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NEUROLOGICAL INJURY

NEUROLOGICAL INJURY

Mechanism of Neurological Injury

Three independent sets of information have been used to discuss a plausible mechanism for neurological impairment observed in humans exposed to contaminated air. The first set includes clinical observations on humans exposed to water-damaged environments. The second set entails animal experiments demonstrating neurological injury from mycotoxins instilled into the olfactory mucosa. The third set of data involves clinical and pathology of brain injury to children and young adults exposed to the polluted air of Mexico City.

A. Clinical findings in patients exposed to water-damaged buildings 

Both central and peripheral neuropathy have been reported in individuals chronically exposed to damp indoor environments (Gray et al, 2003; Campbell et al, 2003; 2004; Crago et al, 2003; Kilburn, 2003, 2004, 2009; Kilburn et al, 2009; Rea et al, 2003; Gordon and Cantor, 2004; Gordon et al, 2004, 2006). Briefly, exposed individuals develop peripheral neuropathy with autoantibodies directed against several neural antigens (Campbell et al, 2004). 

Toxic encephalopathy involves multiple symptoms, including loss of balance, recent memory decline, headaches, lightheadedness, spaciness/disorientation, insomnia, loss of coordination (Gray et al, 2003; Rea et al, 200, 2009; Kilburn 2003, 2004). Exposed individuals had alterations in QEEG involving the frontal cortex and other regions of the brain (Crago et al, 2003) coupled with neurocognitive decline (Crago et al, 2003; Gordon and Cantor, 2004, 2006; Kilburn 2003, 2004), as well as significant changes in various neurological measurements (declines in simple reaction and choice reaction times, increased body sway with eyes open and closed, increased latency of blink reflex, and decreased grip strength, among others) (Kilburn 2003, 2004). 

The probable explanation of the causative mechanism comes from both animal models and humans exposed to air pollution.
     
Recently, Empting (2009) published his clinical observations on mold patients suffering from chronic fungal sinusitis (CFS) with neurological complaints referred to his office by Donald (2009). Trained in Psychiatry and Neurology, he has begun defining systems of a syndrome or cluster of signs/symptoms occurring in individuals with neurological disorders following exposure to microbes (molds and bacteria) in damp indoor spaces. His goal is to delineate these mold and mycotoxin-induced signs and symptoms from classic neurologic disorders. The patients he has seen fall into categories which will be described below:
      
1. Local and Focal Pain Syndrome

(a) Migraine and atypical facial pain result from inflammation of the sinuses irritation to the trigeminal nerve branches as they pass through the walls of the sinuses. Alleviation of the inflammatory condition allows management of the migraines. The migraines occur in patients with or without a history of migraines and/or headaches; 

(b) Pharyngitis and glossopharyngeal neuralgia. This condition results from post nasal drainage from inflamed sinuses leading to irritation of throat and are nociceptive pain generators. The inflammation irritates the innervations of the throat resulting in neuropathic pain. Once started, the condition is more easily instigated by levels of stimulation.; 

(c) Local head and neck myalgias: The inflammatory, nociceptive and migraine pain in the head and throat can feed into the cranial nerve and upper cervical root pain pathways and myofascial pain loops. Secondarily, this can involve increased muscle tone, spasm and local trigger points can develop independent facial, temporal, suboccipital and cervical myofascial pain syndromes. 

2. Inflammation Induction of Distant and Diffuse Pain

According to Dr. Empting, any inflammatory process in the body, including CFS, can induce myalgias and arthralgias. Inflammatory cytokines and circulating immune complexes can reach any joint, muscle or connective tissue in body via the circulatory system. Once instigated, these conditions can be self-perpetuating with continuing and/or additional exposure to the offending environment.

3. Unusual Neuropathic Focal Pain 

Single or multiple peripheral nerves can occasionally become painfully involved leading to peripheral neuropathy. Dorsa root ganglia involvement (e.g., Bilateral L1, L2, L3) may rarely be involved. 

