Froin Syndrome

From EyeWiki

Froin Syndrome



Froin syndrome (FS) is characterized by a combination of cerebrospinal fluid (CSF) xanthochromia, elevated protein levels, and hypercoagulability. FS can lead to increased intracranial pressure and may cause visual loss due to papilledema. FS was first described by Georges Froin in 1910 after performing a lumbar puncture (LP) on a patient with syphilitic meningitis. [1][2]


FS occurs following processes that affect normal CSF flow (e.g., meningeal irritation and inflammation or spinal cord obstruction by tumors), infection and abscess, degenerative stenosis, or disc herniations.[3] Meningeal inflammation can be caused by viral and bacterial infections and can lead to increased CSF protein levels. These inflammatory and obstructive processes contribute to the stagnation of the CSF within the thecal sac and interruption of CSF absorption by the arachnoid granulations. A connection between FS and Pott disease has also been observed, where Pott disease occurred, which caused a myelitis lesion and subsequently blocked the CSF.[4] The disruption of CSF reabsorption subsequently increases transudation which results in hyperproteinosis and hypercoagulation.[3] Elevated CSF bilirubin and albumin produces a characteristic yellow (xanthochromic) color of the CSF. [5]

In FS, CSF protein levels can be elevated in the range of 75 - 500 mg/dL (normal values of 15 - 45 mg/dL) due to infectious causes but may increase to over 500 mg/dL in cases with spinal obstruction.[3] Protein levels greater than 1,500 mg/dL were observed in a patient with multiple myeloma who developed septations and adhesions in the right thecal space.[6] Spinal tumors specifically can lead to transudation or exudation of protein into the CSF from the tumor and can cause break down of the blood brain barrier. [7] Breakdown of the blood brain barrier, CSF stagnation, and CSF proteinosis result in obstruction of CSF outflow and increased intracranial pressure.


Systemic Presentation

The most common symptoms of FS are moderate to severe back pain that is often unresponsive to conventional treatments, progressive bilateral asymmetric lower extremity sensory deficits, weakness, and brisk or absent lower extremity reflexes. [8][9][10] Symptoms of increased intracranial pressure (ICP) can include headaches that worsen with positional changes, nausea, vomiting, and pulsatile tinnitus.[11]

Ophthalmic Presentation

Increased CSF protein levels in FS can often result in papilledema. Transient visual obscurations, horizontal binocular diplopia due to non-localizing sixth nerve palsy, and visual field loss may also occur in FS. In later stages, optic atrophy may develop secondary to chronic papilledema.

Diagnostic Procedures

The conventional workup for increased ICP including patients with papilledema is cranial imaging (e.g., magnetic resonance imaging (MRI) with MR venogram)). Lumbar puncture is then performed and can confirm increased ICP on opening pressure and abnormal CSF indices. Spinal imaging should be considered in cases with elevated CSF protein (with or without spine symptoms). Interestingly, a “dry tap” (failure to obtain CSF during an LP) may occur due to an obstruction from a spinal cord mass leading to a delay in diagnosis and treatment. A dry tap or elevated CSF protein should prompt spinal imaging for suspected FS.

Differential Diagnosis

  • Meningitis [3]
  • Spinal Tumor [7]
  • Spinal epidural abscess [3]
  • Multiple Myeloma [10]
  • Trauma [3]
  • Guillain-Barre Syndrome [12]

A summary on Froin Syndrome by Dr. Andrew G. Lee can be accessed here:



The management of FS should be directed at the underlying etiology (e.g., antibiotics for meningitis, steroids for inflammation, surgery for spine tumors). Papilledema may require pharmacological treatment (e.g. acetazolamide) or surgical interventions (e.g., optic nerve sheath fenestration, CSF diversion procedures). Acute visual loss may occur in FS with fulminant intracranial hypertension which may necessitate urgent surgical intervention (e.g., external ventricular drain or ventriculoperitoneal shunt).


The prognosis of FS depends on the underlying etiology. Papilledema can produce permanent visual loss and fulminant cases with elevated ICP may require urgent or emergent surgical intervention.


FS is characterized by elevated CSF protein level, CSF xanthochromia, and hypercoagulability. Obstruction of CSF flow can occur from inflammatory, infectious, infiltrative, or neoplastic conditions. Ophthalmologists should be aware of FS and the common ophthalmic presentations of increased ICP (papilledema, non-localizing sixth nerve palsy). Fulminant cases may require urgent surgical intervention (as seen in fulminant idiopathic intracranial hypertension ). Negative cranial imaging (e.g., MRI and MRV) may create a false sense of security and may mimic IIH. Spinal imaging is indicated for cases with elevated CSF protein or a “dry tap”.


  1. Froin G. Inflammations me ́ninge ́es avec chromatique, fibri- neuse et cytologique du liquide ce ́phalo-rachidien. Gazette des hoˆpitaux, Paris 1903;76:1005e1006.
  2. Greenfield JG. Original Papers: ON Froin's syndrome, and its relation to allied conditions in the cerebrospinal fluid. J Neurol Psychopathol 1921 Aug;2(6):105-141.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Garispe A, Naji H, Dong F, Arabian S, Neeki M. Froin's Syndrome Secondary to Traumatic and Infectious Etiology. Cureus. 2019 Dec 6;11(12):e6313.
  4. Mantese CE, Lubini R. Froin’s syndrome with tuberculosis myelitis and spinal block. Rev Assoc Med Bras. 2022;68(Rev. Assoc. Med. Bras., 2022 68(1)). doi:10.1590/1806-9282.20190536
  5. Scully FJ. Yellow spinal fluid—its origin and significance. Arch Neur Psych 1923 Jul;10(1):83-99.
  6. Nizam A, Sivakumar K, Yacoub H.  Froin Syndrome, a Rare Complication of Multiple Myeloma.  The Neurologist.  2021; 26 (3): 83-85.  doi: 10.1097/NRL.0000000000000312.
  7. 7.0 7.1 Mirza S, Adams WM, Corkhill RA. Froin’s syndrome revisited, 100 years on. Pseudo-Froin’s syndrome on MRI. Clin Radiol. 2008;63(5):600-604.
  8. Dancel R, Shaban M. IMAGES IN CLINICAL MEDICINE. Froin's Syndrome. N Engl J Med. 2016 Mar 17;374(11):1076.
  9. Maharjan K, Adhikari S, Basnyat B. Froin's syndrome associated with spinal tuberculosis. BMJ Case Rep. 2018 Dec 19;11(1):e228367.
  10. 10.0 10.1 Nizam A, Sivakumar K, Yacoub H. Froin Syndrome, a Rare Complication of Multiple Myeloma. Neurologist. 2021 May 5;26(3):83-85.
  11. Guo P, Sun W, Shi S, Wang W. Patients with pulse-synchronous tinnitus should be suspected to have elevated cerebrospinal fluid pressure. J Int Med Res. 2019 Sep;47(9):4104-4113.
  12. Gardner WJ, Spitler DK, Whitten C. Increased intracranial pressure caused by increased protein content in the cerebrospinal fluid; an explanation of papilledema in certain cases of small intracranial and intraspinal tumors, and in the Guillain-Barre syndrome. N Engl J Med. 1954 Jun 3;250(22):932-6.
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