Severe neurological disorders are associated with the fluoroquinolones which
present as headache, confusion, hallucination, anxiety, nervousness, and
nightmares.  Seizures have also been reported.  Convulsive seizures have mostly
been reported in patients who are cotreated with nonsteroidal anti-inflammatory
drugs (NSAIDS) such as fenbufen. 

Concomitant use of NSAIDs may increase seizure risk.

The fluoroquinolones cause CNS disturbances through the blocking of
GABA receptor-binding, and this has been supported by excitatory
changes observed on EEG

The fluoroquinolones interfere with GABA-ergic neurotransmission

Some (not all) of the unexplained pain induced by the
fluoroquinolones results from disturbances in GABAergic inhibition in
the central subdivisions of the nociceptive system.

CNS excitation also occurs through the inhibition of ƒ|N-methyl-D-
aspartate or adenosine receptors as well as GABA.

Caffeine is able to penetrate the blood brain barrier and directly
influence the CNS. Within thirty minutes after ingestion, caffeine
peaks in the blood levels and affects the CNS. Caffeine reaches its
maximum effect in two hours. Caffeine has a half-life of
approximately three hours; less than ten- percent leaves the body
unchanged. The effects have been found to last up to ten hours in
some individuals. It is a diuretic, causing the loss of water,
vitamins and minerals from the body. It increases heart rate,
digestive secretions, respiration rate, metabolic rate, and urine
output. It delays fatigue and increases restlessness. The
fluoroquinolones dramatically affect the clearance of caffeine
thereby dramatically increasing these effects. As such one cup of
coffee becomes ten, for example. A positive correlation exists
between the doses of fluoroquinolones and the prolongation
(increases) in the caffeine elimination half-life. (In one case a six-
fold increase).

If the fluoroquinolone CNS injury (resulting from inflammation) is
severe enough, a cascade of events occurs that may include injury-
induced neuroexcitation, transient blood-brain barrier breakdown,
changes in cerebral vascular autoregulation, neuronal degeneration,
axonal swelling and retraction, and hypertrophy and proliferation of
glia. It is now known that the resident macrophages of the central
nervous system (CNS), the microglia, when activated may secrete
molecules that cause neuronal dysfunction or degeneration.

The fluoroquinolones significantly reduced brain glucose uptake.

Electrolyte imbalances are common with previous reports of
fluoroquinolone-induced seizures.

The fluoroquinolones inhibit the specific binding of the adenosine
receptor ligands L-3H-N6-phenylisopropyladenosine (L-3H-PIA) and 3H-N-
ethylcarboxamidoadenosine (3H-NECA). The CNS side effects of these
antibiotics result, in part, from interaction with sites which
mediate the inhibitory neurotransmission of adenosine.

The CNS adrs are a combination of the interference with
neurotransmissions, inhibiting of the clearance of other drugs (such
as caffeine), reduction of brain glucose uptake, electrolyte
imbalances, neuronal dysfunction or degeneration and inflammation,
which if severe enough results in transient blood-brain barrier
breakdown.

Peripheral Nervous System

The clinical manifestations of neuropathy depend on the type and
distribution of the nerve populations that are affected, the degree
to which they are damaged, and the course of the disease. When the
motor nerves are damaged, the neuropathy manifests as weakness and
muscle atrophy. Damage to sensory nerves can cause loss of sensation,
paresthesias and dysesthesias, pain, and sensory ataxia. Autonomic
dysfunction can result in postural hypotension, impotence,
gastrointestinal and genitourinary dysfunction, abnormal sweating,
and hair loss. Involvement of small unmyelinated fibers in sensory
neuropathy typically results in loss of pinprick and temperature
sensations, numbness, and painful burning, cold, stinging, or
tingling paresthesias. Large fiber sensory involvement can manifest
as loss of vibration and position sensations, sensory ataxia, and
numbness or tingling paresthesias. Demyelinating neuropathies
primarily affect the myelin sheaths, whereas axonal neuropathies
target the peripheral nerve axons. Deep tendon reflexes are
frequently diminished or absent, particularly in the demyelinating
neuropathies. Since most nerve trunks are mixed, damage to the
peripheral nerves often affects more than one of these functions.

Burning Pain and Numbness

Most often the results of damage to the peripheral nervous system (as
noted above) manifesting as painful burning, cold, stinging, tingling
paresthesias or numbness. This could also result from muscle and
tendon damage as well if the pain is of a burning or stabbing nature
upon use of the limb affected.

