Table 1.

CNS WMDs, cell death mechanisms and therapies.

Type	Disease example	Clinical symptoms	Pathology	Causative factor	Cell death mechanism	Therapy	Reference
Acquired disorders
Inflammatory	MS	Sensory loss, motor deficits, cognitive changes	Inflammation, demyelination, axonal loss and gliosis	Not known	Viral infection Pathogenic T‐ and B‐cells	Targeting immune response	[2]
	NMO	Vision and spinal cord function loss	Lesions in optic nerve and spinal cord. Loss of AQP4 expression	Antibodies against AQP4	Antibody mediated	Targeting immune response	[3]
	ADEM	Motor and neurocognitive deficits	Widespread CNS inflammation and demyelination	Infection	Autoimmune	Immune therapy	[4]
	AHL	Rapid onset fever, neck stiffness, fatigue, headache, nausea, vomiting, seizures, coma	Inflammatory haemorrhagic demyelination of the white matter	Follows viral and bacterial infections and vaccinations	Autoimmune reaction to viral antigens	Steroids and plasma exchange	[5]
Infectious	PML	Progressive weakness, motor deficits, cognitive changes	Focal areas of demyelination	Polyomavirus JC virus replication	Viral cytotoxicity	No effective therapy	[6]
	SSPE	Progressive neurological and psychological deterioration. Seizures, ataxia, photosensitivity, spasticity, coma	Viral inclusion bodies in neurons, neuronal damage and loss	Abnormal viral replication in neurons	Persistent infection with MeV	No effective therapy. Anti‐convulsive therapy for palliative care	[7]
	Congenital cytomegalovirus	Hearing loss, vision impairment, learning disability	Encephalitis, microglial activation	Virus inhibits NSPC proliferation and differentiation. Neuronal cell loss	Neuronal apoptosis, autophagy	Ganciclovir or valganciclovir	[8]
Toxic‐metabolic	Paraneoplastic syndrome	Depends on tumour, e.g. NMO		Tumour expressing CNS antigens	Not reported	IVIG	[9]
Hypoxic–ischaemic	Binswanger disease	Vascular cognitive impairment and dementia	Chronic microvascular leukoencephalopathy, white matter lesions, axonal damage, BBB damage	Endothelia cell dysfunction	Not reported	No effective therapy	[10]
	Cerebral hypoxia and ischaemia in newborns	Cerebral palsy, visual, auditory, motor and behavioural problems. Epilepsy, developmental delay, autism	Diffuse white matter damage, gliosis, decreased oligodendrocytes	Damage to neural stem cells and oligodendrocyte progenitors in the SVZ	Increased glutamate, free radicals, apoptosis autophagy	Hypothermia	[11]
Traumatic	Diffuse axonal injury, chronic traumatic encephalopathy	Dependent on location of injury ‐ motor, memory, neuropsychological changes	Axonal damage, tau accumulation, secondary white matter damage, astrogliosis	White matter loss associated with astrogliosis and microglia activation	Glutamate excitotoxicity, intracellular Ca2+ accumulation, ROS production	Anti‐CD11d, progesterone, valganciclovir tacrolimus, moderate hypothermia (32–33 °C 1 h)	[12]
Genetic disorders
Lysosomal storage	Metachromatic leukodystrophy	Gait abnormalities, spasticity, ataxia, polyneuropathy psychosis, cognitive decline	Demyelination, sparing of U fibres. Eosinophilic granules in macrophages, metachromasia	Decrease in arylsulfatase A1. Sulphated glycolipid accumulation in myelin	Sulphatide accumulation induces apoptosis in vitro	HSCT, enzyme replacement therapy, gene therapy	[13]
Peroxisomal	X‐ALD	Ataxia, dementia, behavioural changes, hyperactivity	Increased saturated VLCFA in serum. Progressive demyelination	Mutations in ABCD1 gene	VLCFA accumulation in CNS	Allogeneic HSCT	[14]
Mitochondrial dysfunction with leukoencephalopathy	Leber's hereditary optic neuropathy	Acute/subacute painless central visual loss	Loss of retinal ganglion cells. Optic nerve degeneration	Mitochondrial DNA mutations	Proposed to be apoptotic	Antioxidants, experimental gene therapy	[15]
Nuclear DNA repair defects	Cockayne syndrome	Growth and development failure, accelerated, aging	Patchy myelin loss, white matter atrophy, neuronal loss, astrocytic gliosis, microglia nodules	Mutations in CSA or CSB genes. Lack of repair of damaged nuclear and mitochondrial DNA	Apoptotic cell death	Diet restriction or high fat diet, vitamin D. Otherwise no cure	[16]
Defects in genes encoding myelin proteins	Pelizaeus–Merzbacher disease	Dystonia, ataxia, nystagmus, spasticity, mild cognitive decline	Splitting and decompaction of myelin sheaths, axonal spheroids	Mutations in PLP1 and accumulation of aberrant protein, or GJC2 mutation	UPR‐induced apoptotic pathway	Experimental neural stem cell and glial progenitor cell transplantation	[17]
Amino acid and organic acid metabolism disorders	Canavan disease	Macrocephaly, loss of head control, developmental delay, hypotonia and spasticity	Diffuse spongiform white matter degeneration, dysmyelination and intramyelinic oedema	Mutation in ASPA encoding aspartoacylase and accumulation of NAA	Not reported	No effective therapy	[18]
Miscellaneous	Alexander disease	Macrocephaly, dementia, spasticity, developmental delay	Myelin damage. Elevated GFAP in cerebrospinal fluid. Rosenthal fibres	GFAP mutation	Reduced GLT‐1, increased autophagy in astrocytes	No effective therapy	[19]
	VWM	Spasticity, loss motor function, epilepsy, ataxia	Progressive demyelination	Mutations in EIF2B1–EIF2B5	Increased cellular stress	No effective therapy	[20]
	CADASIL	Migraines, TIAs, dementia, apathy, depression	Diffuse white matter lesions, subcortical infarcts. Granular osmiophilic material in small vessels	NOTCH3 mutation	Protein misfolding and receptor aggregation	No effective therapy	[15]

BBB, blood–brain barrier; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; GFAP, glial fibrillary acidic protein; HSCT, haematopoietic stem cell therapy; IVIG, intravenous immunoglobulins; NMO, neuromyelitis optica; NSPC, neural stem/progenitor cells; SSPE, subacute sclerosing panencephalitis; SVZ, subventricular zone; TIA, transient ischaemic attack.