy was positive by DFA on day 3 and again on day 19.

Intravenous ribavirin and enteral amantadine, tetrahydrobiopterin, coenzyme Q10, and ascorbic acid were initiated on day 1 upon diagnosis of rabies and after discussion. All subsequent titrations and modifications of the Milwaukee Protocol were made in direct consultation with the primary investigator.

With therapeutic coma, dysautonomia steadily improved. Given concerns for the development of cerebral electrical silence, vasospasm, and edema, intensive neurologic monitoring was initiated. This included continuous electroencephalogram, continuous measurement of cerebral regional oxygen saturation by near-infrared spectroscopy, and daily transcranial Doppler.

Vasospasm-targeted therapies included escalating doses of sapropterin followed by milrinone and L-arginine. Serial EEG showed slowing, progressing to burst suppression on day 13; anticonvulsant prophylaxis included fosphenytoin, midazolam, and phenobarbital. On day 15, pupils became fixed and dilated. Prolonged electrographic seizures developed on day 17. On day 21, topiramate was administered for multifocal spikes; subsequently, the EEG became isoelectric. Medications potentially responsible for this finding were discontinued. CT on day 24 revealed severe cerebral edema; prior neuroimaging, including CT scans on days 1 and 13, along with MRI on days 6 and 12, was normal. Right frontal lobe biopsy on day 25 showed perivascular cuffing with lymphocytes extending into the surrounding brain and associated microglia, consistent with encephalitis. Supportive care was discontinued on day 27.

The hospital course included multiple secondary complications previously described in rabies, i.e. transient hyponatremia, hemidiaphragmatic paralysis, pancreatitis, hypothyroidism, and heart block requiring transvenous pacing. Additional complications included ventilator-associated pneumonia and peripheral thrombophlebitis.

Autopsy showed a cerebral edema with diffuse lymphocytic encephalitis and extensive loss of cortical neurons, with many residual neurons undergoing necrosis. The cerebellum demonstrated extensive loss of Purkinje cells and internal granular cell neurons. Babes-Negri bodies were identified. Scattered microinfarcts and small perivascular hemorrhages were also seen, possibly representing a component of vasospasm and associated thromboembolism. Overall, the pathology showed evidence of severe lymphocytic encephalitis with superimposed secondary hypoxic ischemic encephalopathy. CDC confirmed the presence of rabies virus in brain tissue by DFA and molecular studies.

Critical Appraisal of the Milwaukee Protocol

Despite documented cases of successful treatment of rabies using the Milwaukee Protocol, some authors believe that this treatment protocol is ineffective and should not be used.

For example, the authors of an article published on December 7, 2015 propose a thorough revision of the treatment protocol. They conducted a literature review from 2005 (the inception of the protocol) through 2015. Inclusion criteria were human subjects with rabies encephalitis, prospective or retrospective studies, any study size, and any language.

A total of 29 patients with rabies encephalitis were treated during the described period. Only two patients treated during this period have been reported as survivors. In both cases, however, the patients failed to develop rabies virus-neutralizing antibodies. The authors believe that this raises significant doubts as to whether these individuals actually had rabies encephalitis.

Conclusion

In 2022, rabies remains an absolutely fatal disease once clinical symptoms appear. With the inception of the Milwaukee Protocol, there was hope that such patients could be treated. However, subsequent documented cases give a rather disappointing prognosis. The main reason for this is that the scientific basis is weak. None of the treatments is supported by scientific evidence in the literature. Although this protocol requires a comprehensive review, it is the last hope for this group of patients. This requires more detailed research on the pathogenesis of the disease, more studies on animal models, and the development of novel treatments.