The exact manner in which the fluoroquinolones cause such PNS
damage as opposed to CNS damage remains elusive. Several theories
point to direct toxicity or vascular involvement.

Gatifloxacin-Induced Hallucinations in a 19-Year-Old Man

Concomitant Use of NSAIDs With Norfloxacin (Noroxin) May Increase Seizure Risk

Orofacial dyskinesia after ofloxacin treatment.

Posted: 6/14/2005 8:02:30 PM  Today Eyewitness News talked to a man who says "Cipro" caused him to go crazy. Vince Mule´ says his doctors have even confirmed that it was "Cipro" that caused his irrational behavior. "

Cipro Induced Psychosis
A case of ciprofloxacin-induced acute polymorphic psychosis with a distinct deficit of the executive functions
Grimm, Dr. Oliver and Alm, Dr. Barbara (2005)

Family Says Medication Led to Son's Rampage.  Family members say Brewer had been taking Cipro for about two weeks after toe surgery.

Antimicrobial-induced mania (antibiomania): a review of spontaneous reports. Abouesh A, Stone C, Hobbs WR.

Gatifloxacin Precipitation of Psychosis in Alzheimer Disease
Roy R. Reeves, D.O., Ph.D.

Delirium Associated With Gatifloxacin
C. Loraine Sumner, B.A., and Richard L. Elliott, M.D., Ph.D., F.A.P.A., Macon, Ga.

Ciprofloxacin-induced oral facial dyskinesia in a patient with normal liver and renal function.

Ciprofloxacin-induced chorea.
Azar S, Ramjiani A, Van Gerpen JA.
Mov Disord. 2005 Feb 28; [Epub ahead of print]
PMID: 15739219 [PubMed - as supplied by publisher]

Peripheral neuropathy associated with Avelox and Tequin 2002

Levofloxacin-induced-neurological adverse events such as convulsion, involuntary movement (tremor, myoclonus and chorea like), visual hallucination in two elderly patients
Nippon Ronen Igakkai Zasshi. 1999 Mar;36(3):213-7.

Levofloxacin-induced delirium.
Clin Neurol Neurosurg. 2005 Feb;107(2):158-9.

Treatment Options in Neuropathic Pain

What are the differential diagnoses for peripheral neuropathy?

Seizures Associated with Fluoroquinolones

Potential neurologic toxicity related to ciprofloxacin

Quinolone toxicity: methods of assessment.

Possible gatifloxacin-induced seizure.
Quigley CA, Lederman JR.
Department of Pharmacy Practice, College of Pharmacy, Midwestern University Chicago, Downers Grove, IL 60515-1235, USA. cquigl@midwestern.edu

Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis
Tina Papastavros, Lisa R. Dolovich, Anne Holbrook, Lori Whitehead, and Mark Loeb

Quinolone Induced Psychosis

Additional References

The following citations have no abstract.  The full text can be purchased from the links provide or by contacting the author or the publication cited:

Arch Intern Med. 2001 Oct 8;161(18):2261-2.
Myoclonus and generalized seizures associated with gatifloxacin treatment.
Marinella MA.
Dayton, Ohio.
http://archinte.ama-assn.org/cgi/content/full/161/18/2261

Additional Research from PubMed/Medline

Psychiatric (25)

1    Quigley CA, Lederman JR.Possible gatifloxacin-induced seizure.
Ann Pharmacother. 2004 Feb;38(2):235-7. Epub 2003 Dec 15.
PMID: 14742757 [PubMed - indexed for MEDLINE]

26.  Schmuck G, Schurmann A, Schluter G.
Determination of the excitatory potencies of fluoroquinolones in the central nervous system by an in vitro model.
Antimicrob Agents Chemother. 1998 Jul;42(7):1831-6. Erratum in: Antimicrob Agents Chemother 1998 Sep;42(9):2465.
PMID: 9661029 [PubMed - indexed for MEDLINE]
(article in which Bayer admits CNS adverse reactions)

 Additional Resources

 http://www.remcomp.fr/asmanet/bira-95.html

http://www.urmc.rochester.edu/gebs/faculty/john_Hansen.htm

http://www.sobs.soton.ac.uk/staff/hp.html

http://www.soton.ac.uk/~cig/

http://www.dartmouth.edu/dms/mdphd/cairn_fall99/section3.html

http://neuroscience.nih.gov/Lab.asp?Org_ID=191