4. Disorder Movements

These involve tremors, jerking movements, spastic dysphonia, tic-like motions and idiopathic paroxysmal unique involuntary movements. The movements are similar to, but not stereotypical of, well-defined neurologic signs such as chorea, hemiballismus, Parkinson’s tremor, myoclonic jerks, etc. 

Other neurologic features such as strength, reflexes and sensation are almost always normal. The patient can exert some voluntary control of these movements, which is typical of an impaired, rather than a damaged, motor nervous system.

5. Balance and Ataxia

Imbalance and gait ataxia are observed more commonly than cerebellar findings. Balance relies on multiple sensory inputs (e.g., visual, proprioception, vestibular), the pyramidal motor system, and multiple extrapyramidal and cerebellar modulating systems. Having so many sites susceptible to attack makes imbalance a common symptom.

6. Diffuse Neuropsychiatric Syndromes

A common label affixed to this condition is “Brain Fog.” These individuals have varying degrees of altered mental states, usually with attention, blunted executive function and faulty short-term memory. These conditions can wax and wane (exposure vs re-exposure).

References

Campbell AW, Thrasher JD, Madison RA, Gray MR, Johnson A. 2003. Neural antibodies and neurophysiologic abnormalities in patients exposed to molds in water-damaged buildings. Arch Environ Health. 58:464-74.

Campbell AW, Thrasher JD, Gray MR, Vojdani A. 2004. Mold and mycotoxins: effects on neurological and immune systems in humans. Adv Appl Microbiol 55:375-406.

Crago BR, Grau MR, Nelson LA, Davis M, Arnold L, Thrasher JD. 2003. Psychological, neuropsychological, and electrocortical effects of mixed mold exposure. Arch Environ Health. 45:452-63.

Empting LD. 2009. Neurologic and neuropsychiatric syndrome features of mold and mycotoxin exposure. Toxicol Indust Health 25:577-81.

Dennis D, Robertson D, Curtis L, Black J. 2009. Fungal exposure endocrinopathy in sinusitis with growth hormone deficiency: Dennis-Robertson syndrome. Toxicol Indust Health 25:66.9-80.

Gordon WA, Cantor JB. 2004. Diagnosis of cognitive impairment associated with exposure to mold. Adv. Appl Microbiol 55:361-74.

Gordon WA, Cantor JB, Johanning E, Charatz HJ, et al. 2004. Cognitive impairment associated with toxigenic fungal exposure: a replication and extension of previous findings. Appl Neurophysiol 11:85-74.

Gordon WA, Cantor RB, Spielman L, Ashman TA, Johanning E. 2006. Cognitive impairment associated with toxigenic fungal exposure: response to two critiques. Appl Neurophysiol 13:251-7.

Gray MR, Thrasher JD, Crago R, Madison RA, Arnold L, et al. 2003. Mixed mold mycotoxicosis: Immunological changes in humans following exposure in water-damaged buildings. Arch Environ Health 58:410-20.

Kilburn KH, 2003. Indoor mold exposure associated with neurobehavioral and pulmonary impairment: a preliminary report. Arch Environ Health 58:390-8.

Kilburn. KH . 2004. Role of molds and mycotoxins in being sick in buildings. Adv Appl Microbiol. 55:339-59.

Kilburn KH. 2009. Neurobehavioral and pulmonary impairment in 105 adults with indoor exposure to molds compared to 100 exposed to chemicals. Toxicol Indust Health 25:681-92.

Kilburn KH, Thrasher JD, Immers NB. 2009. Do terbutaline- and mold-associated impairments of the brain and lung relate to autism? Toxicol Indust Health 25:703-10.

Rea WJ. Didrikesen N, Simon TR, Pan Y, et al. 2003. Effects of toxic exposure to mold and mycotoxins in building-related illnesses. Arch Environ Health. 58:399-405.

