# 05 - SECTION 2 Diseases of the Central Nervous System

## SECTION 2 Diseases of the Central Nervous System

a second patient, the genome of the RPE cell line was sequenced, and 
a mutation was discovered in a known oncogene. The trial was halted 
and a decision made to discontinue the effort for customized cell 
therapy in favor of using RPE cells derived from the national repository 
of banked iPSC lines which undergo extensive gene sequencing and 
quality controls. This outcome serves as a caution for the challenges 
involved in bringing a customized cell therapy to the clinic.

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■MESENCHYMAL STEM CELLS
By far the largest number of human trials have been performed using 
MSCs sourced from a variety of sites including bone marrow, periph­
eral blood, adipose tissue, umbilical cord, and other sites. Interest in 
the potential utility of MSCs for regenerative therapy began with the 
optimistic report that bone marrow stem cells were pluripotent and 
capable of generating nerve and heart muscle as well as blood cells. 
The possibility that easily obtainable MSCs could be used to regenerate 
injured or diseased cells or organs to treat diseases ranging from stroke, 
neurodegenerative disease, myocardial infarct, and even diabetes, 
generated enormous enthusiasm. The enthusiasm proved irresistible 
to many, and even after the initial reports were discredited—MSCs 
turned out not to be pluripotent stem cells as initially thought—a 
veritable flood of papers began to appear claiming disease-modifying 
activity of MSCs in mouse models of a wide range of degenerative 
disease and injury models. But when it became clear that the MSCs 
were not transforming into or generating new neurons or cardiac myo­
cytes, alternative mechanisms of action were invoked, including the 
release of trophic factors, cytokines, or inflammatory modulators that 
were credited with producing their remarkable restorative effects. The 
relative ease with which blood or adipose tissue can be harvested from 
patients or donors and MSCs extracted has led to a rapidly expanding 
number of clinical trials for conditions ranging from stroke and MS to 
AD, ALS, and PD. Furthermore, a loophole in the regulatory frame­
work of the FDA allows autologous cell therapy to escape regulation 
provided that the cells have not been significantly processed. This lax 
regulation has spawned a veritable industry of stem cell clinics making 
unsubstantiated claims of success in treating nervous system diseases. 
Patients have died from treatments in unregulated clinics operating 
in countries around the world, and three patients became blind in a 
well-publicized incident following stem cell treatments delivered by a 
Florida clinic. The “stem cells” were derived from the patients’ own fat 
tissue and blood. These activities represent the dark side of the stem 
cell revolution perpetrated by practitioners who exploit the desperation 
of patients and their families. Legitimate and effective stem cell thera­
pies will emerge over time, but given the prevalence and abundance 
of misleading information available on the Internet and elsewhere, 
a trusted and well-informed physician can play a key role in helping 
patients navigate the current cell therapy minefield.
PART 13
Neurologic Disorders
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■MSCS FOR TRAUMATIC BRAIN INJURY
An allogeneic bone marrow–derived MSC line received conditional 
marketing approval in Japan in 2024 for the indication of improving 
chronic motor paralysis resulting from traumatic brain injury. The 
MSCs were transiently transfecting with the human Notch-1 intracel­
lular domain gene to promote FDF-2 secretion in order to “enhance 
their ability to regenerate nerve cells” according to the pharmaceutical 
company that developed the cell-based therapy. The approval fol­
lowed results of a phase 2 clinical trial conducted in Japan and the 
United  States. Forty-six patients with moderate to severe traumatic 
brain injury and chronic motor deficits had MSCs stereotactically 
infused into an area of encephalomalacia identified on MRI scan while 
a sham group of 15 patients had burr holes only. The trial met the 
primary endpoint showing significant improvement in motor function 
at 24 weeks on the Fugle-Meyer Motor Scale (FMMS) (p = .04). Inter­
estingly, a small improvement was noted in the sham-treated group as 
well, indicating the presence of a placebo effect. A larger, double-blind, 
randomized, sham-controlled study is now planned.
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■PERSPECTIVE
The premise that stem cell biology would herald an era of regenerative 
medicine has fueled exaggerated claims, false starts, and a proliferation 

of bogus clinics. But now we may be on the threshold of a new era of 
stem cell-based therapies for neurologic diseases and disorders includ­
ing PD, spinal cord injury, ALS, and epilepsy. Whether this promise 
becomes reality will depend on the outcome of the first wave of piv­
otal double-blind controlled trials that are now being conducted or 
planned.
■
■FURTHER READING
Ayers JI et al: Different α-synuclein prion strains cause dementia with 
Lewy bodies and multiple system atrophy. Proc Natl Acad Sci USA 
119:e2113489119, 2022.
Batista AF et al: The importance of complement-mediated immune 
signaling in Alzheimer’s disease pathogenesis. Int J Mol Sci 25:817, 
2024.
Carlson GA, Prusiner SB: How an infection of sheep revealed prion 
mechanisms in Alzheimer’s disease and other neurodegenerative 
disorders. Int J Mol Sci 22:4861, 2021.
Condello C et al: Expanding the prion paradigm to include Parkinson 
and Alzheimer diseases. JAMA Neurol 81:1023, 2024.
Eichmüller OL, Knoblich JA: Human cerebral organoids: A new 
tool for clinical neurology research. Nat Rev Neurol 18:661, 2022.
Garton T et al: Neurodegeneration and demyelination in multiple 
sclerosis. Neuron 112:3231, 2024.
Kandel ER et al (eds): Principles of Neural Science, 6th ed. McGraw Hill, 
New York, 2021.
Kim TW et al: Pluripotent stem cell therapies for Parkinson disease: 
Present challenges and future opportunities. Front Cell Dev Biol 
8:729, 2020.
Lee HG et al: Neuroinflammation: An astrocyte perspective. Sci Transl 
Med 15:eadi7828, 2023.
Li Q, Barres BA: Microglia and macrophages in brain homeostasis 
and disease. Nat Rev Immunol 18:225, 2018.
Liu L et al: Microbiota and the gut-brain-axis: Implications for new 
therapeutic design in the CNS. EBioMedicine 77:103908, 2022.
Pallarés-Moratalla C, Bergers G: The ins and outs of microglial 
cells in brain health and disease. Front Immunol 15:1305087, 2024.
Pease-Raissi SE, Chan JR: Building a (w)rapport between neurons 
and oligodendroglia: Reciprocal interactions underlying adaptive 
myelination. Neuron 109:1258, 2021.
Section 2	 Diseases of the Central 
Nervous System
Patricia Dugan, Vikram R. Rao

Seizures and Epilepsy
A seizure (from the Latin sacire, “to take possession of”) is a transient 
occurrence of signs or symptoms due to abnormal excessive or syn­
chronous neuronal activity in the brain. Depending on the distribution 
of discharges, this abnormal brain activity can have various manifesta­
tions, ranging from dramatic convulsive activity to experiential phe­
nomena not readily discernible by an observer. Although a variety of 
factors influence the incidence and prevalence of seizures, ~5–10% of 
the population will have at least one seizure, with the highest incidence 
occurring in early childhood and late adulthood.
The meaning of the term seizure needs to be carefully distinguished 
from that of epilepsy. Epilepsy describes a condition in which a person 
has a risk of recurrent seizures due to a chronic, underlying process. 
This definition implies that a person with a single seizure, or recurrent