Froin syndrome (FS) is a syndrome secondary to impaired cerebrospinal fluid (CSF) circulation at the spinal level, presenting with the following triad:
In 1903, French neurologist Georges Froin (1874–1964) first described CSF with xanthochromia, hypercoagulability, and lymphocytosis in a patient with syphilitic meningitis undergoing lumbar puncture1). The term xanthochromia itself was introduced in 1902 by Millian and Chiray in cases of subarachnoid hemorrhage1). In 1924, Greenfield first described the pathophysiology, and in 1936, Robinson and Miller demonstrated in animal experiments that similar CSF findings could be reproduced after spinal cord compression1).
Epidemiological data are extremely limited. A comprehensive literature review from 1903 to 2023 identified only 36 cases1), and the exact incidence and prevalence remain unknown. Among reported cases, 80% were male, with a mean age of 51 years1).
Since the first report in 1903, only 36 cases have been reported in the literature up to 20231), with no precise data on incidence or prevalence. Of the reported cases, 80% were male, with a mean age of 51 years.
Symptoms of FS are a mixture of those due to the underlying disease and those due to increased intracranial pressure. A review of 36 cases by Jacobs et al. reported the following frequencies 1).
| Symptom | Frequency |
|---|---|
| Lower limb paralysis or paresis | 64% |
| Back pain | 38% |
| Impaired consciousness/confusion | 23% |
| Sciatica/headache/sensory disturbance | 17% each |
| Urinary retention/incontinence | 14% |
| Visual impairment | 3% |
Ophthalmic symptoms are caused by increased intracranial pressure.
Ophthalmologically, the following findings are observed.
Systemic findings depend on the underlying disease and may include signs of spinal cord compression (muscle weakness, sensory disturbances, abnormal tendon reflexes) and meningeal irritation signs.
The causes of FS are diverse, encompassing any condition that obstructs CSF circulation. A literature review by Jacobs et al. reported the following classification 1).
Tumors (33%)
Spinal ependymoma: Most frequent neoplastic cause
Multiple myeloma: CSF protein reported >1,500 mg/dL
Meningeal carcinomatosis: Malignant melanoma, hematologic malignancies, etc.
Glioblastoma and solid tumor metastases: CSF obstruction due to CSF dissemination
Mechanical causes (27%)
Degenerative spinal canal stenosis / disc herniation: Most common non-malignant cause
Trauma / spinal cord injury: Hematoma and scar formation after trauma
Iatrogenic: After stereotactic brain biopsy, etc.
Spinal epidural lipomatosis / dermoid cyst: Rare benign lesions
Infection (27%)
Tuberculous meningitis / Pott disease: CSF obstruction due to spinal tuberculosis
Spinal conus tuberculoma: Intramedullary tuberculous granuloma
Bacterial epidural abscess: May have an acute course
Varicella-zoster virus encephalitis: A rare cause
Inflammatory/Vascular (6.5% each)
Hypertrophic pachymeningitis: Chronic inflammatory thickening of the dura mater
Neurosarcoidosis: Non-caseating granuloma formation
Subarachnoid hemorrhage: Hemolysis products cause CSF xanthochromia
Necrotizing vasculitis: CSF barrier disruption due to vascular lesions
CSF protein levels vary by cause. In infectious causes, levels are typically 75–500 mg/dL; in spinal block, they often exceed 500 mg/dL, with a reported mean of 2,800 mg/dL1). Normal CSF protein is 10–50 mg/dL1).
In literature reviews, tumors account for 33% (most common), followed by non-malignant mechanical causes and infections at 27% each1). Conditions that obstruct CSF flow in the spinal canal are the common pathogenesis.
This is the most important test for diagnosing FS. The characteristic triad (xanthochromia, high protein, hypercoagulability) is observed in CSF collected below the level of obstruction.
Routine analysis should be performed immediately after collection: protein, albumin, immunoglobulins, glucose, lactate, cell count, and cytology1). For xanthochromic CSF, spectrophotometry is recommended to differentiate from traumatic tap1).
A “dry tap” (inability to collect CSF) may occur during lumbar puncture. Possible causes include complete obstruction by a spinal mass, markedly low CSF pressure (less than 1 cmH₂O), or high CSF viscosity1).
In patients with an existing ventriculoperitoneal (VP) shunt, parallel analysis of shunt-derived CSF and lumbar CSF is useful for confirming the diagnosis. In a case reported by Fries et al., lumbar CSF protein was 938 mg/dL (approximately 20 times the normal value), while VP shunt CSF protein was 70 mg/dL, a marked dissociation that confirmed FS due to cervical spinal stenosis2).