Rea WJ, Pan Y, Griffiths B. 2009. The treatment of patients with mycotoxin-induced disease. Toxicol Indust Health 25:711-4.

B. Instillation of mycotoxins into the olfactory mucosa of rodents

Satratoxin G, roridin A and aflatoxin B1 instilled into the olfactory area cause sensory olfactory neuron loss, nasal and brain inflammation and neurotoxicity. The mycotoxins are transported into the brain along the olfactory tract leading to inflammation and damage in the tract and the olfactory bulbs. Tritium labeled aflatoxin B1 at 0.2, 1 or 20 ug was intranasally instilled in rats and followed by autoradiography and spectrometry. The mycotoxin was bioactivated in the olfactory/nasal mucosa and transported along the olfactory tract to the bulbs. Twenty-four hours after instillation, the olfactory epithelium was disorganized and undulating with pyknotic nuclei, shrunken cytoplasm and transport of the labelled aflatoxin to the olfactory bulbs. The pathology was still present at 5 days post instillation at 20 ug (Larsson and Tjalve, 2000). 

Satratoxin G was instilled into the olfactory mucosa in mice at 5 and 25 ug/kg body weight.  Apoptosis of olfactory neurons occurred along with the release of proinflammatory cytokines TNF-alpha, IL-6, IL-1 and MIP-2 in the nasal airways, ethmoid turbinates and olfactory bulbs. Marked atrophy of the olfactory nerve and glomerular layers of the bulb were observed (Islam et al, 2006a, b). 

Similarly, roridin A instilled into the olfactory mucosa of mice at 500 ug/kg body weight induced apoptosis of olfactory neurons, atrophy of the olfactory epithelium and olfactory bulbs. The kinetics of the reported pathology was potentiated by the simultaneous exposure to lipopolysaccharide (Islam et al, 2007). 

Also, lipopolysaccharides enhance the hepatoxicity of aflatoxin B1 in rats (Barton et al, 2001; Luyendyk et al, 2002, 2003). 

Finally, C-14 aromatic carboxylic acids are transferred unchanged into the brain and olfactory bulbs following intranasal instillation in mice (Eriksson et al, 1999). These observations point toward at least one probable mechanism for the encephalopathy observed in humans exposed to the biocontaminants in damp indoor spaces.

References

Barton CC, Baron EX, Ganey PE, Kunkel SL, Roth RA. 2001. Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor alpha. Hepatology 33:66-73. 

Eriksson C, Berman U, Franzen A, Sjoblom M, Brittebo EB. 1999. Transfer of some carboxylic acids in the olfactory system following intranasal administration. J Drug Target 7:131-42.

Islam Z, Pestka JJ. 2006. LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse. Toxicol Appl Pharmacol 15:63-53

Hooper, D, Bolton VE, Guilford FT, Straus DC. 2009. Mycotoxin detection in human samples from patients exposed to environmental molds. Int J Mol Sci 10:1465-75.

Islam Z, Harkema JR Pestka JJ. 2006. Satratoxin G from the black mold Stachybotrys chartarum invokes olfactory sensory neuron loss and inflammation in the murine nose and brain. Environ Health Perspect 114:1099-1107. 

Islam Z, Amuzie CJ, Harkema JR, Pestka JJ. 2007. Neurotoxicity and inflammation in the nasal airways of mice exposed to macrocyclic trichothecene mycotoxin roridin: a kinetics and potentiation by bacterial polysaccharide coexposure. Toxicol Sci 98:525-41.

Larsson P, Tjalve H. 2000. Intranasal instillation of aflatoxin B1 in rats: bioactivation in the nasal mucosa and neuronal transport to the olfactory bulb. Toxicol Sci 55:383-91. 

Luyendyk JP. Spores LC, Gamey PE, Roth RA. 2002.  Bacterial lipopolysaccharide exposure alters aflatoxin B1 hepatoxicity: Benchmark does analysis for markers of liver injury. Tox Sci 68:220-5.

Luyendyk JP, Bryant L, Copple CC, Barton P, Ganey E, Roth RA. 2003. Augmentation of aflatoxin B1, hepatoxicity by endotoxin: Involvement of endothelium and the coagulation system. Toxicol Sci 72:272-81.
Neurology

Neurology


C. Children and young adults living in Mexico City

Additional evidence for the role of particles and associated toxins as causation in the onset of toxic encephalopathy is derived from observations of children and young adults residing in Mexico City. Particulate matter in polluted outdoor air consists of fine and ultrafine particles to which toxins are adsorbed.  

Autopsies were performed on children and young adults who had died suddenly and who did not have familial or personal history of neurological disease. Inhaled particles were observed by electron and light microscopy. They were distributed to organs (liver, spleen, kidneys, brain, within RBCs and heart) via the systemic circulation and/or by macrophage and dendritic cell activity and via the olfactory mucosa. 

Observations on the brains showed marked up-regulation of inflammatory markers in the frontal cortex, olfactory bulb, substantia nigrae, vagus nerve and disruption of the blood brain barrier. Pathological observations included deposition of ultrafine particles, accumulation of amyloid beta-42, alpha synuclein and increase of expression of COX2 in the brains. 

These findings were observed in the frontal cortex, olfactory bulb, substantia nigrae and vagus nerve of affected individuals (Peters et al, 2006; Calderon-Garciduenas et al, 2004, 2007, 2008a-c). The pathology resembled that of Alzheimer- and Parkinson-like diseases (Calderon-Garciduenas et al, 2004; 2008a).

Clinically healthy children exposed to air pollutants have systemic inflammation and endothelial damage with significant increases in inflammatory markers (TNF-alpha, PGE2, C- reactive protein, IL-1beta, endothelin-1) with a concomitant down-regulation of soluble adhesion molecules (Calderon-Garciduenas et al, 2008b). 

Finally, exposed children exhibited significant deficits in short- and long-term cognition with neuropsychological testing. Over 50% of them had MRI findings of prefrontal white matter hyperintense lesions. Concomitantly exposed canines had the same MRI changes and increases in COX2 inflammatory markers, i.e., neuroinflammation (Calderon-Garciduenas et al, 2008c; Block and Calderon-Garciduenas).

In conclusion, published observations point toward the role of fine particles in the exposure of occupants in water-damaged structures to mycotoxins and other biocontaminants. 

The observations include: 

1) particulates <1.5 um contain trichothecenes and are associated with growth of the mold (Brasel et al, 2005a,b); 

 2) the trichothecenes were detected in the sera of symptomatic individuals occupying the S. chartarum contaminated structures (Brasel, et al, 2004); 

3) trichothecenes and other mold by-products are present in particles <2 um in other settings and are cytotoxic in the MTT assay (Johanning et aI, 2002); 

4) trichothecenes are in the urine, blood, nasal and lung secretions of individuals exposed to molds in water-damaged homes (Croft et al, 1986; 2002; Hooper et al, 2009); 

5) Finally, the blood concentrations of the hemolytic protein (stachylysin) of five symptomatic individuals exposed to S.chartarum averaged 371 nanograms/ml (Van Emon et al, 2003); and 

6) Toxic strains of Bacilli, Nocardia and Streptomyces were isolated from indoor air in the particle range of 0.56 to 2.1 microns (Peltola, et al, 2001a, b).

References

Block ML, Calderon-Garciduenas L. 2009. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci 32:506-16.

Brasel TL, Campbell AW, Demers RE, Ferguson BS, Fink J, Vojdani A, Wilson SC, Straus DC. 2004.  Detection of trichothecene mycotoxins in sera from individuals exposed to Stachybotrys chartarum in indoor environments. Arch Environ Health 59:417-23. 

Brasel TL, Martin JM, Carriker CG, Wilson SC Straus DC. 2005. Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins in indoor environment. Appl Environ Microbiol 71:7376-88. 