CSF opening pressure greater than 25 cmH₂O is considered abnormally high.
| Test item | Lumbar CSF (Fries 2023 case) 2) | VP shunt CSF |
|---|---|---|
| Protein | 938 mg/dL | 70 mg/dL |
| Albumin | 7,240 mg/L | 421 mg/L |
| White blood cells | 4/μL | 1/μL |
| Lactate | 2.5 mmol/L | Normal range |
Differentiation from idiopathic intracranial hypertension (IIH) is important. Even if head MRI/MRV is normal, FS due to spinal cord lesions is possible. Differentiation from meningitis, spinal cord tumor, spinal epidural abscess, and Guillain-Barré syndrome is also required.
A dry tap can occur due to complete CSF obstruction caused by a spinal mass, etc. 1) FS should be suspected, and spinal MRI should be performed promptly to identify the cause of obstruction.
Curative treatment of the underlying disease is the highest priority.
Treatment for papilledema should be initiated early, as it is key to preserving visual function. Delayed treatment can lead to irreversible visual impairment, so ophthalmologists must promptly detect the risk of elevated intracranial pressure and refer the patient to a neurosurgeon.
According to a review of 36 cases by Jacobs et al. 1), the outcomes are as follows.
Delayed diagnosis has been reported to contribute to poor recovery 1).
In a literature review by Jacobs et al., complete recovery was reported in 22%, death in 22%, and residual sequelae in 14% 1). The type of underlying disease and the promptness of diagnosis and treatment greatly influence the prognosis. It is also important to note that the outcome was unknown in 36% of cases.
Two pathophysiological mechanisms have been proposed for the onset of FS 1).
Serous Mechanism
Alternative name: pseudo-FS (pseudo-Froin syndrome)
Basis: Pure mechanical CSF obstruction (e.g., disc herniation, tumor)
Mechanism: Decreased spinal pressure below the compression → impaired CSF absorption by arachnoid villi → CSF stasis → transudation from dilated pial veins
CSF findings: No red blood cells or hemoglobin. Elevated fibrin, fibrinogen, and albumin
Inflammatory/hemolytic mechanism
Basis: Meningeal/spinal cord inflammation due to infection, tumor, or trauma
Mechanism: Capillary hemorrhage + intravascular leakage → conversion of hemoglobin to bilirubin → yellow discoloration of CSF
Additional factors: Disruption of the blood-brain barrier promotes the migration of inflammatory proteins
CSF findings: Hemolysis products (bilirubin, methemoglobin) are observed
Pulsatile CSF flow in the perivascular spaces is driven by arterial wall pulsations synchronized with the heartbeat. Compression due to spinal stenosis or tumors impedes this pulsatile flow, resulting in a dissociation where CSF is normal above the obstruction and abnormal below it 2). It has also been suggested that active expulsion of CSF from the lumbar region through muscle movement further promotes the low-pressure state below the compression 1).
Due to soluble fibrin monomer complexes or high fibrinogen concentration 1). Whether elevated CSF protein significantly affects CSF viscosity is debated, with some data indicating no significant increase in viscosity at body temperature 1).
In patients with an existing VP shunt, a diagnostic method has been reported that involves simultaneous collection and comparison of shunt-derived CSF (above the obstruction) and lumbar puncture CSF (below the obstruction).
Fries et al. (2023) applied this method to a patient with cervical spinal stenosis and confirmed FS by demonstrating a dissociation of more than 13-fold, with lumbar CSF protein of 938 mg/dL versus VP shunt CSF protein of 70 mg/dL 2). In this case, which was difficult to differentiate from GBS, the parallel analysis confirmed the diagnosis, which has important methodological significance.
On spinal T2-weighted MRI, CSF signal may change above and below the obstruction (pseudo-Froin), and its potential as a diagnostic aid is being discussed. However, in vitro studies show that protein concentration and MRI signal intensity do not directly correlate 1), suggesting that cell membrane-derived macromolecules or paramagnetic substances may contribute to signal changes. FS diagnosis based solely on MRI findings is not yet established.
Research on the dynamics of CSF protein dissociation above and below the obstruction (including quantitative assessment with pressure measurement) may deepen pathophysiological understanding of CSF circulation and contribute to the development of future diagnostic indicators 2). The small number of FS cases itself is a barrier to large-scale studies, and multicenter case accumulation is a future challenge.