Brasel TL, Douglas DR, Wilson SC, Straus DC. 2005. Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins on particulates smaller than conidia. 71:114-22. 

Calderon-Garciduenas L, Reed W, Maronpot RR, Henriquez-Roldan C, Delgado-Chavez R, Calderón-Garcidueñas A, Dragustinovis I, Franco-Lira M, et al. 2004. Brain inflammation and Alzheimer’s-like pathology in individuals exposed to severe air pollution. Toxicol Pathol 32:650-8.

Calderon-Garciduenas L, Franco-Lira M, Toress-Jardo R, Henriquez-Rodan C, et al. 2007. Pediatric respiratory and systemic effects of chronic air pollution exposure: Nose, lung, heart and brain pathology. Toxicol Pathol 35:154-62.

Calderon-Garciduenas L, Solt AC, Henriquez-Roldan C, Torres-Jardon, R, Nuse B, Herritt L, Villarreal-Calderón R, et al. 2008. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol 26:289-310.

Calderon-Garciduenas L, Villarreal-Calderon R, Valencia-Salazar G, Henriquez-Roldan C, Gutiérrez-Castrellón P, Torres-Jardón R, et al. 2008. Systemic inflammation, endothelial dysfunction, and activation in healthy children exposed to air pollution. Inhal Toxicol 20-499-506.

Calderon-Garciduenas L, Mora-Tiscareno A, Ontiveros E, Gomez-Garza G, Barragan-Mejia G, Guillé B, Torres-Jardón R, et al. 2008. Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs. Brain Cognition 68: 117-27.

Johanning E, Gareis M, Nielsen K, Dietrich R, Martlbauer E. 2002. Airborne mycotoxins sampling and screening analysis. Proceedings of the 9th International Conference on Indoor Air Quality and Climate (Indoor Air), Monterey, CA, June 20-July 5. 

Croft WA, Jarvis BB. Yatawara CS. 1986. Airborne outbreak of trichothecene toxicosis. Atmosphere Environ 20:549-52. 

Croft WA, Jastromiski BM, Croft AL, Peters HA. 2002. Clinical confirmation of trichothecene mycotoxicosis in patient urine. J Environ Biol 23:301-20. 

Peltola JSP, Andersson MA, Haahtela T, Mussalo-Rauhamaa J, Rainey F, Kroppenstedt RM, Samson RA, Salkinoja-Salonen MS. 2001. Toxic metabolite producing bacteria and fungus in an indoor environment. Appl Environ Microbiol 67:3269-74.

Peltola JSP, Andersson MA, Kamper P, Auling G, Kroppenstedt RM, Busse HJ, Salkinoja-Salonen MS, Rainey FA. 2001. Isolation of toxigenic Nocardiopsis strains from indoor environments and description of two new Nocardiopsis species, N. exhalans sp. novo and N. umidischolae sp. novo. Appl Environ Microbiol 67:4293-4304.

Peters A, Verones B, Calderon-Garciduenas L, Gehr P, Chen LC, et al. 2006. Translocation and potential neurological effects of fine and ultrafine particles: a critical update. Part Fibre Toxicol 3:13-25.

Van Emon, JM, Reed AW, Yike I, Vesper SJ. 2003. ELISA measurement of stachylysin in serum to quantify human exposures to indoor mold Stachybotrys chartarum. J Occup Environ Med 45:582-91. 

D. Chronic Inflammation of the Brain

It is becoming increasingly apparent that chronic inflammation of the brain is associated with a variety of neurological conditions. These include Multiple Sclerosis, Parkinson's Disease, Alzheimer's, Limbic Encephalitis, Neurocognitive deficits and neuropsychiatric conditions, among others. The inflammation results from both systemic and centrally produced pro-inflammatory cytokines and chemokines. 

Microglia are immune cells that are present within the brain and the spinal cord. These cells can become hyperactivated and release cytokines and chemokines that result in inflammatory damage to myelin and cell death of neurons.

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